{"gene":"CD22","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1993,"finding":"CD22 is a sialic acid-binding lectin that recognizes α2,6-linked sialic acids on ligands; a soluble CD22-Ig fusion protein binds to sialoglycoproteins in an α2,6-linkage-dependent manner, and truncation of sialic acid side chains by periodate oxidation abolishes binding. CD45 was identified as the first CD22 ligand.","method":"Soluble CD22-Ig fusion protein binding assay, COS cell transfection with α2,6-sialyltransferase, periodate oxidation experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro binding reconstitution with mutagenesis-equivalent (enzyme treatment) and transfection controls, replicated across multiple experimental approaches in one rigorous study","pmids":["8463234"],"is_preprint":false},{"year":1990,"finding":"CD22 mediates adhesion of monocytes and erythrocytes to B cells; CD22 shares structural homology with myelin-associated glycoprotein (MAG), placing it in the Ig superfamily as an adhesion molecule.","method":"Cell adhesion assay with CD22-transfected cells, structural analysis","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional adhesion assay with transfected cells, single lab, two complementary approaches (adhesion assay + structural homology)","pmids":["1691828"],"is_preprint":false},{"year":1993,"finding":"CD22 associates with the surface IgM-B cell antigen receptor (BCR) complex; CD22 is co-immunoprecipitated with the sIgM-BCR complex components (Igα/mb-1, Igβ/B29) maintained in digitonin, and CD22 undergoes rapid and striking tyrosine phosphorylation after sIgM crosslinking. CD22 contains the ARHI motif present in antigen receptor molecules.","method":"Co-immunoprecipitation in digitonin, in vitro kinase assay, immunoblot with anti-CD22 antiserum","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — reciprocal co-IP with multiple BCR components, in vitro kinase assay, immunoblot validation, multiple orthogonal methods in one study","pmids":["8475064"],"is_preprint":false},{"year":1993,"finding":"CD22 associates with the B cell antigen receptor (BCR) across multiple isotypes (IgM, IgD, IgG) in both Burkitt lymphoma lines and tonsil cells; the association is specific and stable but of low stoichiometry (0.2–2% of membrane immunoglobulin). CD22 becomes tyrosine phosphorylated within one minute after antigen-receptor cross-linking.","method":"In vitro kinase assay, Western blotting, co-immunoprecipitation with multiple BCR isotypes and cell types","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus co-IP across multiple isotypes and cell types, single lab but multiple orthogonal methods","pmids":["7684686"],"is_preprint":false},{"year":1995,"finding":"Tyrosine-phosphorylated CD22 binds and activates SHP (SHP-1), a protein tyrosine phosphatase that negatively regulates BCR signaling. Ligation of CD22 to prevent its co-aggregation with mIg lowers the threshold for mIg-mediated B cell activation by a factor of 100, establishing CD22 as a molecular switch for SHP.","method":"Co-immunoprecipitation of phospho-CD22 with SHP, B cell activation threshold assay, CD22 ligation experiments","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical demonstration of phospho-CD22/SHP-1 interaction combined with functional activation threshold assay, highly cited and foundational","pmids":["7618087"],"is_preprint":false},{"year":1996,"finding":"BCR cross-linking causes PTP-1C (SHP-1) to translocate from cytosol to particulate fraction and associate with tyrosyl-phosphorylated CD22 (140–150 kDa). The association is mediated by the N-terminal SH2 domain of PTP-1C. CD22/PTP-1C/Syk/PLCγ1 complexes can be isolated from stimulated B cells. Binding of PLCγ1 and Syk to CD22 is mediated by the N-terminal SH2 domain of PLCγ1 and C-terminal SH2 domain of Syk respectively. In COS cells, wild-type PTP-1C dephosphorylates CD22, whereas null-mutant PTP-1C (PTP-1CM) does not.","method":"Co-immunoprecipitation, Western blotting, COS cell transfection with wild-type and catalytically inactive PTP-1C, SH2 domain binding analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-IP of multi-protein complex, domain mapping with SH2 constructs, mutagenesis (null mutant PTP-1C) in COS cells, multiple orthogonal methods","pmids":["8627166"],"is_preprint":false},{"year":1997,"finding":"CD22-deficient mice generated by targeted gene inactivation show normal B cell development but increased Ca2+ influx and increased apoptosis after BCR crosslinking in vitro, increased proliferative response to LPS, shorter B cell lifespan in vivo, impaired T-cell-independent immune responses, and absence of recirculating B cells from bone marrow. This establishes CD22 as a negative regulator of BCR signaling in vivo.","method":"Targeted gene inactivation (knockout mice), flow cytometry, Ca2+ flux assay, proliferation assays, immune response assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with multiple orthogonal phenotypic readouts (Ca2+ flux, apoptosis, proliferation, immune response), replicated across multiple assays","pmids":["9016707"],"is_preprint":false},{"year":1995,"finding":"CD22 is constitutively endocytosed by unstimulated B cell lines and subsequently degraded in an acidic intracellular compartment (presumably lysosomes) without detectable recycling to the cell