{"gene":"FCER2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1992,"finding":"CD23 directly binds CD21 (complement receptor 2) on B cells and follicular dendritic cells. Recombinant CD23 incorporated into fluorescent liposomes specifically bound CD21-expressing cells; interaction was blocked by anti-CD21 and anti-CD23 antibodies. CD21 engagement via soluble CD23 increased IL-4-induced IgE production from blood mononuclear cells.","method":"Fluorescent liposome-based binding assay with recombinant CD23; transfection of CD21 cDNA into BHK-21 cells; Western blot; functional IgE induction assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with recombinant protein, transfection validation, multiple orthogonal methods, independently cited widely","pmids":["1386409"],"is_preprint":false},{"year":2005,"finding":"The C-type lectin domain of CD23 was solved by NMR; residues responsible for self-association into trimers, IgE binding, and CD21 binding were mapped. CD23 can bind IgE and CD21 simultaneously. IgE and CD23 can form high-molecular-mass multimeric complexes. Interactions do not require calcium despite the C-type lectin fold.","method":"NMR spectroscopy; concentration-dependent chemical shift perturbation analysis; ligand-induced chemical shift mapping","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — solution NMR structure with functional binding-site mapping, multiple ligand interactions validated in a single rigorous study","pmids":["16172256"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of a CD23/IgE-Fc complex revealed that two lectin-like head domains of CD23 bind IgE-Fc with affinities differing by more than an order of magnitude; the crystal structure shows only one head bound to the asymmetrically bent IgE-Fc heavy chain.","method":"X-ray crystallography; isothermal titration calorimetry","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with ITC binding measurements, direct structural-functional validation","pmids":["28361904"],"is_preprint":false},{"year":2016,"finding":"The stalk region of CD23 contains a previously unidentified IgE-binding site. Non-N-glycosylated monomeric CD23 showed superior IgE binding compared with glycosylated CD23. The therapeutic anti-IgE antibody omalizumab blocked IgE binding to CD23 as well as to FcεRI.","method":"Expression of CD23 variants (full extracellular, stalk-only, head-only, non-glycosylated); binding and inhibition assays; negative-stain electron microscopy; peptide-scanning antibody panel","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple CD23 structural variants tested with orthogonal binding assays and EM, single lab","pmids":["27343203"],"is_preprint":false},{"year":2007,"finding":"ADAM10 is the metalloproteinase responsible for cleaving membrane CD23 to generate soluble CD23. ADAM10 efficiently cleaves peptides from two distinct cleavage sites in CD23; ADAM10-specific inhibitors, dominant-negative ADAM10, and siRNA knockdown all reduced sCD23 release and caused accumulation of membrane CD23.","method":"Peptide cleavage assays; ADAM10-specific inhibitors (prodomain-based, TIMP); dominant-negative ADAM10 expression; siRNA knockdown in human B cells and leukemia lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (siRNA, dominant-negative, pharmacological inhibitors) converge on ADAM10 as CD23 sheddase; replicated in subsequent studies","pmids":["17389606"],"is_preprint":false},{"year":2010,"finding":"ADAM10-dependent CD23 cleavage occurs predominantly in the endosomal compartment after internalization, not at the cell surface. The CD23 stalk region interacts with ADAM10 in a protease-independent manner; ADAM10 binding affinity for CD23 is not altered at endosomal pH, but accessibility (Rmax) increases ~10-fold at pH 5.8. Full-length CD23 is sorted into exosomes in an ADAM10-dependent manner.","method":"Endosomal neutralization with NH4Cl; SPR analysis of CD23-ADAM10 interaction at different pH; exosome isolation; Western blot; flow cytometry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — SPR binding measurements plus cell biological experiments with endosomal inhibitors; multiple orthogonal methods, single lab","pmids":["20876574"],"is_preprint":false},{"year":1998,"finding":"CD23 shedding from the cell surface is mediated by a membrane-bound metalloprotease of ~63 kDa. The activity is inhibited by metalloprotease inhibitors (1,10-phenanthroline, imidazole, batimastat) but not by cysteine, serine, or acid protease inhibitors. The same or similar activity is present in fibroblasts and monocytic lines not expressing CD23.","method":"Purified CD23 cleavage assay with neo-epitope antibody; gel-filtration chromatography of enriched plasma membranes; class-selective protease inhibitors","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional biochemical characterization with multiple inhibitor classes, single lab; ADAM10 identity not yet established in this paper","pmids":["9677315"],"is_preprint":false},{"year":1991,"finding":"CD23 (FcεRII) is physically associated with the Src-family tyrosine kinase p59fyn. Cross-linking of CD23 with anti-FcεRII antibody induced IL-2 receptor/p55 expression in CD23-transfected YT cells and in EBV-transformed B cells, indicating that CD23 delivers an activation signal via Fyn.","method":"Co-immunoprecipitation of CD23 with p59fyn; cDNA transfection into YT cells; IL-2R induction assay as functional readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying Fyn as associated kinase plus functional activation assay; single lab","pmids":["1717997"],"is_preprint":false},{"year":2000,"finding":"CD23 expressed on intestinal epithelial cells mediates enhanced IgE-dependent transepithelial antigen transport in sensitized rats. Sensitization induced CD23 expression on enterocytes; immunogold labeling showed CD23 and antigen co-localized in the same endosomes; luminal anti-CD23 antibody significantly inhibited antigen transport and the hypersensitivity reaction.","method":"Rat sensitization model; immunohistochemistry; immunogold electron microscopy; anti-CD23 blocking antibody treatment; antigen uptake/flux measurements","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct imaging of CD23-antigen co-localization plus functional blockade experiment, replicated in subsequent studies with CD23 KO mice","pmids":["11018076"],"is_preprint":false},{"year":2006,"finding":"CD23a, but not CD23b, is expressed on primary human intestinal epithelial cells (IECs) and acts as a bidirectional transporter of IgE. In transcytosis assays with polarized T84 cells retrovirally transfected with CD23a or CD23b, only CD23a mediated transcytosis of IgE and IgE-antigen complexes. IgE-antigen complexes diverted antigen from lysosomes, and transcytosed complexes could activate subepithelial mast cells.","method":"RT-PCR of primary human IECs; retroviral transfection of CD23a/b into polarized T84 cells; transcytosis assays; rat basophil leukemia cell degranulation assay","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct gain-of-function transfection of specific CD23 isoforms in polarized epithelial cells with functional readouts; replicated by subsequent studies","pmids":["16831589"],"is_preprint":false},{"year":2003,"finding":"Intestinal enterocytes express CD23b isoform (classic and alternative splice forms lacking exon 5 or 6). The bΔ5 splice form, but not classic CD23b, mediates constitutive internalization and uptake of free IgE; both forms are internalized after binding IgE/antigen complexes, indicating distinct endocytic properties between splice forms.","method":"RT-PCR and sequencing of CD23 isoforms from enterocytes; CD23-/- mouse jejunal challenge experiments; isoform-specific functional endocytosis assays","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CD23 KO validation plus splice-form characterization with functional endocytosis assays; single lab","pmids":["12637252"],"is_preprint":false},{"year":2005,"finding":"CD23 regulates intracellular trafficking in an isoform-specific manner: CD23a undergoes constitutive clathrin-dependent internalization driven by a cytoplasmic internalization signal in the CD23a-specific intracellular exon; CD23b is stable at the plasma membrane, negatively regulated by its intracellular CD23b-specific exon. The CD23a internalization signal also functions as a basolateral targeting signal in polarized epithelial cells.","method":"Systematic comparison of CD23 splice forms; internalization assays; basolateral targeting assay in polarized MDCK cells; domain deletion/swap constructs","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-level functional dissection with multiple splice form constructs; single lab","pmids":["15843555"],"is_preprint":false},{"year":2011,"finding":"CD23 expressed on airway epithelial cells (radioresistant structural cells) is required for IgE and OVA-IgE complex transcytosis across the airway epithelial barrier in vivo. In chimeric mice lacking CD23 only on radioresistant (structural/epithelial) cells, OVA-driven airway eosinophilia, collagen deposition, goblet cell increase, and airway hyperreactivity were significantly reduced compared with wild-type chimeras. CD23-blocking antibody inhaled before or during challenge suppressed these features.","method":"CD23 KO/WT bone marrow chimeric mice; CD23 KO mouse in vivo sensitization/challenge; inhalation of blocking anti-CD23 antibody (B3B4); airway hyperreactivity, eosinophilia, and histology readouts","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — chimeric mouse model dissects cell-type-specific CD23 role; combined with KO and antibody blockade experiments; multiple orthogonal phenotypic readouts","pmids":["25783969"],"is_preprint":false},{"year":2001,"finding":"CD23 forms a non-covalent complex with HLA-DR on the surface of human B cells. After endocytosis triggered by antigen-IgE complex or anti-HLA-DR antibody, the CD23-HLA-DR complex recycles to the cell surface on a 3–6 hour timescale consistent with antigen presentation, with CD23 label observed in compartments resembling class II peptide-loading vesicles. Endocytosis via anti-CD23 antibody alone caused loss of CD23 from cells without recycling.","method":"Surface labeling and intracellular trafficking of CD23 and HLA-DR in RPMI 8866 B cells; confocal microscopy; pulse-chase endocytosis experiments","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell trafficking imaging showing CD23-HLA-DR co-recycling; single lab, single cell type","pmids":["11454061"],"is_preprint":false},{"year":2007,"finding":"Soluble CD23 (sCD23) monomers inhibit IgE synthesis in human B cells, while oligomeric sCD23 stimulates IgE synthesis. Three recombinant CD23 fragments were characterized: monomeric derCD23, monomeric exCD23, and oligomeric lzCD23; the paradoxical stimulatory vs. inhibitory activities depend on the oligomeric state of the soluble fragment.","method":"Recombinant CD23 fragment expression and purification; in vitro IgE synthesis assay with purified tonsil B cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein structure-function study with defined oligomeric variants and functional IgE synthesis readout; single lab","pmids":["17576766"],"is_preprint":false},{"year":2012,"finding":"Membrane CD23 cleavage by ADAM10 and the resulting trimeric sCD23 positively regulate IgE synthesis after class-switch recombination. ADAM10 inhibitor (GI254023X) or siRNA knockdown of CD23 suppressed IgE synthesis; recombinant trimeric sCD23 enhanced IgE synthesis even when endogenous mCD23 cleavage was blocked. Trimeric sCD23 binds to cells co-expressing mIgE and mCD21 and caps these proteins on the B cell membrane.","method":"siRNA knockdown of CD23; ADAM10 inhibitor (GI254023X); recombinant trimeric sCD23 addition; IgE synthesis assay in IL-4/anti-CD40-stimulated tonsil B cells; cell surface capping assay","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal interventions (siRNA, pharmacological inhibitor, recombinant protein) in primary human B cells with isotype-specific IgE readout; single lab","pmids":["22393152"],"is_preprint":false},{"year":2009,"finding":"TLR4 signaling induces transcriptional upregulation of CD23 and sCD23 release via MMP9. LPS induced MMP9 expression in B cells; MMP9-/- cells failed to produce significant sCD23 after LPS. Type 1 transitional (T1) B cells uniquely produce MMP9 in response to LPS, suggesting that T1 cells cleave CD23 on other B cells in trans.","method":"LPS stimulation of murine and human B cells in vitro and in vivo; MMP9 KO mice; transcriptional analysis; CD23 shedding assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO validation (MMP9-/-) with transcriptional and protein shedding assays; single lab","pmids":["19635918"],"is_preprint":false},{"year":2014,"finding":"P2X7 receptor activation by extracellular ATP induces rapid shedding of CD23 from primary human and murine B cells, mediated by ADAM10. P2X7 antagonists and ADAM10-specific inhibitor (GI254023X) impaired ATP-induced CD23 shedding; B cells from P2X7 knockout mice showed markedly reduced shedding.","method":"Flow cytometry and ELISA for CD23 shedding; P2X7 KO mice; P2X7-specific antagonist (AZ10606120); ADAM10 inhibitor (GI254023X); broad metalloprotease inhibitor (BB-94)","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus pharmacological inhibition with two orthogonal antagonists; single lab","pmids":["25155463"],"is_preprint":false},{"year":2013,"finding":"β2 adrenergic receptor (β2AR) engagement on IL-4/CD40L-primed B cells increases ADAM10 and CD23 expression in a protein kinase A- and p38 MAPK-dependent manner, and promotes localization of both proteins to exosomes. Transfer of exosomes from β2AR agonist-treated B cells to naïve primed B cells increased IgE production per cell; effects required β2AR expression on donor B cells.","method":"β2AR agonist treatment; Western blot for ADAM10 and CD23 on exosomes; electron microscopy of exosomes; ELISPOT for IgE; β2AR-deficient B cells; PKA and p38 pathway inhibitors","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — exosome transfer experiment with KO validation; pathway inhibitors; multiple readouts; single lab","pmids":["24140643"],"is_preprint":false},{"year":2007,"finding":"In vivo destabilization of membrane CD23 by an anti-CD23 stalk monoclonal antibody (19G5) that enhances proteolysis enhanced sCD23 shedding and IgE production. The effect was IL-4-dependent and CD21-independent (demonstrated using IL-4Rα-/- and CD21/35-/- mice), establishing that trimeric surface CD23 initiates an IgE-inhibitory signal.","method":"In vivo injection of anti-CD23 stalk antibody in BALB/c and C57BL/6 mice; IL-4Rα KO and CD21/35 KO mice; serum sCD23 and IgE measurements","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO validation of pathway dependencies; in vivo mouse model; single lab","pmids":["17324389"],"is_preprint":false},{"year":2007,"finding":"The R62W SNP (rs28364072) in CD23 confers resistance to enzymatic cleavage, preventing sCD23 release. Multiple proteases (human leukocyte elastase, cathepsin G, Der p I, ADAM33) cleave wild-type CD23 (R62) but not the W62 mutant in transfected Cos-7 cells. The resistance is associated with diminished N-glycosylation at the R62W locus.","method":"Site-directed mutagenesis; transfection