surface. Ligation of CD22 with anti-CD22 mAbs markedly increases internalization but does not affect degradation rate. Internalization is not affected by phorbol ester or ligation of CD19 or sIgM.","method":"Flow cytometry, neuraminidase protection and neuraminidase shift assays, stimulation with phorbol esters and mAbs","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple direct biochemical assays of internalization and degradation kinetics under multiple conditions, rigorous controls","pmids":["7722303"],"is_preprint":false},{"year":1997,"finding":"CD22 negatively regulates Vav tyrosine phosphorylation downstream of BCR crosslinking; in CD22-deficient B cells, Vav phosphorylation is uniquely augmented after BCR or CD19 crosslinking. Simultaneous crosslinking of CD19 with the BCR substantially decreases Vav phosphorylation when CD22 is expressed, revealing reciprocal regulation of BCR signaling thresholds by CD19 (positive) and CD22 (negative) via Vav.","method":"Immunoprecipitation and Western blot for phospho-Vav in CD22-deficient and CD19-deficient mice B cells, BCR and CD19 crosslinking","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — use of multiple genetic knockout mouse models (CD22-/- and CD19-/-) with direct biochemical readout (Vav phosphorylation), multiple conditions tested","pmids":["9371816"],"is_preprint":false},{"year":2001,"finding":"CD22 cytoplasmic domain contains two functionally distinct domains: (1) two C-terminal ITIM tyrosines (Tyr-843 and Tyr-863) required for efficient SHP-1 recruitment after BCR ligation, and (2) a separate tyrosine (Tyr-828) required for inducible Grb2 recruitment. Both Lyn and Syk are individually required for maximal CD22 tyrosine phosphorylation; together they account for all constitutive and induced phosphorylation.","method":"Mutagenesis of CD22 cytoplasmic tyrosines, co-immunoprecipitation of SHP-1 and Grb2, use of Src kinase inhibitor PP1, kinase-deficient cell experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis of multiple tyrosine residues with co-IP readout, pharmacological inhibitor validation, multiple orthogonal methods","pmids":["11551923"],"is_preprint":false},{"year":2004,"finding":"CD22 attenuates B cell Ca2+ signaling by potentiating plasma membrane calcium-ATPase (PMCA) activity. PMCA co-immunoprecipitates with CD22 in an activation-dependent manner. CD22 cytoplasmic tyrosine residues are required for PMCA association and enhanced Ca2+ efflux. CD22 regulation of Ca2+ efflux and the Ca2+ response also requires SHP-1. Disruption of PMCA4a/4b by homologous recombination attenuates CD22-mediated Ca2+ effects.","method":"Co-immunoprecipitation of PMCA with CD22, PMCA inhibition, homologous recombination knockout of PMCA4, CD22 cytoplasmic tyrosine mutants, Ca2+ flux assay","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution-level biochemistry (co-IP), mutagenesis of CD22 tyrosines, genetic knockout of PMCA, multiple complementary approaches in one study","pmids":["15133509"],"is_preprint":false},{"year":2005,"finding":"Mice deficient in both CD22 and the ST6Gal-I enzyme that synthesizes the CD22 α2,6-sialic acid ligand (Cd22-/- St6gal1-/- double knockouts) show restored BCR signaling compared to St6gal1-/- single knockouts, demonstrating that the suppressed BCR signaling in ligand-deficient B cells is mediated through CD22. B cells lacking ST6Gal-I show a net redistribution of BCR to clathrin-rich microdomains containing most CD22.","method":"Double knockout mouse generation, Ca2+ flux assay, confocal microscopy/membrane microdomain fractionation","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double knockout mouse, Ca2+ flux readout, subcellular localization by confocal microscopy, clean mechanistic placement","pmids":["16369536"],"is_preprint":false},{"year":2006,"finding":"ST6Gal-I deficiency (loss of CD22 α2,6-sialic acid ligands) induces constitutive IgM receptor endocytosis coincident with increased colocalization of BCR with CD22 and constitutive SHP-1 recruitment to CD22 independent of Lyn kinase. Co-deficiency with CD22 restores IgM receptor half-life at the cell surface and reverses membrane trafficking and signaling alterations, establishing a CD22-dependent mechanism.","method":"ST6Gal-I and CD22 double knockout mice, antigen receptor half-life and endocytosis assays, SHP-1 co-immunoprecipitation, Lyn kinase inhibitor studies","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic double knockout epistasis, multiple biochemical and cell biological readouts, direct causal link established","pmids":["16782884"],"is_preprint":false},{"year":1992,"finding":"CD22 directly interacts with multiple isoforms of CD45 including CD45RO on T cells; cross-linking of CD3 and CD22 ligands together (anti-CD3 + soluble CD22) blocks anti-CD3-induced intracellular Ca2+ increase and inhibits tyrosine phosphorylation of PLCγ1 in T cells, indicating CD22 can modulate T cell signaling via CD45 engagement.","method":"Direct binding assay of CD22 with CD45 isoforms, Ca2+ flux assay in T cells, tyrosine phosphorylation Western blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding plus functional Ca2+ and phosphorylation assays, single lab, two complementary methods","pmids":["1438211"],"is_preprint":false},{"year":1995,"finding":"CD22-mediated engagement of CD45 on T cells can modulate early T cell signals in antigen receptor/CD3-mediated stimulation. Addition of sialic acid by β-galactoside α-2,6-sialyltransferase to CD22 abrogates CD22-CD45 interactions, establishing that CD22-CD45 binding is sialic acid-dependent.","method":"Soluble CD22-Ig fusion protein binding to CD45-chimeric T cells, Ca2+ assay, enzymatic sialylation of CD22","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — soluble fusion protein binding assay with enzymatic modification, functional T cell signaling readout, single lab","pmids":["7537381"],"is_preprint":false},{"year":1999,"finding":"Cross-linking of CD22 on primary B cells activates stress-activated protein kinases (SAPKs/JNKs) but not ERK-2, distinct from BCR ligation which activates ERK-2 without significant SAPK activation. CD22 ligation leads to increased nuclear AP-1 and c-jun levels and downregulation of anti-apoptotic Bcl-xL and Mcl-1, providing a mechanism for CD22-induced apoptosis in Burkitt lymphoma cells.","method":"SAPK/JNK and ERK kinase activity assays, nuclear extract AP-1 EMSA, Western blot for Bcl-2 family members, primary B cell and B cell line experiments","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (kinase assays, EMSA, Western blot) in primary cells and lines, single lab","pmids":["10438726"],"is_preprint":false},{"year":2003,"finding":"CD22 interacts with AP50, the medium chain subunit of the clathrin adaptor AP-2 complex, via tyrosine-based internalization motifs in its cytoplasmic domain. Tyr-843 is the primary binding site for AP50 with Tyr-863 sufficient for mAb-mediated internalization. This interaction mediates clathrin-dependent endocytosis of CD22.","method":"Yeast two-hybrid analysis, co-precipitation of α-adaptin with CD22 mutants, transfectant Jurkat cell internalization assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — yeast two-hybrid identification confirmed by co-precipitation and functional internalization assays with specific tyrosine mutants, multiple orthogonal methods","pmids":["12646615"],"is_preprint":false},{"year":2013,"finding":"CD22 cis-ligand binding domain is crucial for regulating BCR signaling by controlling CD22 association with the BCR. Mice with mutated CD22 ligand-binding domain show strongly reduced Ca2+ signaling. Conversely, mice with mutated CD22 ITIM motifs have increased B cell Ca2+ responses, increased B cell turnover, and impaired B cell survival. Thus the ligand-binding and signaling domains of CD22 reciprocally regulate BCR Ca2+ signaling.","method":"Knockin mice with mutated CD22 ligand-binding domain or ITIM motifs, Ca2+ flux assay, B cell survival assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — dual knockin mouse genetic approach with domain-specific mutations, Ca2+ flux readout, multiple orthogonal assays in one study","pmids":["23836650"],"is_preprint":false},{"year":2009,"finding":"Sialylated multivalent antigens engage CD22 in trans and inhibit BCR signaling and B cell activation. Exposure of B cells to sialylated antigens inhibits key steps in BCR signaling, revealing that trans interactions (CD22 bound by antigen-displayed sialic acid ligands) are sufficient to suppress B cell activation.","method":"Sialylated multivalent antigen synthesis, BCR signaling assays (Ca2+ flux, phosphorylation), B cell activation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay with defined synthetic ligands, Ca2+ and signaling readouts, single lab","pmids":["19202057"],"is_preprint":false},{"year":2015,"finding":"CD22 is organized into highly mobile nanodomains in naïve B cells, as revealed by super-resolution microscopy and single-particle tracking. CD22 lateral diffusion is perturbed in the absence of CD45 or when the CD22 lectin domain is mutated. Brownian dynamic simulations and ex vivo experiments suggest CD22's inhibitory function is enabled by its fast diffusion providing 'global BCR surveillance' at the plasma membrane. The cortical cytoskeleton cooperates with CD22 to restrain BCR signaling.","method":"Super-resolution microscopy (STORM/PALM), single-particle tracking, Brownian dynamic simulations, CD22 lectin-domain mutant B cells, CD45-deficient B cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — super-resolution imaging plus single-particle tracking plus genetic mutants plus computational simulation, multiple orthogonal methods","pmids":["26671981"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of human CD22 ectodomain solved at 2.1 Å resolution, revealing that specificity for α2-6 sialic acid ligands is dictated by a pre-formed β-hairpin unique among Siglec family members. The CD22 ectodomain adopts an extended conformation facilitating CD22 nanocluster formation on B cells and trans ligand binding. The structure of CD22 with therapeutic antibody epratuzumab was determined at 3.1 Å, delineating the epratuzumab binding site and revealing a critical role for N-linked glycosylation in antibody engagement.","method":"X-ray crystallography (2.1 Å and 3.1 Å structures), structural analysis of ligand-binding β-hairpin, glycosylation site mapping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at high resolution with functional validation of ligand specificity determinant and antibody epitope, single rigorous study with multiple structural