of CD23a constructs (R62 vs W62) in Cos-7 cells; protease cleavage assays; tunicamycin treatment to block N-glycosylation","journal":"Genes and immunity","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — site-directed mutagenesis with multiple protease cleavage assays; glycosylation mechanistic follow-up; single lab","pmids":["17301828"],"is_preprint":false},{"year":2002,"finding":"Notch2 intracellular domain (NotchIC) is a component of a transcription factor complex (C1) that binds CBF1 recognition sites in the CD23a core promoter. Transient transfection of activated Notch2 into REH pre-B cells induced endogenous CD23a expression, identifying CD23a as a transcriptional target of Notch2/CBF1 signaling.","method":"EMSA; supershift assay identifying Notch2 nuclear form in complex C1; transient transfection of activated Notch2 into REH cells; RT-PCR kinetic analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA + supershift + gain-of-function transfection; single lab; converging data from CLL and EBV B cell models","pmids":["11986231"],"is_preprint":false},{"year":2009,"finding":"PKC-delta links to NOTCH2-dependent CD23 expression in CLL cells. PMA (PKC activator) maintained NOTCH2 activity and CD23 expression; PKC-delta siRNA knockdown or rottlerin (PKC-delta inhibitor) antagonized PMA-induced NOTCH2 activation and suppressed CD23 expression in CLL cells with constitutively active NOTCH2.","method":"siRNA knockdown of PKC-delta; rottlerin pharmacological inhibition; EMSA for DNA-bound NOTCH2 complexes; gamma-secretase inhibitor experiments","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown plus pharmacological inhibitor converge on PKC-delta→NOTCH2→CD23 axis; single lab","pmids":["19995395"],"is_preprint":false},{"year":1998,"finding":"STAT6 binds the CD23a promoter (with lower affinity than the consensus site); STAT6-/- mice show reduced CD23 expression after CD40L stimulation. STAT3 and STAT5 can substitute for STAT6 to induce CD23 in STAT6-/- B cells stimulated with CD40 and IL-4. NF-κB (p50) binds two sites in the CD23a promoter; p50-/- mice show normal CD23 induction. C/EBPβ was not required for CD23 induction.","method":"EMSA with competition and supershift; Western blot for nuclear STATs; STAT6-/-, p50-/-, and C/EBPβ-/- mouse analysis; flow cytometry for CD23 expression","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple KO mouse lines plus EMSA analysis; single lab; multiple transcription factors evaluated","pmids":["9796920"],"is_preprint":false},{"year":2016,"finding":"CD23 negatively regulates B cell receptor (BCR) signaling. CD23 KO B cells show increased B cell spreading area, enhanced BCR clustering, and elevated phosphorylation of tyrosine and Btk upon membrane-antigen stimulation. Increased F-actin and phosphorylated WASp (an actin nucleation-promoting factor) were also observed in CD23 KO B cell contact zones, indicating CD23 suppresses BCR signaling by influencing actin-mediated BCR clustering.","method":"CD23 KO mice; membrane-antigen stimulation assay; flow cytometry for BCR clustering and cell spreading; phosphotyrosine and phospho-Btk immunoblotting; F-actin and phospho-WASp imaging","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple downstream signaling readouts; single lab; novel pathway placement","pmids":["27181049"],"is_preprint":false},{"year":2010,"finding":"CD23-mediated cell signaling differs between B cells and monocytic cells. In primary tonsillar B cells, CD23 ligation activates Fyn tyrosine kinase and Akt serine/threonine kinase; these activations were not observed in monocytic cell lines (U937, THP-1).","method":"CD23 ligation in primary B cells and monocytic cell lines; kinase activation assays (Fyn, Akt); comparison of signaling intermediates by immunoblot","journal":"Clinical immunology (Orlando, Fla.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct comparison of signaling in primary B cells vs. monocytic lines; two kinases assessed; single lab","pmids":["20805040"],"is_preprint":false},{"year":2017,"finding":"JNK1 suppresses antifungal immunity by inhibiting CD23 expression via NFATc1. JNK1-deficient mice had significantly higher CD23 induction and survival after C. albicans infection. Blocking CD23 upregulation or CD23-dependent nitric oxide production eliminated the enhanced antifungal response in JNK1-deficient mice, placing CD23 downstream of JNK1/NFATc1 in innate antifungal signaling.","method":"JNK1 KO mice; C. albicans infection model; CD23 blockade; NFATc1 promoter regulation assays; NO production assay; JNK inhibitor treatment in mouse and human cells","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with functional blockade of CD23 and downstream NO, defining pathway position; replicated in human cells; published in high-tier journal","pmids":["28112734"],"is_preprint":false},{"year":2012,"finding":"CD23 is a functional receptor for the secreted cytokine AIMP1/p43 on monocytic cells. CD23 was identified as a high-affinity binding partner of AIMP1 in a screen of 499 soluble receptors; CD23 downregulation attenuated AIMP1-induced TNF-α secretion. AIMP1-induced TNF-α release via CD23 involves ERK1/2 activation. The C-terminal fragment EMAP II could not bind CD23 or activate ERK1/2.","method":"Screen of 499 soluble receptors; co-immunoprecipitation; siRNA knockdown of CD23; ERK1/2 phosphorylation assay; EMAP II vs. AIMP1 binding comparison","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor screen validated by siRNA knockdown with functional TNF-α and ERK1/2 readouts; single lab","pmids":["22767513"],"is_preprint":false},{"year":2009,"finding":"CD23 expressed on human macrophages infected with M. avium mediates antimicrobial activity via inducible nitric oxide synthase-dependent NO production and TNF-α secretion. CD23 cross-linking on infected macrophages induced NO-dependent bacterial killing; IL-10 downregulated CD23 pathway and decreased NO generation and mycobacterial elimination.","method":"M. avium infection of human monocyte-derived macrophages; CD23 cross-linking; iNOS inhibition; anti-TNF-α neutralizing antibody; IL-10 treatment","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cross-linking experiments with pharmacological inhibition of iNOS and cytokine neutralization; single lab; primary human macrophages","pmids":["19805542"],"is_preprint":false},{"year":1999,"finding":"CD23 ligation on glial cells induces iNOS expression and NO release, and upregulates TNF-α production in a NO-dependent manner. In vitro, IFN-γ + IL-1β + TNF-α induced CD23 expression in glial cells; subsequent CD23 ligation with specific antibodies induced iNOS and NO, which in turn drove TNF-α upregulation.","method":"In vitro cytokine stimulation of glial cells; CD23 ligation with antibodies; iNOS expression assays; NO release measurement; TNF-α production assay with NO scavenger controls; immunohistochemistry of Parkinson's disease SN","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro ligation experiment with pharmacological dissection of NO→TNF-α cascade; single lab; mechanistic pathway defined in primary glial cells","pmids":["10212304"],"is_preprint":false},{"year":2019,"finding":"FcεRI preferentially binds free IgE, while CD23 preferentially binds IgE-immune complexes (IgE-ICs). IgE-ICs showed reduced FcεRI binding and enhanced CD23-dependent serum clearance, making them non-inflammatory. Free IgE initiated allergic inflammation through FcεRI.","method":"Binding and activation assays with human cells in vitro; IgE pharmacokinetics and anaphylaxis experiments in vivo; differential receptor-targeting experiments","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assays plus in vivo pharmacokinetics and anaphylaxis models; single lab; orthogonal in vitro and in vivo methods","pmids":["31437490"],"is_preprint":false},{"year":1994,"finding":"CD23 interacts with CD21 to regulate IgE synthesis; two main epitopes on CD21 are recognized by CD23 (SCRs 1-2 and SCRs 5-8), with Asn370 and Asn295 on CD21 critical for interaction with the lectin CD23. Anti-CD23 antibodies inhibit IL-4-induced IgE production in vitro and antigen-specific IgE responses in rats in an isotype-selective manner.","method":"CD21 epitope-mapping with blocking antibodies; glycosylation mutagenesis of CD21; in vitro IgE synthesis inhibition assay; in vivo rat IgE model","journal":"International archives of allergy and immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epitope mapping with mutagenesis and functional inhibition; in vitro and in vivo data; single group","pmids":["7542093"],"is_preprint":false},{"year":2011,"finding":"CD23 expressed on polarized human airway epithelial cells (Calu-3 and primary AECs) mediates bidirectional transcytosis of IgE and IgE-immune complexes. IL-4 upregulated CD23 and enhanced transcytosis efficiency. CD23-specific antibody or soluble CD23 significantly reduced IgE/IC transcytosis. Transcytosed IgE-antigen complexes could induce mast cell degranulation.","method":"Transcytosis assay across polarized Calu-3 monolayers; primary human AEC monolayers; IL-4 stimulation; anti-CD23 blocking antibody; mast cell degranulation assay","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polarized epithelial transcytosis assay with antibody blockade and functional downstream readout; confirmed in primary cells; single lab","pmids":["21307287"],"is_preprint":false},{"year":1998,"finding":"IgE directly upregulates CD23 expression on murine B cells in vivo. IgE-/- mice had ~3-fold less CD23 surface expression than wild-type despite normal proportions of CD23+ B cells. Intravenous infusion of IgE into IgE-/- mice restored CD23 to wild-type levels, establishing a positive feedback loop between IgE and membrane CD23.","method":"IgE-/- mice; flow cytometry; in vitro IL-4 and CD40L stimulation; intravenous IgE infusion in vivo","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO model with in vivo IgE reconstitution; clear gain-of-function rescue; single lab","pmids":["9786437"],"is_preprint":false},{"year":2022,"finding":"CD23 mediates bidirectional transcytosis of IgE in mouse inner ear hair cells (HEI-OC1 cells). siRNA knockdown of CD23 significantly reduced IgE transcytosis efficiency in HEI-OC1 cell monolayers. IL-4 increased CD23 expression and enhanced IgE transcytosis in HEI-OC1 cells and primary vestibular end organs.","method":"Transcytosis assay in HEI-OC1 cell monolayer; siRNA knockdown of CD23; IL-4 stimulation; measurement of IgE transcytosis by ELISA","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with functional transcytosis assay in inner ear cell line; confirmed in primary vestibular tissue; single lab","pmids":["35046106"],"is_preprint":false}],"current_model":"CD23 (FCER2/FcεRII) is a type II transmembrane C-type lectin that functions as the low-affinity IgE receptor: its lectin head domain (with a structurally mapped IgE-binding site also in the stalk region) binds IgE and CD21 simultaneously without requiring calcium; it is cleaved from the cell surface predominantly in endosomes by ADAM10 (and also by MMP9 downstream of TLR4, or in a P2X7-dependent manner) to yield soluble fragments whose oligomeric state determines whether they stimulate (trimeric) or inhibit (monomeric) IgE synthesis; membrane CD23 on B cells associates with Fyn and signals through Fyn/Akt to regulate BCR clustering and B cell activation via actin remodeling; CD23a on epithelial cells mediates bidirectional IgE and IgE-allergen complex transcytosis, a process critical for initiating airway and intestinal allergic inflammation; in macrophages and glial cells, CD23 ligation triggers iNOS-dependent NO production and TNF-α secretion; CD23a gene transcription is controlled by Notch2/CBF1, STAT6/STAT3/STAT5, and NF-κB, and is repressed by JNK1 via NFATc1; and IgE itself stabilizes surface CD23 expression through a positive feedback loop."},"narrative":{"mechanistic_narrative":"CD23 (FCER2/FcεRII) is a type II transmembrane C-type lectin that serves as the low-affinity IgE receptor and a central regulatory hub of IgE homeostasis and allergic inflammation [PMID:16172256, PMID:28361904]. Its lectin-like head domain binds IgE-Fc — with two heads engaging asymmetrically at affinities differing by over an order of magnitude — and an additional IgE-binding site resides in the stalk region; binding occurs independently of calcium despite the C-type lectin fold, and non-glycosylated monomeric CD23 binds IgE more avidly [PMID:28361904, PMID:27343203, PMID:16172256]. CD23 simultaneously binds the complement receptor CD21 (via CD21 SCR1-2 and SCR5-8), and this CD23-CD21 axis modulates IL-4-induced IgE synthesis [PMID:1386409, PMID:7542093]. Surface CD23 is shed by the metalloproteinase ADAM10, which engages the CD23 stalk and cleaves it predominantly within acidified endosomes after internalization, also routing full-length CD23 into exosomes [PMID:17389606, PMID:20876574]; the oligomeric state of the resulting soluble fragments dictates function, with oligomeric/trimeric sCD23 stimulating and monomeric sCD23 inhibiting IgE synthesis [PMID:17576766, PMID:22393152]. Shedding is regulated by alternative inputs including TLR4/MMP9 and P2X7-dependent ADAM10 activation, while the R62W polymorphism renders CD23 resistant to proteolysis [PMID:19635918, PMID:25155463, PMID:17301828]. As a signaling receptor, membrane CD23 associates with the Src-family kinase Fyn and signals through Fyn/Akt in B cells, where it negatively regulates BCR clustering through actin-dependent mechanisms [PMID:1717997, PMID:20805040, PMID:27181049]. The CD23a isoform, through an internalization/basolateral-targeting signal in its cytoplasmic exon, mediates bidirectional transcytosis of IgE and IgE-allergen complexes across epithelial barriers — a process driving airway and intestinal allergic inflammation and operative in additional epithelia such as inner ear hair cells [PMID:15843555, PMID:16831589, PMID:11018076, PMID:25783969, PMID:21307287, PMID:35046106]. In macrophages and glial cells, CD23 ligation triggers iNOS-dependent nitric oxide production and TNF-α secretion contributing to antimicrobial and innate immunity [PMID:19805542, PMID:10212304, PMID:28112734]. CD23a transcription is controlled by Notch2/CBF1 (downstream of PKC-delta), STAT6/STAT3/STAT5, and NF-κB, and is repressed by JNK1 via NFATc1, while IgE itself stabilizes surface CD23 in a positive feedback loop [PMID:11986231, PMID:19995395, PMID:9796920, PMID:28112734, PMID:9786437].","teleology":[{"year":1991,"claim":"Established that CD23 is not merely a passive IgE-binding protein but a signaling receptor, by showing it physically couples to a Src-family kinase and can transmit an activation signal.","evidence":"Co-immunoprecipitation of CD23 with p59fyn and IL-2R induction in CD23-transfected YT and EBV-transformed B cells","pmids":["1717997"],"confidence":"Medium","gaps":["Downstream effectors beyond Fyn not defined here","Signal dependence on ligand engagement not dissected"]},{"year":1992,"claim":"Defined CD23 as a ligand for CD21, providing a molecular basis for CD23 regulation of IgE production beyond IgE binding alone.","evidence":"Recombinant CD23 liposome binding to CD21-transfected cells with antibody blockade and IgE induction assay (Nature)","pmids":["1386409"],"confidence":"High","gaps":["Structural basis of the interaction not resolved","Relative contributions of soluble vs membrane CD23 unclear"]},{"year":1994,"claim":"Mapped the CD21 epitopes and glycan determinants required for CD23 binding, linking the interaction to isotype-selective IgE regulation.","evidence":"CD21 epitope mapping with blocking antibodies and glycosylation mutagenesis; in vitro and rat IgE inhibition assays","pmids":["7542093"],"confidence":"Medium","gaps":["Single-group data","In vivo significance in human allergic disease not established"]},{"year":1998,"claim":"Characterized the CD23 sheddase activity biochemically as a membrane metalloprotease, setting up later identification of the responsible enzyme.","evidence":"Purified CD23 cleavage assay with class-selective protease inhibitors and gel-filtration of plasma membranes","pmids":["9677315"],"confidence":"Medium","gaps":["Enzyme identity not established","Cleavage compartment not addressed"]},{"year":1998,"claim":"Defined the transcriptional inputs (STAT6, redundant STAT3/STAT5, NF-κB) controlling CD23a expression, explaining IL-4/CD40 inducibility.","evidence":"EMSA/supershift plus STAT6-/-, p50-/-, and C/EBPβ-/- mouse analysis of CD23 induction","pmids":["9796920"],"confidence":"Medium","gaps":["Relative quantitative contribution of each factor unresolved","Promoter occupancy in human cells not tested"]},{"year":1998,"claim":"Established a positive feedback loop in which IgE stabilizes surface CD23, explaining amplification of CD23 in allergic states.","evidence":"IgE-/- mice with reduced CD23 rescued by in vivo IgE infusion","pmids":["9786437"],"confidence":"Medium","gaps":["Molecular mechanism of stabilization not defined","Whether shedding rate is altered not addressed"]},{"year":1999,"claim":"Extended CD23 signaling beyond B cells by showing ligation on glial cells drives an iNOS/NO→TNF-α inflammatory cascade.","evidence":"Cytokine-induced CD23 expression and antibody ligation of glial cells with iNOS/NO and TNF-α readouts","pmids":["10212304"],"confidence":"Medium","gaps":["Proximal signaling intermediates not mapped","In vivo relevance to neuroinflammation correlative"]},{"year":2000,"claim":"Demonstrated that epithelial CD23 mediates IgE-dependent transepithelial antigen transport in vivo, linking CD23 to mucosal allergic hypersensitivity.","evidence":"Rat sensitization model with immunogold co-localization of CD23/antigen in endosomes and luminal anti-CD23 blockade (JCI)","pmids":["11018076"],"confidence":"High","gaps":["Isoform responsible not identified here","Directionality of transport not resolved"]},{"year":2001,"claim":"Identified CD23-HLA-DR co-recycling, suggesting CD23 participates in IgE-targeted antigen presentation.","evidence":"Surface labeling and pulse-chase trafficking of CD23/HLA-DR in RPMI 8866 B cells by confocal microscopy","pmids":["11454061"],"confidence":"Medium","gaps":["Functional antigen presentation not directly demonstrated","Single cell type"]},{"year":2002,"claim":"Placed CD23a as a direct transcriptional target of Notch2/CBF1 signaling, identifying a developmental regulatory input.","evidence":"EMSA/supershift of Notch2 in promoter complex C1 plus activated Notch2 transfection inducing CD23a in REH cells (Blood)","pmids":["11986231"],"confidence":"Medium","gaps":["Interplay with STAT/NF-κB inputs not integrated","Endogenous Notch ligand context not defined"]},{"year":2003,"claim":"Showed enterocyte CD23 splice forms have distinct endocytic behaviors, establishing isoform-specific IgE handling.","evidence":"RT-PCR isoform identification and isoform-specific endocytosis assays with CD23-/- mouse jejunal challenge","pmids":["12637252"],"confidence":"Medium","gaps":["Mechanistic basis of bΔ5 constitutive uptake unclear","Single lab"]},{"year":2005,"claim":"Mapped the cytoplasmic determinants of CD23 trafficking, showing CD23a's intracellular exon drives clathrin-dependent internalization and basolateral targeting.","evidence":"Splice-form comparison, internalization assays, and basolateral targeting in polarized MDCK cells","pmids":["15843555"],"confidence":"Medium","gaps":["Adaptor proteins recognizing the signal not identified","Link to transcytosis machinery not resolved"]},{"year":2005,"claim":"Provided the atomic structure of the CD23 lectin head and mapped its trimerization, IgE, and CD21 binding surfaces, showing calcium-independent, simultaneous ligand engagement.","evidence":"Solution NMR with chemical shift perturbation mapping (JEM)","pmids":["16172256"],"confidence":"High","gaps":["Full-length multimeric architecture not resolved","Stalk contribution not captured"]},{"year":2006,"claim":"Identified CD23a as the specific isoform mediating bidirectional epithelial IgE and IgE-antigen transcytosis with mast cell-activating consequences.","evidence":"Retroviral CD23a/b expression in polarized T84 cells with transcytosis and basophil degranulation assays (Gastroenterology)","pmids":["16831589"],"confidence":"High","gaps":["In vivo isoform requirement in human gut not directly shown","Sorting determinants linking to transcytosis incompletely defined"]},{"year":2007,"claim":"Identified ADAM10 as the physiological CD23 sheddase, resolving the long-standing metalloprotease question.","evidence":"Peptide cleavage assays, ADAM10 inhibitors, dominant-negative ADAM10, and siRNA in human B cells (JBC)","pmids":["17389606"],"confidence":"High","gaps":["Subcellular site of cleavage not yet established here","Regulation of ADAM10 activity not addressed"]},{"year":2007,"claim":"Established that the oligomeric state of soluble CD23 determines whether it stimulates or inhibits IgE synthesis, reconciling paradoxical reports.","evidence":"Defined monomeric vs oligomeric recombinant sCD23 fragments in tonsil B cell IgE synthesis assays","pmids":["17576766"],"confidence":"Medium","gaps":["Receptor distinguishing the two states not defined","In vivo balance of fragments unclear"]},{"year":2007,"claim":"Showed that destabilizing membrane CD23 enhances shedding and IgE production via an IL-4-dependent, CD21-independent route, defining trimeric surface CD23 as an IgE-inhibitory signal.","evidence":"In vivo anti-CD23 stalk antibody in IL-4Rα-/- and CD21/35-/- mice with serum sCD23/IgE readouts","pmids":["17324389"],"confidence":"Medium","gaps":["Molecular signal from intact trimer not identified","Single lab"]},{"year":2007,"claim":"Defined the R62W polymorphism as a cleavage-resistant CD23 variant, linking genotype to altered sCD23 release.","evidence":"Site-directed mutagenesis and multi-protease cleavage assays in Cos-7 with glycosylation analysis","pmids":["17301828"],"confidence":"Medium","gaps":["Clinical/allergic phenotype consequences not established here","Effect on ADAM10 cleavage specifically not tested"]},{"year":2009,"claim":"Connected innate TLR4 signaling to CD23 shedding through MMP9, revealing an alternative sheddase pathway and a trans-acting B cell mechanism.","evidence":"LPS stimulation and MMP9-/- mouse analysis of CD23 transcription and shedding","pmids":["19635918"],"confidence":"Medium","gaps":["Relative contribution of MMP9 vs ADAM10 in vivo unclear","T1 B cell trans-cleavage model needs confirmation"]},{"year":2009,"claim":"Linked PKC-delta to NOTCH2-driven CD23 expression in CLL, identifying an upstream regulator of constitutive CD23.","evidence":"PKC-delta siRNA and rottlerin with EMSA of NOTCH2 complexes in CLL cells","pmids":["19995395"],"confidence":"Medium","gaps":["Mechanism by which PKC-delta sustains NOTCH2 unclear","Restricted to malignant cells"]},{"year":2009,"claim":"Demonstrated CD23 mediates macrophage antimicrobial activity against M. avium via iNOS-dependent NO and TNF-α, with IL-10 as a negative regulator.","evidence":"CD23 cross-linking on infected human macrophages with iNOS inhibition and TNF-α neutralization","pmids":["19805542"],"confidence":"Medium","gaps":["Proximal CD23 signaling in macrophages not mapped","In vivo relevance not tested"]},{"year":2010,"claim":"Localized ADAM10-mediated CD23 cleavage to acidified endosomes and identified pH-dependent accessibility plus exosomal sorting of full-length CD23.","evidence":"Endosomal neutralization, SPR at varying pH, and exosome isolation (JBC)","pmids":["20876574"],"confidence":"High","gaps":["Trigger for internalization-coupled cleavage not defined","Fate/function of CD23+ exosomes only partly characterized"]},{"year":2010,"claim":"Showed CD23 signaling is cell-type specific, activating Fyn and Akt in B cells but not in monocytic lines.","evidence":"CD23 ligation with Fyn/Akt kinase assays in primary B cells vs U937/THP-1","pmids":["20805040"],"confidence":"Medium","gaps":["Basis for monocytic non-responsiveness unclear","Functional output of Fyn/Akt not linked to phenotype here"]},{"year":2011,"claim":"Extended epithelial CD23 transcytosis to the airway and showed IL-4 enhances it, linking CD23 to airway allergic responses.","evidence":"Bidirectional transcytosis across polarized Calu-3 and primary AEC monolayers with anti-CD23 blockade and mast cell degranulation readout","pmids":["21307287"],"confidence":"Medium","gaps":["In vivo airway requirement addressed in separate study","Isoform usage in airway not dissected here"]},{"year":2011,"claim":"Demonstrated in vivo that CD23 on radioresistant epithelial cells is required for allergen transcytosis and airway disease, establishing structural-cell CD23 as a therapeutic target.","evidence":"CD23 KO/WT bone marrow chimeras, CD23 KO challenge, and inhaled blocking antibody with airway hyperreactivity/eosinophilia readouts (Mucosal Immunology)","pmids":["25783969"],"confidence":"High","gaps":["Direction of physiological transport in vivo not fully resolved","Contribution of hematopoietic CD23 not isolated"]},{"year":2012,"claim":"Connected ADAM10-generated trimeric sCD23 to positive regulation of IgE synthesis post-class-switch, integrating shedding with IgE output and CD21/IgE capping.","evidence":"ADAM10 inhibitor, CD23 siRNA, and recombinant trimeric sCD23 in stimulated tonsil B cells with capping assay","pmids":["22393152"],"confidence":"High","gaps":["Reconciliation with inhibitory monomeric sCD23 at the cell level incomplete","Signaling through mIgE/CD21 cap not detailed"]},{"year":2012,"claim":"Identified CD23 as a high-affinity receptor for the secreted cytokine AIMP1/p43 on monocytes, expanding its ligand repertoire and TNF-α-inducing function.","evidence":"Receptor screen, co-IP, CD23 siRNA, and ERK1/2 phosphorylation/TNF-α assays","pmids":["22767513"],"confidence":"Medium","gaps":["Structural basis of AIMP1-CD23 binding unknown","Physiological context of this axis unclear"]},{"year":2013,"claim":"Showed β2-adrenergic signaling upregulates ADAM10 and CD23 and routes them to exosomes that enhance IgE production, linking neuroendocrine input to CD23 biology.","evidence":"β2AR agonist treatment, exosome characterization/transfer, β2AR-deficient B cells, and PKA/p38 inhibitors with IgE ELISPOT","pmids":["24140643"],"confidence":"Medium","gaps":["Exosomal CD23 mechanism of action on recipient cells unclear","In vivo relevance not established"]},{"year":2014,"claim":"Defined a P2X7/ATP-driven, ADAM10-dependent route of rapid CD23 shedding, adding a danger-signal input to CD23 release.","evidence":"Flow/ELISA shedding with P2X7 KO mice, P2X7 antagonist, and ADAM10 inhibitor","pmids":["25155463"],"confidence":"Medium","gaps":["How P2X7 activates ADAM10 mechanistically unknown","Functional consequence of this shedding mode not addressed"]},{"year":2016,"claim":"Identified the stalk region as a second IgE-binding site and showed non-glycosylated monomeric CD23 binds IgE best and that omalizumab blocks CD23-IgE binding.","evidence":"CD23 domain variants, binding/inhibition assays, negative-stain EM, and peptide-scanning antibodies (JACI)","pmids":["27343203"],"confidence":"High","gaps":["Physiological role of stalk binding vs head binding unclear","Glycosylation regulation in vivo not defined"]},{"year":2016,"claim":"Placed membrane CD23 as a negative regulator of BCR signaling acting through actin-dependent control of BCR clustering.","evidence":"CD23 KO B cells with spreading/clustering, phospho-Btk/tyrosine, and F-actin/phospho-WASp imaging","pmids":["27181049"],"confidence":"Medium","gaps":["Link between CD23-Fyn signaling and actin machinery not mechanistically closed","Ligand requirement for this regulation unclear"]},{"year":2017,"claim":"Provided the crystal structure of a CD23/IgE-Fc complex, revealing asymmetric two-head engagement of IgE-Fc with distinct affinities.","evidence":"X-ray crystallography and ITC (Scientific Reports)","pmids":["28361904"],"confidence":"High","gaps":["Full multimeric IgE-CD23 lattice not captured","Stalk-site contribution not included in crystal"]},{"year":2017,"claim":"Defined CD23 as a downstream effector of innate antifungal immunity, repressed by JNK1 via NFATc1 and acting through NO production.","evidence":"JNK1 KO mice, C. albicans infection, CD23 blockade, NFATc1 promoter assays, and NO readouts (Nature Medicine)","pmids":["28112734"],"confidence":"High","gaps":["Cell type executing antifungal CD23 function not fully resolved","Receptor for CD23 ligation in this context unknown"]},{"year":2019,"claim":"Established a division of labor between FcεRI and CD23, with CD23 preferentially clearing non-inflammatory IgE-immune complexes while free IgE drives inflammation via FcεRI.","evidence":"In vitro binding/activation and in vivo IgE pharmacokinetics/anaphylaxis with differential receptor targeting","pmids":["31437490"],"confidence":"Medium","gaps":["Tissue site of CD23-mediated clearance not pinpointed","Single lab"]},{"year":2022,"claim":"Generalized CD23 transcytosis to inner ear hair cells, broadening the tissue scope of CD23-mediated IgE transport.","evidence":"siRNA knockdown and IL-4-modulated IgE transcytosis in HEI-OC1 monolayers and primary vestibular tissue","pmids":["35046106"],"confidence":"Medium","gaps":["Physiological role in inner ear allergy/disease unclear","Isoform usage not dissected"]},{"year":null,"claim":"How the competing stimulatory (trimeric/membrane) and inhibitory (monomeric) CD23 states are balanced at the level of an individual B cell, and which receptors transduce each, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined receptor distinguishing monomeric vs oligomeric sCD23 signaling","Integration of CD23-Fyn/Akt signaling with BCR and actin machinery incomplete","In vivo balance of shedding pathways (ADAM10/MMP9/P2X7) across tissues not quantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[9,8,32,34]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[7,25,24]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,5,7,24]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5,11,13]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[5,18]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,15,26,28]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[9,8,32,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,24,25]}],"complexes":[],"partners":["IGHE","CR2","ADAM10","FYN","HLA-DRA","AIMP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P06734","full_name":"Low affinity immunoglobulin epsilon Fc receptor","aliases":["BLAST-2","C-type lectin domain family 4 member J","Fc-epsilon-RII","Immunoglobulin E-binding factor","Lymphocyte IgE receptor"],"length_aa":321,"mass_kda":36.5,"function":"Low-affinity receptor for immunoglobulin E (IgE) and CR2/CD21. Has essential roles in the regulation of IgE production and in the differentiation of B cells. On B cells, initiates IgE-dependent antigen uptake and presentation to T cells (PubMed:2167225). On macrophages, upon IgE binding and antigen cross-linking induces intracellular killing of parasites through activation of L-Arginine-nitric oxide pathway (PubMed:7544003)","subcellular_location":"Cell membrane; Cell membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/P06734/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FCER2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FCER2","total_profiled":1310},"omim":[{"mim_id":"620105","title":"C-TYPE LECTIN DOMAIN FAMILY 4, MEMBER F; CLEC4F","url":"https://www.omim.org/entry/620105"},{"mim_id":"616256","title":"C-TYPE LECTIN DOMAIN FAMILY 4, MEMBER G; CLEC4G","url":"https://www.omim.org/entry/616256"},{"mim_id":"604590","title":"Fc FRAGMENT OF IgG RECEPTOR IIb; FCGR2B","url":"https://www.omim.org/entry/604590"},{"mim_id":"604002","title":"RHO-ASSOCIATED COILED-COIL-CONTAINING PROTEIN KINASE 2; ROCK2","url":"https://www.omim.org/entry/604002"},{"mim_id":"602192","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 10; ADAM10","url":"https://www.omim.org/entry/602192"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":39.5}],"url":"https://www.proteinatlas.org/search/FCER2"},"hgnc":{"alias_symbol":["CLEC4J","CD23","FCErII","FcepsilonRII"],"prev_symbol":["CD23A","FCE2"]},"alphafold":{"accession":"P06734","domains":[{"cath_id":"3.10.100.10","chopping":"162-290","consensus_level":"high","plddt":92.6336,"start":162,"end":290}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P06734","model_url":"https://alphafold.ebi.ac.uk/files/AF-P06734-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P06734-F1-predicted_aligned_error_v6.png","plddt_mean":86.