datasets","pmids":["28970495"],"is_preprint":false},{"year":2019,"finding":"CD22 is upregulated on aged microglia and mediates the anti-phagocytic effect of α2,6-linked sialic acid; CD22 was identified as a negative regulator of microglial phagocytosis by CRISPR-Cas9 knockout screens. Inhibition of CD22 promotes clearance of myelin debris, amyloid-β oligomers, and α-synuclein fibrils in vivo. Long-term CNS delivery of a CD22-blocking antibody reprograms microglia toward a homeostatic transcriptional state and improves cognitive function in aged mice.","method":"CRISPR-Cas9 knockout screen, RNA sequencing, in vivo antibody blockade, phagocytosis assays, cognitive behavioral testing","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen identification confirmed by in vivo antibody blockade with multiple phagocytosis substrates and cognitive readouts, multiple orthogonal methods","pmids":["30944478"],"is_preprint":false},{"year":1999,"finding":"CD45 regulates tyrosine phosphorylation of CD22 and its association with SHP-1; cross-linking of CD45 induces physical sequestration from CD22, leading to increased CD22 tyrosine phosphorylation and SHP-1 recruitment. In CD45-deficient B cells, CD22 shows increased basal and inducible tyrosine phosphorylation and enhanced SHP-1 recruitment. Expression of catalytically inactive SHP-1 in CD45-deficient cells restored intracellular Ca2+ mobilization.","method":"CD45-deficient B cell line, CD45 cross-linking and capping, co-immunoprecipitation of SHP-1 with CD22, expression of catalytically inactive SHP-1, Ca2+ flux assay","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (CD45-deficient cells) plus dominant-negative SHP-1 approach, co-IP, and functional Ca2+ readout, multiple orthogonal methods","pmids":["10228003"],"is_preprint":false},{"year":2006,"finding":"CD22 phosphorylation upon BCR ligation is not uniform: Y762 undergoes the most rapid phosphorylation, and ultimately all four tyrosine motifs (Y762, Y807, Y822, Y842) are phosphorylated at ~35% of CD22 molecules. Anti-CD40 stimulation specifically upregulates BCR-induced phosphorylation of ITIM tyrosines Y762 and Y842, but not Y807 (Grb2 site), revealing qualitative differences in CD22 phosphorylation patterns depending on stimulus.","method":"Phospho-specific polyclonal antibodies to four CD22 tyrosine motifs, flow cytometry, Western blot, anti-IgM and anti-CD40 stimulation","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific phospho-antibodies for four residues, multiple stimulation conditions, single lab","pmids":["16393971"],"is_preprint":false},{"year":2010,"finding":"CD22-deficient mice show hyperactivation to TLR3, TLR4, and TLR9 ligands, and this hyperactivation is associated with impaired induction of SOCS1 and SOCS3 (suppressors of cytokine signaling). Antibody-mediated CD22 sequestration on wild-type B cells augments TLR-induced proliferation. Ectopic CD22 expression in CD22-deficient B cell lines blunts TLR responses. CD22 expression in a TLR4 reporter cell line inhibits LPS-induced NF-κB transcription. This establishes CD22 as a negative regulator of TLR signaling in addition to BCR signaling.","method":"CD22 knockout mice, TLR ligand stimulation proliferation assays, SOCS1/3 expression analysis, ectopic CD22 expression in knockout B cell line, TLR4-NF-κB reporter assay","journal":"Journal of innate immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus rescue by ectopic expression plus reporter assay, multiple TLR ligands tested, multiple cell systems","pmids":["21178327"],"is_preprint":false},{"year":2011,"finding":"CD22 serves as a receptor for soluble IgM (sIgM); CD22 is efficiently activated in trans by complexes of antigen and sIgM due to the presence of α2,6-sialic acid glycan ligands on sIgM, establishing sIgM as a natural trans ligand for CD22 and implicating a negative feedback loop for B cell activation analogous to FcγRIIB.","method":"Trans activation assay with sIgM-antigen complexes, glycan ligand analysis, Ca2+ signaling readout","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional demonstration of trans activation by sIgM complexes, single lab, mechanistic link to glycan ligands shown","pmids":["21956693"],"is_preprint":false},{"year":2008,"finding":"Immature but not mature dendritic cells (DCs) inhibit BCR-induced B cell proliferation in a contact-dependent manner that requires CD22 but is independent of the ST6Gal-I-generated α2,6-sialic acid CD22 ligand. A second, distinct CD22 ligand is expressed on DCs that is resistant to neuraminidase and sodium metaperiodate, indicating a non-sialylated DC-associated CD22 ligand mediates CD22-dependent DC-B cell inhibitory interaction.","method":"Co-culture of bone marrow-derived DCs with B cells, CD22 knockout and ST6Gal-I knockout mice, neuraminidase and periodate treatment, proliferation assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic knockouts with direct co-culture functional assay, enzyme-resistance controls identify second ligand, single lab","pmids":["18354178"],"is_preprint":false},{"year":2021,"finding":"CD22 associates in a sialic acid-dependent manner with integrin β7 on B cell surfaces, and recruits intracellular Shp1 to β7, restraining β7 endocytosis and enhancing surface α4β7 display. B cells lacking CD22, expressing CD22 with mutated Shp1-binding domains, or mutated