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FCER2","jax_strain_url":"https://www.jax.org/strain/search?query=FCER2"},"sequence":{"accession":"P06734","fasta_url":"https://rest.uniprot.org/uniprotkb/P06734.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P06734/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P06734"}},"corpus_meta":[{"pmid":"1386409","id":"PMC_1386409","title":"CD21 is a ligand for CD23 and regulates IgE production.","date":"1992","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/1386409","citation_count":433,"is_preprint":false},{"pmid":"10212304","id":"PMC_10212304","title":"FcepsilonRII/CD23 is expressed in Parkinson's disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells.","date":"1999","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/10212304","citation_count":332,"is_preprint":false},{"pmid":"2525911","id":"PMC_2525911","title":"CD23: a multi-functional receptor/lymphokine?","date":"1989","source":"Immunology today","url":"https://pubmed.ncbi.nlm.nih.gov/2525911","citation_count":253,"is_preprint":false},{"pmid":"20831712","id":"PMC_20831712","title":"CD23/FcεRII: molecular multi-tasking.","date":"2010","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20831712","citation_count":141,"is_preprint":false},{"pmid":"14707045","id":"PMC_14707045","title":"Cutting edge: BAFF regulates CD21/35 and CD23 expression independent of its B cell survival function.","date":"2004","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/14707045","citation_count":123,"is_preprint":false},{"pmid":"11986231","id":"PMC_11986231","title":"Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11986231","citation_count":115,"is_preprint":false},{"pmid":"17980418","id":"PMC_17980418","title":"FCER2: a pharmacogenetic basis for severe exacerbations in children with asthma.","date":"2007","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17980418","citation_count":113,"is_preprint":false},{"pmid":"16172256","id":"PMC_16172256","title":"The structure of human CD23 and its interactions with IgE and CD21.","date":"2005","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16172256","citation_count":113,"is_preprint":false},{"pmid":"7686210","id":"PMC_7686210","title":"Human B cell precursors proliferate and express CD23 after CD40 ligation.","date":"1993","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7686210","citation_count":111,"is_preprint":false},{"pmid":"11018076","id":"PMC_11018076","title":"Enhanced intestinal transepithelial antigen transport in allergic rats is mediated by IgE and CD23 (FcepsilonRII).","date":"2000","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/11018076","citation_count":107,"is_preprint":false},{"pmid":"28112734","id":"PMC_28112734","title":"JNK1 negatively controls antifungal innate immunity by suppressing CD23 expression.","date":"2017","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28112734","citation_count":86,"is_preprint":false},{"pmid":"38324641","id":"PMC_38324641","title":"CD23+IgG1+ memory B cells are poised to switch to pathogenic IgE production in food allergy.","date":"2024","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38324641","citation_count":85,"is_preprint":false},{"pmid":"26497523","id":"PMC_26497523","title":"Structure and dynamics of IgE-receptor interactions: FcεRI and CD23/FcεRII.","date":"2015","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/26497523","citation_count":85,"is_preprint":false},{"pmid":"2522048","id":"PMC_2522048","title":"Expression and functional role of CD23 on T cells.","date":"1989","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2522048","citation_count":79,"is_preprint":false},{"pmid":"7931486","id":"PMC_7931486","title":"Soluble CD23 reliably reflects disease activity in B-cell chronic lymphocytic leukemia.","date":"1994","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/7931486","citation_count":76,"is_preprint":false},{"pmid":"7945782","id":"PMC_7945782","title":"B-cell signalling via the C-type lectins CD23 and CD72.","date":"1994","source":"Immunology today","url":"https://pubmed.ncbi.nlm.nih.gov/7945782","citation_count":75,"is_preprint":false},{"pmid":"16831589","id":"PMC_16831589","title":"Transcytosis of IgE-antigen complexes by CD23a in human intestinal epithelial cells and its role in food allergy.","date":"2006","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/16831589","citation_count":74,"is_preprint":false},{"pmid":"17389606","id":"PMC_17389606","title":"The low affinity IgE receptor (CD23) is cleaved by the metalloproteinase ADAM10.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17389606","citation_count":74,"is_preprint":false},{"pmid":"17697638","id":"PMC_17697638","title":"CD23: an overlooked regulator of allergic disease.","date":"2007","source":"Current allergy and asthma reports","url":"https://pubmed.ncbi.nlm.nih.gov/17697638","citation_count":72,"is_preprint":false},{"pmid":"16034084","id":"PMC_16034084","title":"IgE enhances antibody and T cell responses in vivo via CD23+ B cells.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16034084","citation_count":72,"is_preprint":false},{"pmid":"10949720","id":"PMC_10949720","title":"Circulating cytokines and soluble CD23, CD26 and CD30 in ANCA-associated vasculitides.","date":"2000","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/10949720","citation_count":70,"is_preprint":false},{"pmid":"33378583","id":"PMC_33378583","title":"The role of CD23 in the regulation of allergic responses.","date":"2021","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/33378583","citation_count":69,"is_preprint":false},{"pmid":"10353405","id":"PMC_10353405","title":"Up-regulation of interleukin-4 and CD23/FcepsilonRII in minimal change nephrotic syndrome.","date":"1999","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/10353405","citation_count":69,"is_preprint":false},{"pmid":"12022472","id":"PMC_12022472","title":"CD23 (the low-affinity IgE receptor) as a C-type lectin: a multidomain and multifunctional molecule.","date":"2002","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/12022472","citation_count":68,"is_preprint":false},{"pmid":"36445014","id":"PMC_36445014","title":"IgG memory B cells expressing IL4R and FCER2 are associated with atopic diseases.","date":"2022","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/36445014","citation_count":66,"is_preprint":false},{"pmid":"31367246","id":"PMC_31367246","title":"Human Mesenchymal Stem Cell-Treated Regulatory CD23+CD43+ B Cells Alleviate Intestinal Inflammation.","date":"2019","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/31367246","citation_count":66,"is_preprint":false},{"pmid":"1532590","id":"PMC_1532590","title":"CD23 antigen regulation and signaling in chronic lymphocytic leukemia.","date":"1992","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/1532590","citation_count":66,"is_preprint":false},{"pmid":"16222084","id":"PMC_16222084","title":"Anti-CD23.","date":"2005","source":"Clinical reviews in allergy & immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16222084","citation_count":65,"is_preprint":false},{"pmid":"2531185","id":"PMC_2531185","title":"IgE receptor on human eosinophils (FcERII). Comparison with B cell CD23 and association with an adhesion molecule.","date":"1989","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2531185","citation_count":64,"is_preprint":false},{"pmid":"10374772","id":"PMC_10374772","title":"High expression of CD23 in the proliferation centers of chronic lymphocytic leukemia in lymph nodes and spleen.","date":"1999","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10374772","citation_count":60,"is_preprint":false},{"pmid":"17576766","id":"PMC_17576766","title":"Soluble CD23 monomers inhibit and oligomers stimulate IGE synthesis in human B cells.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17576766","citation_count":60,"is_preprint":false},{"pmid":"7546400","id":"PMC_7546400","title":"CD23 and B-cell activation.","date":"1995","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7546400","citation_count":59,"is_preprint":false},{"pmid":"22393152","id":"PMC_22393152","title":"Soluble CD23 controls IgE synthesis and homeostasis in human B cells.","date":"2012","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/22393152","citation_count":58,"is_preprint":false},{"pmid":"10712348","id":"PMC_10712348","title":"CD23 exhibits negative regulatory effects on allergic sensitization and airway hyperresponsiveness.","date":"2000","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10712348","citation_count":58,"is_preprint":false},{"pmid":"1717997","id":"PMC_1717997","title":"Fyn tyrosine kinase associated with Fc epsilon RII/CD23: possible multiple roles in lymphocyte activation.","date":"1991","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1717997","citation_count":58,"is_preprint":false},{"pmid":"12637252","id":"PMC_12637252","title":"Intestinal epithelial CD23 mediates enhanced antigen transport in allergy: evidence for novel splice forms.","date":"2003","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12637252","citation_count":57,"is_preprint":false},{"pmid":"11454061","id":"PMC_11454061","title":"Endocytosis and recycling of the complex between CD23 and HLA-DR in human B cells.","date":"2001","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11454061","citation_count":56,"is_preprint":false},{"pmid":"15569053","id":"PMC_15569053","title":"CD23 expression in mediastinal large B-cell lymphomas.","date":"2004","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/15569053","citation_count":55,"is_preprint":false},{"pmid":"27181049","id":"PMC_27181049","title":"CD23 can negatively regulate B-cell receptor signaling.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27181049","citation_count":54,"is_preprint":false},{"pmid":"10482830","id":"PMC_10482830","title":"Altered expression and action of the low-affinity IgE receptor FcepsilonRII (CD23) in asthmatic airway smooth muscle.","date":"1999","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10482830","citation_count":52,"is_preprint":false},{"pmid":"21958076","id":"PMC_21958076","title":"FCER2 T2206C variant associated with chronic symptoms and exacerbations in steroid-treated asthmatic children.","date":"2011","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/21958076","citation_count":52,"is_preprint":false},{"pmid":"8089484","id":"PMC_8089484","title":"Transgene CD23 expression on lymphoid cells modulates IgE and IgG1 responses.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8089484","citation_count":52,"is_preprint":false},{"pmid":"21307287","id":"PMC_21307287","title":"CD23-dependent transcytosis of IgE and immune complex across the polarized human respiratory epithelial cells.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21307287","citation_count":52,"is_preprint":false},{"pmid":"9651788","id":"PMC_9651788","title":"Structure and functions of CD23.","date":"1997","source":"International reviews of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9651788","citation_count":50,"is_preprint":false},{"pmid":"14608904","id":"PMC_14608904","title":"CD23 expression in mantle cell lymphoma: clinicopathologic features of 18 cases.","date":"2003","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/14608904","citation_count":50,"is_preprint":false},{"pmid":"8080994","id":"PMC_8080994","title":"Role for low-affinity receptor for IgE (CD23) in normal and leukemic B-cell proliferation.","date":"1994","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/8080994","citation_count":50,"is_preprint":false},{"pmid":"2137545","id":"PMC_2137545","title":"Expression of CD23 antigen and its regulation by IL-4 in chronic lymphocytic leukemia.","date":"1990","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/2137545","citation_count":49,"is_preprint":false},{"pmid":"32198890","id":"PMC_32198890","title":"CD23 expression on switched memory B cells bridges T-B cell interaction in allergic rhinitis.","date":"2020","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/32198890","citation_count":48,"is_preprint":false},{"pmid":"21884592","id":"PMC_21884592","title":"CD23(+)/CD21(hi) B-cell translocation and ipsilateral lymph node collapse is associated with asymmetric arthritic flare in TNF-Tg mice.","date":"2011","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/21884592","citation_count":48,"is_preprint":false},{"pmid":"9796920","id":"PMC_9796920","title":"STAT6, NF-kappaB and C/EBP in CD23 expression and IgE production.","date":"1998","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9796920","citation_count":47,"is_preprint":false},{"pmid":"7542093","id":"PMC_7542093","title":"Regulation of IgE synthesis by CD23/CD21 interaction.","date":"1995","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7542093","citation_count":47,"is_preprint":false},{"pmid":"15794857","id":"PMC_15794857","title":"CD5, CD10, and CD23 expression in Waldenstrom's macroglobulinemia.","date":"2005","source":"Clinical lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/15794857","citation_count":45,"is_preprint":false},{"pmid":"11920534","id":"PMC_11920534","title":"The clinical and diagnostic relevance of CD23 expression in the chronic lymphoproliferative disease.","date":"2002","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/11920534","citation_count":45,"is_preprint":false},{"pmid":"20876574","id":"PMC_20876574","title":"CD23 Sheddase A disintegrin and metalloproteinase 10 (ADAM10) is also required for CD23 sorting into B cell-derived exosomes.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20876574","citation_count":42,"is_preprint":false},{"pmid":"11080714","id":"PMC_11080714","title":"Early expression of iepsilon, CD23 (FcepsilonRII), IL-4Ralpha, and IgE in the human fetus.","date":"2000","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11080714","citation_count":41,"is_preprint":false},{"pmid":"25783969","id":"PMC_25783969","title":"Inhibition of CD23-mediated IgE transcytosis suppresses the initiation and development of allergic airway inflammation.","date":"2015","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25783969","citation_count":41,"is_preprint":false},{"pmid":"1717283","id":"PMC_1717283","title":"Heterogeneous expression of CD23 epitopes by eosinophils from patients. Relationships with IgE-mediated functions.","date":"1991","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1717283","citation_count":41,"is_preprint":false},{"pmid":"31437490","id":"PMC_31437490","title":"CD23 provides a noninflammatory pathway for IgE-allergen complexes.","date":"2019","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31437490","citation_count":39,"is_preprint":false},{"pmid":"20647033","id":"PMC_20647033","title":"P2X7 receptor activation induces cell death and CD23 shedding in human RPMI 8226 multiple myeloma cells.","date":"2010","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/20647033","citation_count":39,"is_preprint":false},{"pmid":"10712310","id":"PMC_10712310","title":"Association study of the chromosomal region containing the FCER2 gene suggests it has a regulatory role in atopic disorders.","date":"2000","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10712310","citation_count":36,"is_preprint":false},{"pmid":"11211615","id":"PMC_11211615","title":"Diagnostic usefulness of CD23 and FMC-7 antigen expression patterns in B-cell lymphoma classification.","date":"2001","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/11211615","citation_count":35,"is_preprint":false},{"pmid":"9677315","id":"PMC_9677315","title":"CD23 (FcepsilonRII) release from cell membranes is mediated by a membrane-bound metalloprotease.","date":"1998","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/9677315","citation_count":34,"is_preprint":false},{"pmid":"19290077","id":"PMC_19290077","title":"Expression of CD27 and CD23 on peripheral blood B lymphocytes in humans of different ages.","date":"2009","source":"Blood transfusion = Trasfusione del sangue","url":"https://pubmed.ncbi.nlm.nih.gov/19290077","citation_count":34,"is_preprint":false},{"pmid":"8144946","id":"PMC_8144946","title":"Induction of B cell and T cell tolerance in vivo by anti-CD23 mAb.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8144946","citation_count":34,"is_preprint":false},{"pmid":"35046106","id":"PMC_35046106","title":"Bidirectional Transport of IgE by CD23 in the Inner Ear of Patients with Meniere's Disease.","date":"2022","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/35046106","citation_count":33,"is_preprint":false},{"pmid":"1287120","id":"PMC_1287120","title":"Expression, regulation and function of human Fc epsilon RII (CD23) antigen.","date":"1992","source":"Immunologic research","url":"https://pubmed.ncbi.nlm.nih.gov/1287120","citation_count":32,"is_preprint":false},{"pmid":"20357824","id":"PMC_20357824","title":"CD5+CD23+ leukemic cell populations in TCL1 transgenic mice show significantly increased proliferation and Akt phosphorylation.","date":"2010","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/20357824","citation_count":32,"is_preprint":false},{"pmid":"28361904","id":"PMC_28361904","title":"IgE binds asymmetrically to its B cell receptor CD23.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28361904","citation_count":31,"is_preprint":false},{"pmid":"1834078","id":"PMC_1834078","title":"Biology and chemistry of low affinity IgE receptor (Fc epsilon RII/CD23).","date":"1991","source":"Critical reviews in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1834078","citation_count":31,"is_preprint":false},{"pmid":"8574430","id":"PMC_8574430","title":"Interleukin-4 and soluble CD23 serum levels in asthmatic atopic children.","date":"1995","source":"Journal of investigational allergology & clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8574430","citation_count":29,"is_preprint":false},{"pmid":"16585575","id":"PMC_16585575","title":"Differential T cell-mediated regulation of CD23 (Fc epsilonRII) in B cells and follicular dendritic cells.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16585575","citation_count":27,"is_preprint":false},{"pmid":"21173123","id":"PMC_21173123","title":"CD23 expression in follicular lymphoma: clinicopathologic correlations.","date":"2011","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21173123","citation_count":26,"is_preprint":false},{"pmid":"11064465","id":"PMC_11064465","title":"Quantitative expression of CD23 and its ligand CD21 in chronic lymphocytic leukemia.","date":"2000","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/11064465","citation_count":26,"is_preprint":false},{"pmid":"9786437","id":"PMC_9786437","title":"The expression of murine B cell CD23, in vivo, is regulated by its ligand, IgE.","date":"1998","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9786437","citation_count":26,"is_preprint":false},{"pmid":"19995395","id":"PMC_19995395","title":"NOTCH2 links protein kinase C delta to the expression of CD23 in chronic lymphocytic leukaemia (CLL) cells.","date":"2009","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/19995395","citation_count":26,"is_preprint":false},{"pmid":"25155463","id":"PMC_25155463","title":"Activation of the P2X7 receptor induces the rapid shedding of CD23 from human and murine B cells.","date":"2014","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25155463","citation_count":25,"is_preprint":false},{"pmid":"24354852","id":"PMC_24354852","title":"A role of FCER1A and FCER2 polymorphisms in IgE regulation.","date":"2013","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/24354852","citation_count":24,"is_preprint":false},{"pmid":"35259043","id":"PMC_35259043","title":"Lenalidomide enhances CD23.CAR T cell therapy in chronic lymphocytic leukemia.","date":"2022","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/35259043","citation_count":24,"is_preprint":false},{"pmid":"27343203","id":"PMC_27343203","title":"Critical and direct involvement of the CD23 stalk region in IgE binding.","date":"2016","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27343203","citation_count":24,"is_preprint":false},{"pmid":"8221262","id":"PMC_8221262","title":"CD23 expression on B-lymphocytes and its modulation by cytokines in allergic patients.","date":"1993","source":"Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8221262","citation_count":24,"is_preprint":false},{"pmid":"20805040","id":"PMC_20805040","title":"CD23-mediated cell signaling in human B cells differs from signaling in cells of the monocytic lineage.","date":"2010","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/20805040","citation_count":24,"is_preprint":false},{"pmid":"17635803","id":"PMC_17635803","title":"IgE enhances specific antibody and T-cell responses in mice overexpressing CD23.","date":"2007","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17635803","citation_count":23,"is_preprint":false},{"pmid":"19635918","id":"PMC_19635918","title":"TLR4-mediated signaling induces MMP9-dependent cleavage of B cell surface CD23.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19635918","citation_count":23,"is_preprint":false},{"pmid":"27695350","id":"PMC_27695350","title":"Study of the correlations between fractional exhaled nitric oxide in exhaled breath and atopic status, blood eosinophils, FCER2 mutation, and asthma control in Vietnamese children.","date":"2016","source":"Journal of asthma and allergy","url":"https://pubmed.ncbi.nlm.nih.gov/27695350","citation_count":22,"is_preprint":false},{"pmid":"22767513","id":"PMC_22767513","title":"Identification of CD23 as a functional receptor for the proinflammatory cytokine AIMP1/p43.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22767513","citation_count":22,"is_preprint":false},{"pmid":"15843555","id":"PMC_15843555","title":"Intracellular trafficking of CD23: differential regulation in humans and mice by both extracellular and intracellular exons.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15843555","citation_count":21,"is_preprint":false},{"pmid":"18381689","id":"PMC_18381689","title":"The cut-off levels of CD23 expression in the differential diagnosis of MCL and CLL.","date":"2008","source":"Hematological oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18381689","citation_count":21,"is_preprint":false},{"pmid":"24140643","id":"PMC_24140643","title":"Adrenergic regulation of IgE involves modulation of CD23 and ADAM10 expression on exosomes.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24140643","citation_count":21,"is_preprint":false},{"pmid":"8008965","id":"PMC_8008965","title":"CD23 and IgE expression during the human immune response to cutaneous leishmaniasis: possible role in monocyte activation.","date":"1994","source":"Research in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8008965","citation_count":21,"is_preprint":false},{"pmid":"11857591","id":"PMC_11857591","title":"Clinical utility of CD23 and FMC7 antigen coexistent expression in B-cell lymphoproliferative disorder subclassification.","date":"2002","source":"Cytometry","url":"https://pubmed.ncbi.nlm.nih.gov/11857591","citation_count":21,"is_preprint":false},{"pmid":"8018941","id":"PMC_8018941","title":"CD23 and chronic lymphocytic leukemia.","date":"1993","source":"Blood cells","url":"https://pubmed.ncbi.nlm.nih.gov/8018941","citation_count":20,"is_preprint":false},{"pmid":"17140663","id":"PMC_17140663","title":"Analysis of the regulatory role of BAFF in controlling the expression of CD21 and CD23.","date":"2006","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17140663","citation_count":20,"is_preprint":false},{"pmid":"18183502","id":"PMC_18183502","title":"Analysis of CD23 antigen expression in B-chronic lymphocytic leukaemia and its correlation with clinical parameters.","date":"2008","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18183502","citation_count":19,"is_preprint":false},{"pmid":"8133030","id":"PMC_8133030","title":"Regulation of CD23 expression by IL-4 and corticosteroid in human B lymphocytes. Altered response after EBV infection.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8133030","citation_count":19,"is_preprint":false},{"pmid":"2149121","id":"PMC_2149121","title":"Regulation of CD23 expression, soluble CD23 release and immunoglobulin synthesis of peripheral blood lymphocytes by glucocorticoids.","date":"1990","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2149121","citation_count":19,"is_preprint":false},{"pmid":"1287119","id":"PMC_1287119","title":"Eosinophil IgE receptor and CD23.","date":"1992","source":"Immunologic research","url":"https://pubmed.ncbi.nlm.nih.gov/1287119","citation_count":18,"is_preprint":false},{"pmid":"17301828","id":"PMC_17301828","title":"Polymorphism R62W results in resistance of CD23 to enzymatic cleavage in cultured cells.","date":"2007","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/17301828","citation_count":18,"is_preprint":false},{"pmid":"19805542","id":"PMC_19805542","title":"CD23 mediates antimycobacterial activity of human macrophages.","date":"2009","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/19805542","citation_count":18,"is_preprint":false},{"pmid":"17324389","id":"PMC_17324389","title":"In vivo murine CD23 destabilization enhances CD23 shedding and IgE synthesis.","date":"2007","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17324389","citation_count":18,"is_preprint":false},{"pmid":"19279679","id":"PMC_19279679","title":"Molecular blocking of CD23 supports its role in the pathogenesis of arthritis.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19279679","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49351,"output_tokens":9582,"usd":0.145892,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19830,"output_tokens":8748,"usd":0.158925,"stage2_stop_reason":"end_turn"},"total_usd":0.304817,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"CD23 directly binds CD21 (complement receptor 2) on B cells and follicular dendritic cells. Recombinant CD23 incorporated into fluorescent liposomes specifically bound CD21-expressing cells; interaction was blocked by anti-CD21 and anti-CD23 antibodies. CD21 engagement via soluble CD23 increased IL-4-induced IgE production from blood mononuclear cells.\",\n      \"method\": \"Fluorescent liposome-based binding assay with recombinant CD23; transfection of CD21 cDNA into BHK-21 cells; Western blot; functional IgE induction assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with recombinant protein, transfection validation, multiple orthogonal methods, independently cited widely\",\n      \"pmids\": [\"1386409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The C-type lectin domain of CD23 was solved by NMR; residues responsible for self-association into trimers, IgE binding, and CD21 binding were mapped. CD23 can bind IgE and CD21 simultaneously. IgE and CD23 can form high-molecular-mass multimeric complexes. Interactions do not require calcium despite the C-type lectin fold.\",\n      \"method\": \"NMR spectroscopy; concentration-dependent chemical shift perturbation analysis; ligand-induced chemical shift mapping\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — solution NMR structure with functional binding-site mapping, multiple ligand interactions validated in a single rigorous study\",\n      \"pmids\": [\"16172256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of a CD23/IgE-Fc complex revealed that two lectin-like head domains of CD23 bind IgE-Fc with affinities differing by more than an order of magnitude; the crystal structure shows only one head bound to the asymmetrically bent IgE-Fc heavy chain.\",\n      \"method\": \"X-ray crystallography; isothermal titration calorimetry\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with ITC binding measurements, direct structural-functional validation\",\n      \"pmids\": [\"28361904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The stalk region of CD23 contains a previously unidentified IgE-binding site. Non-N-glycosylated monomeric CD23 showed superior IgE binding compared with glycosylated CD23. The therapeutic anti-IgE antibody omalizumab blocked IgE binding to CD23 as well as to FcεRI.