carbohydrate-binding domains show reduced surface α4β7 and impaired homing to gut-associated lymphoid tissue (GALT). This establishes a CD22-Shp1-integrin β7 axis controlling B cell trafficking in mucosal immunity.","method":"CD22 knockout mice, CD22 domain-specific mutant knockin mice, co-immunoprecipitation of CD22 with β7 integrin, flow cytometry of surface α4β7, B cell homing assay to GALT, Shp1-conditional knockout","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple knockin/knockout genetic models with domain-specific mutations, co-IP, direct homing assay, multiple orthogonal methods","pmids":["33589816"],"is_preprint":false},{"year":2021,"finding":"Soluble CD22 (sCD22) binds to insulin-like growth factor 2 receptor (IGF2R) on human myeloid cells as identified by unbiased genetic and proteomic screens. sCD22 docks near mannose 6-phosphate-binding domains of IGF2R and disrupts lysosomal protein trafficking. CD22 blocking antibodies ameliorate lysosome dysfunction in human NPC1 mutant iPSC-derived microglia-like cells.","method":"Unbiased genetic screen, proteomic screen, IGF2R targeted truncation, lysosomal trafficking assays in iPSC-derived microglia, CD22 blocking antibody treatment","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased genome-wide screens confirmed by domain truncation experiment and functional lysosomal trafficking assay, multiple orthogonal methods","pmids":["34851695"],"is_preprint":false},{"year":2023,"finding":"Notch1 signaling in regulatory T cells (Tregs) induces CD22 expression, which destabilizes Tregs in an mTORC1-dependent manner and promotes systemic inflammation. Dominant-negative mutations in Notch1 regulators NUMB and NUMBL in MIS-C patients lead to Notch1 upregulation and downstream CD22 induction. This Notch1/CD22 signaling axis disrupts Treg function.","method":"Genetic analysis of patient variants (NUMB/NUMBL mutations), Notch1 signaling perturbation in Tregs, CD22 expression analysis, mTORC1 pathway assays, functional Treg stability assays","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic patient variant analysis combined with Notch1/CD22/mTORC1 pathway mechanistic experiments, single study","pmids":["36282598"],"is_preprint":false},{"year":2007,"finding":"Human B lymphocytes express α2-6-sialylated 6-sulfo-N-acetyllactosamine (6-sulfo-LacNAc) as a preferred endogenous ligand for CD22; NaClO3 inhibition of cellular sulfation and a mAb specific to this determinant almost completely abrogates human B cell binding to CD22, establishing that both α2-6-sialylation and 6-GlcNAc-sulfation are required for optimal CD22 ligand recognition.","method":"Sulfation inhibition (NaClO3), blocking mAb to sulfo-LacNAc determinant, B cell-CD22 binding assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition of sulfation plus specific mAb blocking with direct binding assay, single lab","pmids":["17728258"],"is_preprint":false},{"year":2017,"finding":"Proximity labeling of CD22 cis-ligands on B cell surface reveals that CD22, CD45, and IgM associate with CD22 through α2,6-sialic acid-dependent lectin-glycan interactions in cis; these molecules are absent from CD22 proximity in ST6GalI-/- B cells lacking α2,6 sialic acids, but are already located at relative proximity through non-lectin-glycan interactions.","method":"Biotin-tyramide proximity labeling on living B cells, ST6GalI-/- and Cmah-/- knockout mice, mass spectrometry identification of labeled proteins","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling with genetic controls, direct identification of cis-ligands in situ, single lab","pmids":["29146181"],"is_preprint":false}],"current_model":"CD22 (Siglec-2) is a B cell-restricted inhibitory co-receptor that functions as a sialic acid-binding lectin recognizing α2,6-linked sialic acid ligands; upon BCR crosslinking, CD22 is rapidly tyrosine-phosphorylated by Lyn and Syk kinases, recruits SHP-1 via ITIM motifs to dephosphorylate BCR signaling components and PMCA to enhance Ca2+ efflux, while separately recruiting Grb2 (via Tyr-828) and controlling clathrin-mediated endocytosis via AP-2 adaptor binding; cis sialic acid interactions regulate CD22 nanocluster organization and BCR co-localization, whereas trans ligand engagement strongly inhibits BCR signaling; CD22 also negatively regulates TLR signaling via SOCS1/3 induction, controls integrin β7 display in mucosal B cell homing via a CD22-Shp1-β7 axis, and in microglia/aged brain cells acts as a negative regulator of phagocytosis whose blockade restores homeostatic function partly through the sCD22-IGF2R lysosomal trafficking pathway."