\",\n      \"method\": \"Expression of CD23 variants (full extracellular, stalk-only, head-only, non-glycosylated); binding and inhibition assays; negative-stain electron microscopy; peptide-scanning antibody panel\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple CD23 structural variants tested with orthogonal binding assays and EM, single lab\",\n      \"pmids\": [\"27343203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ADAM10 is the metalloproteinase responsible for cleaving membrane CD23 to generate soluble CD23. ADAM10 efficiently cleaves peptides from two distinct cleavage sites in CD23; ADAM10-specific inhibitors, dominant-negative ADAM10, and siRNA knockdown all reduced sCD23 release and caused accumulation of membrane CD23.\",\n      \"method\": \"Peptide cleavage assays; ADAM10-specific inhibitors (prodomain-based, TIMP); dominant-negative ADAM10 expression; siRNA knockdown in human B cells and leukemia lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (siRNA, dominant-negative, pharmacological inhibitors) converge on ADAM10 as CD23 sheddase; replicated in subsequent studies\",\n      \"pmids\": [\"17389606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ADAM10-dependent CD23 cleavage occurs predominantly in the endosomal compartment after internalization, not at the cell surface. The CD23 stalk region interacts with ADAM10 in a protease-independent manner; ADAM10 binding affinity for CD23 is not altered at endosomal pH, but accessibility (Rmax) increases ~10-fold at pH 5.8. Full-length CD23 is sorted into exosomes in an ADAM10-dependent manner.\",\n      \"method\": \"Endosomal neutralization with NH4Cl; SPR analysis of CD23-ADAM10 interaction at different pH; exosome isolation; Western blot; flow cytometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — SPR binding measurements plus cell biological experiments with endosomal inhibitors; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"20876574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD23 shedding from the cell surface is mediated by a membrane-bound metalloprotease of ~63 kDa. The activity is inhibited by metalloprotease inhibitors (1,10-phenanthroline, imidazole, batimastat) but not by cysteine, serine, or acid protease inhibitors. The same or similar activity is present in fibroblasts and monocytic lines not expressing CD23.\",\n      \"method\": \"Purified CD23 cleavage assay with neo-epitope antibody; gel-filtration chromatography of enriched plasma membranes; class-selective protease inhibitors\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional biochemical characterization with multiple inhibitor classes, single lab; ADAM10 identity not yet established in this paper\",\n      \"pmids\": [\"9677315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"CD23 (FcεRII) is physically associated with the Src-family tyrosine kinase p59fyn. Cross-linking of CD23 with anti-FcεRII antibody induced IL-2 receptor/p55 expression in CD23-transfected YT cells and in EBV-transformed B cells, indicating that CD23 delivers an activation signal via Fyn.\",\n      \"method\": \"Co-immunoprecipitation of CD23 with p59fyn; cDNA transfection into YT cells; IL-2R induction assay as functional readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying Fyn as associated kinase plus functional activation assay; single lab\",\n      \"pmids\": [\"1717997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD23 expressed on intestinal epithelial cells mediates enhanced IgE-dependent transepithelial antigen transport in sensitized rats. Sensitization induced CD23 expression on enterocytes; immunogold labeling showed CD23 and antigen co-localized in the same endosomes; luminal anti-CD23 antibody significantly inhibited antigen transport and the hypersensitivity reaction.\",\n      \"method\": \"Rat sensitization model; immunohistochemistry; immunogold electron microscopy; anti-CD23 blocking antibody treatment; antigen uptake/flux measurements\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct imaging of CD23-antigen co-localization plus functional blockade experiment, replicated in subsequent studies with CD23 KO mice\",\n      \"pmids\": [\"11018076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD23a, but not CD23b, is expressed on primary human intestinal epithelial cells (IECs) and acts as a bidirectional transporter of IgE. In transcytosis assays with polarized T84 cells retrovirally transfected with CD23a or CD23b, only CD23a mediated transcytosis of IgE and IgE-antigen complexes. IgE-antigen complexes diverted antigen from lysosomes, and transcytosed complexes could activate subepithelial mast cells.\",\n      \"method\": \"RT-PCR of primary human IECs; retroviral transfection of CD23a/b into polarized T84 cells; transcytosis assays; rat basophil leukemia cell degranulation assay\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct gain-of-function transfection of specific CD23 isoforms in polarized epithelial cells with functional readouts; replicated by subsequent studies\",\n      \"pmids\": [\"16831589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Intestinal enterocytes express CD23b isoform (classic and alternative splice forms lacking exon 5 or 6). The bΔ5 splice form, but not classic CD23b, mediates constitutive internalization and uptake of free IgE; both forms are internalized after binding IgE/antigen complexes, indicating distinct endocytic properties between splice forms.\",\n      \"method\": \"RT-PCR and sequencing of CD23 isoforms from enterocytes; CD23-/- mouse jejunal challenge experiments; isoform-specific functional endocytosis assays\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CD23 KO validation plus splice-form characterization with functional endocytosis assays; single lab\",\n      \"pmids\": [\"12637252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD23 regulates intracellular trafficking in an isoform-specific manner: CD23a undergoes constitutive clathrin-dependent internalization driven by a cytoplasmic internalization signal in the CD23a-specific intracellular exon; CD23b is stable at the plasma membrane, negatively regulated by its intracellular CD23b-specific exon. The CD23a internalization signal also functions as a basolateral targeting signal in polarized epithelial cells.\",\n      \"method\": \"Systematic comparison of CD23 splice forms; internalization assays; basolateral targeting assay in polarized MDCK cells; domain deletion/swap constructs\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-level functional dissection with multiple splice form constructs; single lab\",\n      \"pmids\": [\"15843555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD23 expressed on airway epithelial cells (radioresistant structural cells) is required for IgE and OVA-IgE complex transcytosis across the airway epithelial barrier in vivo. In chimeric mice lacking CD23 only on radioresistant (structural/epithelial) cells, OVA-driven airway eosinophilia, collagen deposition, goblet cell increase, and airway hyperreactivity were significantly reduced compared with wild-type chimeras. CD23-blocking antibody inhaled before or during challenge suppressed these features.\",\n      \"method\": \"CD23 KO/WT bone marrow chimeric mice; CD23 KO mouse in vivo sensitization/challenge; inhalation of blocking anti-CD23 antibody (B3B4); airway hyperreactivity, eosinophilia, and histology readouts\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — chimeric mouse model dissects cell-type-specific CD23 role; combined with KO and antibody blockade experiments; multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"25783969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD23 forms a non-covalent complex with HLA-DR on the surface of human B cells. After endocytosis triggered by antigen-IgE complex or anti-HLA-DR antibody, the CD23-HLA-DR complex recycles to the cell surface on a 3–6 hour timescale consistent with antigen presentation, with CD23 label observed in compartments resembling class II peptide-loading vesicles. Endocytosis via anti-CD23 antibody alone caused loss of CD23 from cells without recycling.\",\n      \"method\": \"Surface labeling and intracellular trafficking of CD23 and HLA-DR in RPMI 8866 B cells; confocal microscopy; pulse-chase endocytosis experiments\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell trafficking imaging showing CD23-HLA-DR co-recycling; single lab, single cell type\",\n      \"pmids\": [\"11454061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Soluble CD23 (sCD23) monomers inhibit IgE synthesis in human B cells, while oligomeric sCD23 stimulates IgE synthesis. Three recombinant CD23 fragments were characterized: monomeric derCD23, monomeric exCD23, and oligomeric lzCD23; the paradoxical stimulatory vs. inhibitory activities depend on the oligomeric state of the soluble fragment.\",\n      \"method\": \"Recombinant CD23 fragment expression and purification; in vitro IgE synthesis assay with purified tonsil B cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein structure-function study with defined oligomeric variants and functional IgE synthesis readout; single lab\",\n      \"pmids\": [\"17576766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Membrane CD23 cleavage by ADAM10 and the resulting trimeric sCD23 positively regulate IgE synthesis after class-switch recombination. ADAM10 inhibitor (GI254023X) or siRNA knockdown of CD23 suppressed IgE synthesis; recombinant trimeric sCD23 enhanced IgE synthesis even when endogenous mCD23 cleavage was blocked. Trimeric sCD23 binds to cells co-expressing mIgE and mCD21 and caps these proteins on the B cell membrane.\",\n      \"method\": \"siRNA knockdown of CD23; ADAM10 inhibitor (GI254023X); recombinant trimeric sCD23 addition; IgE synthesis assay in IL-4/anti-CD40-stimulated tonsil B cells; cell surface capping assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal interventions (siRNA, pharmacological inhibitor, recombinant protein) in primary human B cells with isotype-specific IgE readout; single lab\",\n      \"pmids\": [\"22393152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TLR4 signaling induces transcriptional upregulation of CD23 and sCD23 release via MMP9. LPS induced MMP9 expression in B cells; MMP9-/- cells failed to produce significant sCD23 after LPS. Type 1 transitional (T1) B cells uniquely produce MMP9 in response to LPS, suggesting that T1 cells cleave CD23 on other B cells in trans.\",\n      \"method\": \"LPS stimulation of murine and human B cells in vitro and in vivo; MMP9 KO mice; transcriptional analysis; CD23 shedding assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO validation (MMP9-/-) with transcriptional and protein shedding assays; single lab\",\n      \"pmids\": [\"19635918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"P2X7 receptor activation by extracellular ATP induces rapid shedding of CD23 from primary human and murine B cells, mediated by ADAM10. P2X7 antagonists and ADAM10-specific inhibitor (GI254023X) impaired ATP-induced CD23 shedding; B cells from P2X7 knockout mice showed markedly reduced shedding.\",\n      \"method\": \"Flow cytometry and ELISA for CD23 shedding; P2X7 KO mice; P2X7-specific antagonist (AZ10606120); ADAM10 inhibitor (GI254023X); broad metalloprotease inhibitor (BB-94)\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus pharmacological inhibition with two orthogonal antagonists; single lab\",\n      \"pmids\": [\"25155463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"β2 adrenergic receptor (β2AR) engagement on IL-4/CD40L-primed B cells increases ADAM10 and CD23 expression in a protein kinase A- and p38 MAPK-dependent manner, and promotes localization of both proteins to exosomes. Transfer of exosomes from β2AR agonist-treated B cells to naïve primed B cells increased IgE production per cell; effects required β2AR expression on donor B cells.\",\n      \"method\": \"β2AR agonist treatment; Western blot for ADAM10 and CD23 on exosomes; electron microscopy of exosomes; ELISPOT for IgE; β2AR-deficient B cells; PKA and p38 pathway inhibitors\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — exosome transfer experiment with KO validation; pathway inhibitors; multiple readouts; single lab\",\n      \"pmids\": [\"24140643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In vivo destabilization of membrane CD23 by an anti-CD23 stalk monoclonal antibody (19G5) that enhances proteolysis enhanced sCD23 shedding and IgE production. The effect was IL-4-dependent and CD21-independent (demonstrated using IL-4Rα-/- and CD21/35-/- mice), establishing that trimeric surface CD23 initiates an IgE-inhibitory signal.\",\n      \"method\": \"In vivo injection of anti-CD23 stalk antibody in BALB/c and C57BL/6 mice; IL-4Rα KO and CD21/35 KO mice; serum sCD23 and IgE measurements\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO validation of pathway dependencies; in vivo mouse model; single lab\",\n      \"pmids\": [\"17324389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The R62W SNP (rs28364072) in CD23 confers resistance to enzymatic cleavage, preventing sCD23 release. Multiple proteases (human leukocyte elastase, cathepsin G, Der p I, ADAM33) cleave wild-type CD23 (R62) but not the W62 mutant in transfected Cos-7 cells. The resistance is associated with diminished N-glycosylation at the R62W locus.\",\n      \"method\": \"Site-directed mutagenesis; transfection of CD23a constructs (R62 vs W62) in Cos-7 cells; protease cleavage assays; tunicamycin treatment to block N-glycosylation\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-directed mutagenesis with multiple protease cleavage assays; glycosylation mechanistic follow-up; single lab\",\n      \"pmids\": [\"17301828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Notch2 intracellular domain (NotchIC) is a component of a transcription factor complex (C1) that binds CBF1 recognition sites in the CD23a core promoter. Transient transfection of activated Notch2 into REH pre-B cells induced endogenous CD23a expression, identifying CD23a as a transcriptional target of Notch2/CBF1 signaling.\",\n      \"method\": \"EMSA; supershift assay identifying Notch2 nuclear form in complex C1; transient transfection of activated Notch2 into REH cells; RT-PCR kinetic analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA + supershift + gain-of-function transfection; single lab; converging data from CLL and EBV B cell models\",\n      \"pmids\": [\"11986231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PKC-delta links to NOTCH2-dependent CD23 expression in CLL cells. PMA (PKC activator) maintained NOTCH2 activity and CD23 expression; PKC-delta siRNA knockdown or rottlerin (PKC-delta inhibitor) antagonized PMA-induced NOTCH2 activation and suppressed CD23 expression in CLL cells with constitutively active NOTCH2.\",\n      \"method\": \"siRNA knockdown of PKC-delta; rottlerin pharmacological inhibition; EMSA for DNA-bound NOTCH2 complexes; gamma-secretase inhibitor experiments\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown plus pharmacological inhibitor converge on PKC-delta→NOTCH2→CD23 axis; single lab\",\n      \"pmids\": [\"19995395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"STAT6 binds the CD23a promoter (with lower affinity than the consensus site); STAT6-/- mice show reduced CD23 expression after CD40L stimulation. STAT3 and STAT5 can substitute for STAT6 to induce CD23 in STAT6-/- B cells stimulated with CD40 and IL-4. NF-κB (p50) binds two sites in the CD23a promoter; p50-/- mice show normal CD23 induction. C/EBPβ was not required for CD23 induction.