},"narrative":{"mechanistic_narrative":"CD22 (Siglec-2) is a B cell-restricted inhibitory co-receptor that sets the threshold for B cell antigen receptor (BCR) signaling by recognizing α2,6-linked sialic acid glycans through its N-terminal lectin domain [PMID:8463234, PMID:28970495]. It associates with the BCR complex across multiple immunoglobulin isotypes and becomes rapidly tyrosine-phosphorylated by Lyn and Syk within a minute of receptor crosslinking [PMID:8475064, PMID:7684686, PMID:11551923]. Phosphorylation of its cytoplasmic ITIM tyrosines recruits and activates the phosphatase SHP-1, which dephosphorylates BCR signaling components and raises the activation threshold, while a separate tyrosine (Tyr-828/Y807) recruits Grb2 [PMID:7618087, PMID:8627166, PMID:11551923]. Through this SHP-1 axis CD22 attenuates downstream Vav phosphorylation and dampens calcium signaling, in part by activation-dependent association with and potentiation of the plasma membrane calcium-ATPase (PMCA) to enhance Ca2+ efflux [PMID:9371816, PMID:15133509]. CD22-deficient mice exhibit heightened Ca2+ flux, increased BCR-induced apoptosis, shortened B cell lifespan, and impaired T-independent responses, establishing its role as a negative regulator of B cell activation in vivo [PMID:9016707, PMID:23836650]. CD22's ligand-binding and signaling domains act reciprocally: cis engagement by α2,6-sialylated ligands (including CD45, IgM, and the preferred 6-sulfo-LacNAc determinant) organizes CD22 into mobile nanodomains controlling its proximity to the BCR, whereas trans engagement by sialylated multivalent antigens or soluble IgM strongly inhibits BCR signaling [PMID:16369536, PMID:23836650, PMID:19202057, PMID:26671981, PMID:21956693, PMID:17728258, PMID:29146181]. CD22 also directs its own clathrin-mediated endocytosis via tyrosine-based motifs that bind the AP-2 adaptor subunit AP50 [PMID:7722303, PMID:12646615]. Beyond B cells, CD22 negatively regulates TLR signaling through induction of SOCS1/3 [PMID:21178327], controls B cell mucosal homing via a CD22-SHP1-integrin β7 axis [PMID:33589816], and acts as a negative regulator of microglial phagocytosis in the aged brain whose blockade restores homeostatic function, with soluble CD22 engaging IGF2R to disrupt lysosomal trafficking [PMID:30944478, PMID:34851695].","teleology":[{"year":1990,"claim":"Established CD22 as an Ig-superfamily adhesion molecule before its signaling role was known, placing it structurally among MAG-related proteins.","evidence":"Cell adhesion assay with CD22-transfected cells and structural homology analysis","pmids":["1691828"],"confidence":"Medium","gaps":["Did not identify the molecular nature of the adhesion ligand","No link to signaling function"]},{"year":1993,"claim":"Defined the molecular basis of CD22 ligand recognition as a sialic acid-binding lectin specific for α2,6-linked sialic acids, identifying CD45 as the first ligand.","evidence":"Soluble CD22-Ig fusion binding assays, sialyltransferase transfection, and periodate oxidation","pmids":["8463234"],"confidence":"High","gaps":["Did not resolve cis versus trans ligand biology","Endogenous physiological ligands not yet defined"]},{"year":1993,"claim":"Showed CD22 physically associates with the BCR complex and is rapidly tyrosine-phosphorylated on receptor crosslinking, linking it to BCR signaling.","evidence":"Co-immunoprecipitation with Igα/Igβ in digitonin and in vitro kinase assays across multiple BCR isotypes","pmids":["8475064","7684686"],"confidence":"High","gaps":["Low stoichiometry of association left functional consequence unclear","Kinases responsible not yet identified"]},{"year":1995,"claim":"Identified SHP-1 as the effector recruited by phospho-CD22 and demonstrated functionally that CD22 raises the BCR activation threshold ~100-fold, defining it as an inhibitory switch.","evidence":"Co-IP of phospho-CD22 with SHP and B cell activation threshold assays","pmids":["7618087"],"confidence":"High","gaps":["Specific ITIM residues mediating recruitment not yet mapped","Downstream substrates of SHP-1 not delineated"]},{"year":1996,"claim":"Resolved the inhibitory complex architecture, showing SHP-1 binds CD22 via its N-terminal SH2 domain within CD22/SHP-1/Syk/PLCγ1 assemblies and dephosphorylates CD22.","evidence":"Co-IP of multiprotein complex, SH2 domain mapping, and COS-cell reconstitution with catalytically inactive PTP-1C","pmids":["8627166"],"confidence":"High","gaps":["In vivo significance of complex not established at this stage"]},{"year":1995,"claim":"Showed CD22 is constitutively endocytosed and degraded in an acidic compartment, establishing trafficking behavior independent of BCR or CD19 signaling.","evidence":"Flow cytometry and neuraminidase shift/protection assays under multiple stimulation conditions","pmids":["7722303"],"confidence":"High","gaps":["Endocytic machinery not identified","Functional role of constitutive turnover unclear"]},{"year":1997,"claim":"Genetic knockout established CD22 as a bona fide negative regulator of BCR signaling in vivo, with effects on Ca2+ flux, apoptosis, B cell lifespan, and immune responses.","evidence":"CD22-deficient mice with Ca2+ flux, proliferation, and immune response assays","pmids":["9016707"],"confidence":"High","gaps":["Molecular pathway linking CD22 loss to phenotypes not fully resolved"]},{"year":1997,"claim":"Identified Vav as a regulated node and revealed reciprocal CD19 (positive) / CD22 (negative) control of BCR signaling thresholds.","evidence":"Phospho-Vav immunoblotting in CD22- and CD19-deficient mouse B cells under BCR/CD19 crosslinking","pmids":["9371816"],"confidence":"High","gaps":["Mechanism connecting SHP-1 to Vav not directly demonstrated"]},{"year":1999,"claim":"Connected CD22 to apoptotic outcome by showing CD22 ligation activates SAPK/JNK and downregulates Bcl-xL/Mcl-1, distinct from BCR-driven ERK activation.","evidence":"Kinase activity assays, AP-1 EMSA, and Bcl-2 family Western blots in primary and lymphoma B cells","pmids":["10438726"],"confidence":"Medium","gaps":["Single-lab pathway analysis without genetic confirmation","Relevance to physiological CD22 ligation unclear"]},{"year":1999,"claim":"Placed CD45 upstream of CD22 phosphorylation, showing CD45 sequestration enhances CD22 phosphorylation and SHP-1 recruitment to restrain Ca2+ signaling.","evidence":"CD45-deficient B cells, CD45 capping, SHP-1 co-IP, and dominant-negative SHP-1 rescue of Ca2+ flux","pmids":["10228003"],"confidence":"High","gaps":["Whether CD45 acts via lectin-glycan or phosphatase activity not fully separated"]},{"year":2001,"claim":"Mapped distinct cytoplasmic modules — ITIM tyrosines for SHP-1 versus Tyr-828 for Grb2 — and assigned Lyn and Syk as the kinases driving CD22 phosphorylation.","evidence":"Systematic tyrosine mutagenesis, SHP-1/Grb2 co-IP, and PP1 inhibitor in kinase-deficient cells","pmids":["11551923"],"confidence":"High","gaps":["Functional role of Grb2 recruitment to CD22 not resolved"]},{"year":2003,"claim":"Identified AP50/AP-2 binding to CD22 tyrosine-based motifs as the basis for clathrin-mediated endocytosis, explaining the earlier observed constitutive internalization.","evidence":"Yeast two-hybrid, α-adaptin co-precipitation with CD22 mutants, and internalization assays in Jurkat transfectants","pmids":["12646615"],"confidence":"High","gaps":["Interplay between AP-2 endocytic motif (Tyr-843) and ITIM signaling not fully separated"]},{"year":2004,"claim":"Revealed a non-SHP-1 mechanism of Ca2+ control: CD22 associates with and potentiates PMCA in an activation- and tyrosine-dependent manner to enhance Ca2+ efflux.","evidence":"PMCA/CD22 co-IP, CD22 tyrosine mutants, and PMCA4 knockout with Ca2+ flux assays","pmids":["15133509"],"confidence":"High","gaps":["Direct versus SHP-1-bridged nature of CD22-PMCA association not fully resolved"]},{"year":2005,"claim":"Used genetic epistasis to prove that suppressed BCR signaling in ST6Gal-I-deficient B cells is mediated through CD22 and linked ligand loss to BCR redistribution into clathrin-rich microdomains.","evidence":"Cd22-/- St6gal1-/- double knockout mice, Ca2+ flux, and membrane microdomain analysis","pmids":["16369536"],"confidence":"High","gaps":["Mechanism of ligand-controlled CD22-BCR positioning not yet at molecular resolution"]},{"year":2006,"claim":"Showed that loss of α2,6-sialic acid ligands drives constitutive IgM endocytosis and Lyn-independent SHP-1 recruitment to CD22, all reversed by CD22 co-deficiency.","evidence":"ST6Gal-I/CD22 double knockouts, receptor half-life and endocytosis assays, SHP-1 co-IP, Lyn inhibition","pmids":["16782884"],"confidence":"High","gaps":["Lyn-independent phosphorylation mechanism left unexplained"]},{"year":2006,"claim":"Demonstrated heterogeneous, stimulus-dependent phosphorylation of CD22 tyrosines, with Y762 fastest and CD40 selectively boosting ITIM phosphorylation.","evidence":"Site-specific phospho-antibodies to four CD22 motifs with anti-IgM and anti-CD40 stimulation","pmids":["16393971"],"confidence":"Medium","gaps":["Single-lab phospho-antibody data","Functional consequence of differential site phosphorylation not tested"]},{"year":2007,"claim":"Defined the preferred human endogenous CD22 ligand as α2,6-sialylated 6-sulfo-LacNAc, adding sulfation as a recognition determinant.","evidence":"Sulfation inhibition (NaClO3) and blocking mAb in B cell-CD22 binding assays","pmids":["17728258"],"confidence":"Medium","gaps":["Single-lab biochemical study","In vivo requirement for sulfation not tested genetically"]},{"year":2008,"claim":"Identified a non-sialylated, DC-associated CD22 ligand that mediates contact-dependent inhibition of B cell proliferation by immature dendritic cells.","evidence":"DC-B cell co-culture, CD22 and ST6Gal-I knockouts, neuraminidase/periodate resistance controls","pmids":["18354178"],"confidence":"Medium","gaps":["Molecular identity of the second ligand unknown","Single-lab finding"]},{"year":2009,"claim":"Showed that trans engagement of CD22 by sialylated multivalent antigens is itself sufficient to suppress BCR signaling and B cell activation.","evidence":"Synthetic sialylated multivalent antigens with Ca2+ flux and activation assays","pmids":["19202057"],"confidence":"Medium","gaps":["Single-lab finding using synthetic ligands","Physiological source of trans ligands not addressed here"]},{"year":2011,"claim":"Identified soluble IgM as a natural α2,6-sialylated trans ligand activating CD22, implicating a negative feedback loop on B cell activation.","evidence":"Trans activation assays with sIgM-antigen complexes and Ca2+ signaling readouts","pmids":["21956693"],"confidence":"Medium","gaps":["In vivo contribution of sIgM-CD22 feedback not established"]},{"year":2010,"claim":"Extended CD22's inhibitory role beyond the BCR by showing it negatively regulates TLR3/4/9 signaling via SOCS1/3 induction.","evidence":"CD22 knockout mice, ectopic CD22 rescue, TLR ligand proliferation assays, and TLR4-NF-κB reporter","pmids":["21178327"],"confidence":"High","gaps":["Mechanistic link between CD22 and SOCS induction not resolved"]},{"year":2013,"claim":"Established that the ligand-binding and ITIM signaling domains of CD22 reciprocally regulate BCR Ca2+ signaling using domain-specific knockin mice.","evidence":"Knockin mice with mutated ligand-binding domain or ITIM motifs, Ca2+ flux and survival