\",\n      \"method\": \"EMSA with competition and supershift; Western blot for nuclear STATs; STAT6-/-, p50-/-, and C/EBPβ-/- mouse analysis; flow cytometry for CD23 expression\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple KO mouse lines plus EMSA analysis; single lab; multiple transcription factors evaluated\",\n      \"pmids\": [\"9796920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD23 negatively regulates B cell receptor (BCR) signaling. CD23 KO B cells show increased B cell spreading area, enhanced BCR clustering, and elevated phosphorylation of tyrosine and Btk upon membrane-antigen stimulation. Increased F-actin and phosphorylated WASp (an actin nucleation-promoting factor) were also observed in CD23 KO B cell contact zones, indicating CD23 suppresses BCR signaling by influencing actin-mediated BCR clustering.\",\n      \"method\": \"CD23 KO mice; membrane-antigen stimulation assay; flow cytometry for BCR clustering and cell spreading; phosphotyrosine and phospho-Btk immunoblotting; F-actin and phospho-WASp imaging\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple downstream signaling readouts; single lab; novel pathway placement\",\n      \"pmids\": [\"27181049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD23-mediated cell signaling differs between B cells and monocytic cells. In primary tonsillar B cells, CD23 ligation activates Fyn tyrosine kinase and Akt serine/threonine kinase; these activations were not observed in monocytic cell lines (U937, THP-1).\",\n      \"method\": \"CD23 ligation in primary B cells and monocytic cell lines; kinase activation assays (Fyn, Akt); comparison of signaling intermediates by immunoblot\",\n      \"journal\": \"Clinical immunology (Orlando, Fla.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct comparison of signaling in primary B cells vs. monocytic lines; two kinases assessed; single lab\",\n      \"pmids\": [\"20805040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JNK1 suppresses antifungal immunity by inhibiting CD23 expression via NFATc1. JNK1-deficient mice had significantly higher CD23 induction and survival after C. albicans infection. Blocking CD23 upregulation or CD23-dependent nitric oxide production eliminated the enhanced antifungal response in JNK1-deficient mice, placing CD23 downstream of JNK1/NFATc1 in innate antifungal signaling.\",\n      \"method\": \"JNK1 KO mice; C. albicans infection model; CD23 blockade; NFATc1 promoter regulation assays; NO production assay; JNK inhibitor treatment in mouse and human cells\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with functional blockade of CD23 and downstream NO, defining pathway position; replicated in human cells; published in high-tier journal\",\n      \"pmids\": [\"28112734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD23 is a functional receptor for the secreted cytokine AIMP1/p43 on monocytic cells. CD23 was identified as a high-affinity binding partner of AIMP1 in a screen of 499 soluble receptors; CD23 downregulation attenuated AIMP1-induced TNF-α secretion. AIMP1-induced TNF-α release via CD23 involves ERK1/2 activation. The C-terminal fragment EMAP II could not bind CD23 or activate ERK1/2.\",\n      \"method\": \"Screen of 499 soluble receptors; co-immunoprecipitation; siRNA knockdown of CD23; ERK1/2 phosphorylation assay; EMAP II vs. AIMP1 binding comparison\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor screen validated by siRNA knockdown with functional TNF-α and ERK1/2 readouts; single lab\",\n      \"pmids\": [\"22767513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD23 expressed on human macrophages infected with M. avium mediates antimicrobial activity via inducible nitric oxide synthase-dependent NO production and TNF-α secretion. CD23 cross-linking on infected macrophages induced NO-dependent bacterial killing; IL-10 downregulated CD23 pathway and decreased NO generation and mycobacterial elimination.\",\n      \"method\": \"M. avium infection of human monocyte-derived macrophages; CD23 cross-linking; iNOS inhibition; anti-TNF-α neutralizing antibody; IL-10 treatment\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cross-linking experiments with pharmacological inhibition of iNOS and cytokine neutralization; single lab; primary human macrophages\",\n      \"pmids\": [\"19805542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD23 ligation on glial cells induces iNOS expression and NO release, and upregulates TNF-α production in a NO-dependent manner. In vitro, IFN-γ + IL-1β + TNF-α induced CD23 expression in glial cells; subsequent CD23 ligation with specific antibodies induced iNOS and NO, which in turn drove TNF-α upregulation.\",\n      \"method\": \"In vitro cytokine stimulation of glial cells; CD23 ligation with antibodies; iNOS expression assays; NO release measurement; TNF-α production assay with NO scavenger controls; immunohistochemistry of Parkinson's disease SN\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro ligation experiment with pharmacological dissection of NO→TNF-α cascade; single lab; mechanistic pathway defined in primary glial cells\",\n      \"pmids\": [\"10212304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FcεRI preferentially binds free IgE, while CD23 preferentially binds IgE-immune complexes (IgE-ICs). IgE-ICs showed reduced FcεRI binding and enhanced CD23-dependent serum clearance, making them non-inflammatory. Free IgE initiated allergic inflammation through FcεRI.\",\n      \"method\": \"Binding and activation assays with human cells in vitro; IgE pharmacokinetics and anaphylaxis experiments in vivo; differential receptor-targeting experiments\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assays plus in vivo pharmacokinetics and anaphylaxis models; single lab; orthogonal in vitro and in vivo methods\",\n      \"pmids\": [\"31437490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CD23 interacts with CD21 to regulate IgE synthesis; two main epitopes on CD21 are recognized by CD23 (SCRs 1-2 and SCRs 5-8), with Asn370 and Asn295 on CD21 critical for interaction with the lectin CD23. Anti-CD23 antibodies inhibit IL-4-induced IgE production in vitro and antigen-specific IgE responses in rats in an isotype-selective manner.\",\n      \"method\": \"CD21 epitope-mapping with blocking antibodies; glycosylation mutagenesis of CD21; in vitro IgE synthesis inhibition assay; in vivo rat IgE model\",\n      \"journal\": \"International archives of allergy and immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epitope mapping with mutagenesis and functional inhibition; in vitro and in vivo data; single group\",\n      \"pmids\": [\"7542093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD23 expressed on polarized human airway epithelial cells (Calu-3 and primary AECs) mediates bidirectional transcytosis of IgE and IgE-immune complexes. IL-4 upregulated CD23 and enhanced transcytosis efficiency. CD23-specific antibody or soluble CD23 significantly reduced IgE/IC transcytosis. Transcytosed IgE-antigen complexes could induce mast cell degranulation.\",\n      \"method\": \"Transcytosis assay across polarized Calu-3 monolayers; primary human AEC monolayers; IL-4 stimulation; anti-CD23 blocking antibody; mast cell degranulation assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polarized epithelial transcytosis assay with antibody blockade and functional downstream readout; confirmed in primary cells; single lab\",\n      \"pmids\": [\"21307287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"IgE directly upregulates CD23 expression on murine B cells in vivo. IgE-/- mice had ~3-fold less CD23 surface expression than wild-type despite normal proportions of CD23+ B cells. Intravenous infusion of IgE into IgE-/- mice restored CD23 to wild-type levels, establishing a positive feedback loop between IgE and membrane CD23.\",\n      \"method\": \"IgE-/- mice; flow cytometry; in vitro IL-4 and CD40L stimulation; intravenous IgE infusion in vivo\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO model with in vivo IgE reconstitution; clear gain-of-function rescue; single lab\",\n      \"pmids\": [\"9786437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD23 mediates bidirectional transcytosis of IgE in mouse inner ear hair cells (HEI-OC1 cells). siRNA knockdown of CD23 significantly reduced IgE transcytosis efficiency in HEI-OC1 cell monolayers. IL-4 increased CD23 expression and enhanced IgE transcytosis in HEI-OC1 cells and primary vestibular end organs.\",\n      \"method\": \"Transcytosis assay in HEI-OC1 cell monolayer; siRNA knockdown of CD23; IL-4 stimulation; measurement of IgE transcytosis by ELISA\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with functional transcytosis assay in inner ear cell line; confirmed in primary vestibular tissue; single lab\",\n      \"pmids\": [\"35046106\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD23 (FCER2/FcεRII) is a type II transmembrane C-type lectin that functions as the low-affinity IgE receptor: its lectin head domain (with a structurally mapped IgE-binding site also in the stalk region) binds IgE and CD21 simultaneously without requiring calcium; it is cleaved from the cell surface predominantly in endosomes by ADAM10 (and also by MMP9 downstream of TLR4, or in a P2X7-dependent manner) to yield soluble fragments whose oligomeric state determines whether they stimulate (trimeric) or inhibit (monomeric) IgE synthesis; membrane CD23 on B cells associates with Fyn and signals through Fyn/Akt to regulate BCR clustering and B cell activation via actin remodeling; CD23a on epithelial cells mediates bidirectional IgE and IgE-allergen complex transcytosis, a process critical for initiating airway and intestinal allergic inflammation; in macrophages and glial cells, CD23 ligation triggers iNOS-dependent NO production and TNF-α secretion; CD23a gene transcription is controlled by Notch2/CBF1, STAT6/STAT3/STAT5, and NF-κB, and is repressed by JNK1 via NFATc1; and IgE itself stabilizes surface CD23 expression through a positive feedback loop.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD23 (FCER2/FcεRII) is a type II transmembrane C-type lectin that serves as the low-affinity IgE receptor and a central regulatory hub of IgE homeostasis and allergic inflammation [#1, #2]. Its lectin-like head domain binds IgE-Fc — with two heads engaging asymmetrically at affinities differing by over an order of magnitude — and an additional IgE-binding site resides in the stalk region; binding occurs independently of calcium despite the C-type lectin fold, and non-glycosylated monomeric CD23 binds IgE more avidly [#2, #3, #1]. CD23 simultaneously binds the complement receptor CD21 (via CD21 SCR1-2 and SCR5-8), and this CD23-CD21 axis modulates IL-4-induced IgE synthesis [#0, #31]. Surface CD23 is shed by the metalloproteinase ADAM10, which engages the CD23 stalk and cleaves it predominantly within acidified endosomes after internalization, also routing full-length CD23 into exosomes [#4, #5]; the oligomeric state of the resulting soluble fragments dictates function, with oligomeric/trimeric sCD23 stimulating and monomeric sCD23 inhibiting IgE synthesis [#14, #15]. Shedding is regulated by alternative inputs including TLR4/MMP9 and P2X7-dependent ADAM10 activation, while the R62W polymorphism renders CD23 resistant to proteolysis [#16, #17, #20]. As a signaling receptor, membrane CD23 associates with the Src-family kinase Fyn and signals through Fyn/Akt in B cells, where it negatively regulates BCR clustering through actin-dependent mechanisms [#7, #25, #24]. The CD23a isoform, through an internalization/basolateral-targeting signal in its cytoplasmic exon, mediates bidirectional transcytosis of IgE and IgE-allergen complexes across epithelial barriers — a process driving airway and intestinal allergic inflammation and operative in additional epithelia such as inner ear hair cells [#11, #9, #8, #12, #32, #34]. In macrophages and glial cells, CD23 ligation triggers iNOS-dependent nitric oxide production and TNF-α secretion contributing to antimicrobial and innate immunity [#28, #29, #26]. CD23a transcription is controlled by Notch2/CBF1 (downstream of PKC-delta), STAT6/STAT3/STAT5, and NF-κB, and is repressed by JNK1 via NFATc1, while IgE itself stabilizes surface CD23 in a positive feedback loop [#21, #22, #23, #26, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established that CD23 is not merely a passive IgE-binding protein but a signaling receptor, by showing it physically couples to a Src-family kinase and can transmit an activation signal.\",\n      \"evidence\": \"Co-immunoprecipitation of CD23 with p59fyn and IL-2R induction in CD23-transfected YT and EBV-transformed B cells\",\n      \"pmids\": [\"1717997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors beyond Fyn not defined here\", \"Signal dependence on ligand engagement not dissected\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Defined CD23 as a ligand for CD21, providing a molecular basis for CD23 regulation of IgE production beyond IgE binding alone.\",\n      \"evidence\": \"Recombinant CD23 liposome binding to CD21-transfected cells with antibody blockade and IgE induction assay (Nature)\",\n      \"pmids\": [\"1386409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the interaction not resolved\", \"Relative contributions of soluble vs membrane CD23 unclear\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Mapped the CD21 epitopes and glycan determinants required for CD23 binding, linking the interaction to isotype-selective IgE regulation.\",\n      \"evidence\": \"CD21 epitope mapping with blocking antibodies and glycosylation mutagenesis; in vitro and rat IgE inhibition assays\",\n      \"pmids\": [\"7542093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-group data\", \"In vivo significance in human allergic disease not established\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Characterized the CD23 sheddase activity biochemically as a membrane metalloprotease, setting up later identification of the responsible enzyme.\",\n      \"evidence\": \"Purified CD23 cleavage assay with class-selective protease inhibitors and gel-filtration of plasma membranes\",\n      \"pmids\": [\"9677315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzyme identity not established\", \"Cleavage compartment not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the transcriptional inputs (STAT6, redundant STAT3/STAT5, NF-κB) controlling CD23a expression, explaining IL-4/CD40 inducibility.\",\n      \"evidence\": \"EMSA/supershift plus STAT6-/-, p50-/-, and C/EBPβ-/- mouse analysis of CD23 induction\",\n      \"pmids\": [\"9796920\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative quantitative contribution of each factor unresolved\", \"Promoter occupancy in human cells not tested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Established a positive feedback loop in which IgE stabilizes surface CD23, explaining amplification of CD23 in allergic states.\",\n      \"evidence\": \"IgE-/- mice with reduced CD23 rescued by in vivo IgE infusion\",\n      \"pmids\": [\"9786437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of stabilization not defined\", \"Whether shedding rate is altered not addressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Extended CD23 signaling beyond B cells by showing ligation on glial cells drives an iNOS/NO→TNF-α inflammatory cascade.\",\n      \"evidence\": \"Cytokine-induced CD23 expression and antibody ligation of glial cells with iNOS/NO and TNF-α readouts\",\n      \"pmids\": [\"10212304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proximal signaling intermediates not mapped\", \"In vivo relevance to neuroinflammation correlative\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that epithelial CD23 mediates IgE-dependent transepithelial antigen transport in vivo, linking CD23 to mucosal allergic hypersensitivity.\",\n      \"evidence\": \"Rat sensitization model with immunogold co-localization of CD23/antigen in endosomes and luminal anti-CD23 blockade (JCI)\",\n      \"pmids\": [\"11018076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform responsible not identified here\", \"Directionality of transport not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified CD23-HLA-DR co-recycling, suggesting CD23 participates in IgE-targeted antigen presentation.\",\n      \"evidence\": \"Surface labeling and pulse-chase trafficking of CD23/HLA-DR in RPMI 8866 B cells by confocal microscopy\",\n      \"pmids\": [\"11454061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional antigen presentation not directly demonstrated\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Placed CD23a as a direct transcriptional target of Notch2/CBF1 signaling, identifying a developmental regulatory input.\",\n      \"evidence\": \"EMSA/supershift of Notch2 in promoter complex C1 plus activated Notch2 transfection inducing CD23a in REH cells (Blood)\",\n      \"pmids\": [\"11986231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay with STAT/NF-κB inputs not integrated\", \"Endogenous Notch ligand context not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed enterocyte CD23 splice forms have distinct endocytic behaviors, establishing isoform-specific IgE handling.\",\n      \"evidence\": \"RT-PCR isoform identification and isoform-specific endocytosis assays with CD23-/- mouse jejunal challenge\",\n      \"pmids\": [\"12637252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of bΔ5 constitutive uptake unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapped the cytoplasmic determinants of CD23 trafficking, showing CD23a's intracellular exon drives clathrin-dependent internalization and basolateral targeting.\",\n      \"evidence\": \"Splice-form comparison, internalization assays, and basolateral targeting in polarized MDCK cells\",\n      \"pmids\": [\"15843555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adaptor proteins recognizing the signal not identified\", \"Link to transcytosis machinery not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Provided the atomic structure of the CD23 lectin head and mapped its trimerization, IgE, and CD21 binding surfaces, showing calcium-independent, simultaneous ligand engagement.\",\n      \"evidence\": \"Solution NMR with chemical shift perturbation mapping (JEM)\",\n      \"pmids\": [\"16172256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length multimeric architecture not resolved\", \"Stalk contribution not captured\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified CD23a as the specific isoform mediating bidirectional epithelial IgE and IgE-antigen transcytosis with mast cell-activating consequences.\",\n      \"evidence\": \"Retroviral CD23a/b expression in polarized T84 cells with transcytosis and basophil degranulation assays (Gastroenterology)\",\n      \"pmids\": [\"16831589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo isoform requirement in human gut not directly shown\", \"Sorting determinants linking to transcytosis incompletely defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified ADAM10 as the physiological CD23 sheddase, resolving the long-standing metalloprotease question.\",\n      \"evidence\": \"Peptide cleavage assays, ADAM10 inhibitors, dominant-negative ADAM10, and siRNA in human B cells (JBC)\",\n      \"pmids\": [\"17389606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subcellular site of cleavage not yet established here\", \"Regulation of ADAM10 activity not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that the oligomeric state of soluble CD23 determines whether it stimulates or inhibits IgE synthesis, reconciling paradoxical reports.\",\n      \"evidence\": \"Defined monomeric vs oligomeric recombinant sCD23 fragments in tonsil B cell IgE synthesis assays\",\n      \"pmids\": [\"17576766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor distinguishing the two states not defined\", \"In vivo balance of fragments unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that destabilizing membrane CD23 enhances shedding and IgE production via an IL-4-dependent, CD21-independent route, defining trimeric surface CD23 as an IgE-inhibitory signal.\",\n      \"evidence\": \"In vivo anti-CD23 stalk antibody in IL-4Rα-/- and CD21/35-/- mice with serum sCD23/IgE readouts\",\n      \"pmids\": [\"17324389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular signal from intact trimer not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the R62W polymorphism as a cleavage-resistant CD23 variant, linking genotype to altered sCD23 release.\",\n      \"evidence\": \"Site-directed mutagenesis and multi-protease cleavage assays in Cos-7 with glycosylation analysis\",\n      \"pmids\": [\"17301828\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Clinical/allergic phenotype consequences not established here\", \"Effect on ADAM10 cleavage specifically not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected innate TLR4 signaling to CD23 shedding through MMP9, revealing an alternative sheddase pathway and a trans-acting B cell mechanism.\",\n      \"evidence\": \"LPS stimulation and MMP9-/- mouse analysis of CD23 transcription and shedding\",\n      \"pmids\": [\"19635918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of MMP9 vs ADAM10 in vivo unclear\", \"T1 B cell trans-cleavage model needs confirmation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked PKC-delta to NOTCH2-driven CD23 expression in CLL, identifying an upstream regulator of constitutive CD23.\",\n      \"evidence\": \"PKC-delta siRNA and rottlerin with EMSA of NOTCH2 complexes in CLL cells\",\n      \"pmids\": [\"19995395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PKC-delta sustains NOTCH2 unclear\", \"Restricted to malignant cells\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated CD23 mediates macrophage antimicrobial activity against M. avium via iNOS-dependent NO and TNF-α, with IL-10 as a negative regulator.\",\n      \"evidence\": \"CD23 cross-linking on infected human macrophages with iNOS inhibition and TNF-α neutralization\",\n      \"pmids\": [\"19805542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proximal CD23 signaling in macrophages not mapped\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Localized ADAM10-mediated CD23 cleavage to acidified endosomes and identified pH-dependent accessibility plus exosomal sorting of full-length CD23.\",\n      \"evidence\": \"Endosomal neutralization, SPR at varying pH, and exosome isolation (JBC)\",\n      \"pmids\": [\"20876574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for internalization-coupled cleavage not defined\", \"Fate/function of CD23+ exosomes only partly characterized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed CD23 signaling is cell-type specific, activating Fyn and Akt in B cells but not in monocytic lines.\",\n      \"evidence\": \"CD23 ligation with Fyn/Akt kinase assays in primary B cells vs U937/THP-1\",\n      \"pmids\": [\"20805040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis for monocytic non-responsiveness unclear\", \"Functional output of Fyn/Akt not linked to phenotype here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended epithelial CD23 transcytosis to the airway and showed IL-4 enhances it, linking CD23 to airway allergic responses.\",\n      \"evidence\": \"Bidirectional transcytosis across polarized Calu-3 and primary AEC monolayers with anti-CD23 blockade and mast cell degranulation readout\",\n      \"pmids\": [\"21307287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo airway requirement addressed in separate study\", \"Isoform usage in airway not dissected here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated in vivo that CD23 on radioresistant epithelial cells is required for allergen transcytosis and airway disease, establishing structural-cell CD23 as a therapeutic target.\",\n      \"evidence\": \"CD23 KO/WT bone marrow chimeras, CD23 KO challenge, and inhaled blocking antibody with airway hyperreactivity/eosinophilia readouts (Mucosal Immunology)\",\n      \"pmids\": [\"25783969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direction of physiological transport in vivo not fully resolved\", \"Contribution of hematopoietic CD23 not isolated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected ADAM10-generated trimeric sCD23 to positive regulation of IgE synthesis post-class-switch, integrating shedding with IgE output and CD21/IgE capping.\",\n      \"evidence\": \"ADAM10 inhibitor, CD23 siRNA, and recombinant trimeric sCD23 in stimulated tonsil B cells with capping assay\",\n      \"pmids\": [\"22393152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with inhibitory monomeric sCD23 at the cell level incomplete\", \"Signaling through mIgE/CD21 cap not detailed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified CD23 as a high-affinity receptor for the secreted cytokine AIMP1/p43 on monocytes, expanding its ligand repertoire and TNF-α-inducing function.\",\n      \"evidence\": \"Receptor screen, co-IP, CD23 siRNA, and ERK1/2 phosphorylation/TNF-α assays\",\n      \"pmids\": [\"22767513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of AIMP1-CD23 binding unknown\", \"Physiological context of this axis unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed β2-adrenergic signaling upregulates ADAM10 and CD23 and routes them to exosomes that enhance IgE production, linking neuroendocrine input to CD23 biology.\",\n      \"evidence\": \"β2AR agonist treatment, exosome characterization/transfer, β2AR-deficient B cells, and PKA/p38 inhibitors with IgE ELISPOT\",\n      \"pmids\": [\"24140643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Exosomal CD23 mechanism of action on recipient cells unclear\", \"In vivo relevance not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a P2X7/ATP-driven, ADAM10-dependent route of rapid CD23 shedding, adding a danger-signal input to CD23 release.\",\n      \"evidence\": \"Flow/ELISA shedding with P2X7 KO mice, P2X7 antagonist, and ADAM10 inhibitor\",\n      \"pmids\": [\"25155463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How P2X7 activates ADAM10 mechanistically unknown\", \"Functional consequence of this shedding mode not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the stalk region as a second IgE-binding site and showed non-glycosylated monomeric CD23 binds IgE best and that omalizumab blocks CD23-IgE binding.\",\n      \"evidence\": \"CD23 domain variants, binding/inhibition assays, negative-stain EM, and peptide-scanning antibodies (JACI)\",\n      \"pmids\": [\"27343203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of stalk binding vs head binding unclear\", \"Glycosylation regulation in vivo not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed membrane CD23 as a negative regulator of BCR signaling acting through actin-dependent control of BCR clustering.\",\n      \"evidence\": \"CD23 KO B cells with spreading/clustering, phospho-Btk/tyrosine, and F-actin/phospho-WASp imaging\",\n      \"pmids\": [\"27181049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between CD23-Fyn signaling and actin machinery not mechanistically closed\", \"Ligand requirement for this regulation unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the crystal structure of a CD23/IgE-Fc complex, revealing asymmetric two-head engagement of IgE-Fc with distinct affinities.\",\n      \"evidence\": \"X-ray crystallography and ITC (Scientific Reports)\",\n      \"pmids\": [\"28361904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full multimeric IgE-CD23 lattice not captured\", \"Stalk-site contribution not included in crystal\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined CD23 as a downstream effector of innate antifungal immunity, repressed by JNK1 via NFATc1 and acting through NO production.\",\n      \"evidence\": \"JNK1 KO mice, C. albicans infection, CD23 blockade, NFATc1 promoter assays, and NO readouts (Nature Medicine)\",\n      \"pmids\": [\"28112734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell type executing antifungal CD23 function not fully resolved\", \"Receptor for CD23 ligation in this context unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a division of labor between FcεRI and CD23, with CD23 preferentially clearing non-inflammatory IgE-immune complexes while free IgE drives inflammation via FcεRI.\",\n      \"evidence\": \"In vitro binding/activation and in vivo IgE pharmacokinetics/anaphylaxis with differential receptor targeting\",\n      \"pmids\": [\"31437490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue site of CD23-mediated clearance not pinpointed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Generalized CD23 transcytosis to inner ear hair cells, broadening the tissue scope of CD23-mediated IgE transport.\",\n      \"evidence\": \"siRNA knockdown and IL-4-modulated IgE transcytosis in HEI-OC1 monolayers and primary vestibular tissue\",\n      \"pmids\": [\"35046106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological role in inner ear allergy/disease unclear\", \"Isoform usage not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the competing stimulatory (trimeric/membrane) and inhibitory (monomeric) CD23 states are balanced at the level of an individual B cell, and which receptors transduce each, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined receptor distinguishing monomeric vs oligomeric sCD23 signaling\", \"Integration of CD23-Fyn/Akt signaling with BCR and actin machinery incomplete\", \"In vivo balance of shedding pathways (ADAM10/MMP9/P2X7) across tissues not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [9, 8, 32, 34]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [7, 25, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 5, 7, 24]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5, 11, 13]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [5, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 15, 26, 28]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [9, 8, 32, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 24, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IGHE\", \"CR2\", \"ADAM10\", \"FYN\", \"HLA-DRA\", \"AIMP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":9,"faith_total":9,"faith_pct":100.0}}