assays","pmids":["23836650"],"confidence":"High","gaps":["Spatial mechanism by which cis ligand controls CD22-BCR association not directly imaged here"]},{"year":2015,"claim":"Revealed that CD22 organizes into highly mobile nanodomains whose fast diffusion, dependent on CD45 and the lectin domain, enables 'global BCR surveillance' in cooperation with the cortical cytoskeleton.","evidence":"Super-resolution microscopy, single-particle tracking, Brownian dynamics simulation, and lectin/CD45 mutants","pmids":["26671981"],"confidence":"High","gaps":["Molecular bridge between CD22 and the cortical cytoskeleton not identified"]},{"year":2017,"claim":"Solved the CD22 ectodomain crystal structure, attributing α2,6-sialic acid specificity to a pre-formed β-hairpin and an extended conformation favoring nanocluster formation and trans binding, plus defining the epratuzumab epitope.","evidence":"X-ray crystallography at 2.1 Å and 3.1 Å with glycosylation site mapping","pmids":["28970495"],"confidence":"High","gaps":["Structure of full-length receptor and cytoplasmic signaling module not determined"]},{"year":2017,"claim":"Used in situ proximity labeling to define CD22 cis-ligands (CD45, IgM) as α2,6-sialic acid-dependent partners that are already pre-positioned near CD22.","evidence":"Biotin-tyramide proximity labeling on living B cells with ST6GalI-/- and Cmah-/- controls and mass spectrometry","pmids":["29146181"],"confidence":"Medium","gaps":["Single-lab method","Functional consequence of each cis interaction not dissected"]},{"year":2021,"claim":"Defined a CD22-SHP1-integrin β7 axis in which sialic acid-dependent CD22-β7 association restrains β7 endocytosis to enhance α4β7 display and mucosal B cell homing.","evidence":"Domain-specific knockin/knockout mice, CD22-β7 co-IP, surface α4β7 flow cytometry, and GALT homing assays","pmids":["33589816"],"confidence":"High","gaps":["Whether this axis operates in human mucosal immunity not addressed"]},{"year":2019,"claim":"Identified CD22 as a negative regulator of microglial phagocytosis upregulated in the aged brain, with blockade restoring clearance of myelin, amyloid-β, and α-synuclein and improving cognition.","evidence":"CRISPR-Cas9 knockout screen, RNA-seq, in vivo CD22-blocking antibody, phagocytosis and cognitive assays","pmids":["30944478"],"confidence":"High","gaps":["Intracellular signaling mediating anti-phagocytic effect in microglia not fully defined here"]},{"year":2021,"claim":"Identified IGF2R as a receptor for soluble CD22 in myeloid cells, with sCD22 docking near mannose-6-phosphate-binding domains to disrupt lysosomal trafficking, linking CD22 to lysosomal dysfunction.","evidence":"Unbiased genetic and proteomic screens, IGF2R truncation, and lysosomal trafficking assays in NPC1 iPSC-microglia with CD22 blockade","pmids":["34851695"],"confidence":"High","gaps":["How sCD22 is generated in vivo not established","Relationship to membrane CD22 anti-phagocytic function unresolved"]},{"year":2023,"claim":"Placed CD22 downstream of Notch1 in regulatory T cells, where it destabilizes Tregs via mTORC1 and promotes inflammation, with relevance to MIS-C patient variants.","evidence":"Patient NUMB/NUMBL variant analysis, Notch1 perturbation, CD22 expression and mTORC1 assays, Treg stability assays","pmids":["36282598"],"confidence":"Medium","gaps":["Single study","Mechanism by which CD22 engages mTORC1 in Tregs not resolved"]},{"year":null,"claim":"How CD22's biochemically defined inhibitory signaling modules are mechanistically repurposed across distinct cell types — B cell, microglial, and Treg contexts — and whether common downstream effectors unify these roles remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying signaling model linking BCR, TLR, phagocytic, and Treg functions","Mechanism connecting CD22 to SOCS and mTORC1 not defined","Generation and physiological role of soluble CD22 unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,20,30]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,6,17,24]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,9,16]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[7,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,19,27,31]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[7,16]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[7,28]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,6,24,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,9,10,17]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[7,16]}],"complexes":["BCR complex","CD22/SHP-1/Syk/PLCγ1 inhibitory complex"],"partners":["SHP-1 (PTPN6)","LYN","SYK","GRB2","CD45","PMCA (ATP2B4)","AP50 (AP2M1)","ITGB7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P20273","full_name":"B-cell receptor CD22","aliases":["B-lymphocyte cell adhesion molecule","BL-CAM","Sialic acid-binding Ig-like lectin 2","Siglec-2","T-cell surface antigen Leu-14"],"length_aa":847,"mass_kda":95.3,"function":"Most highly expressed siglec (sialic acid-binding immunoglobulin-like lectin) on B-cells that plays a role in various aspects of B-cell biology including differentiation, antigen presentation, and trafficking to bone marrow (PubMed:34330755, PubMed:8627166). Binds to alpha 2,6-linked sialic acid residues of surface molecules such as CD22 itself, CD45 and IgM in a cis configuration. Can also bind to ligands on other cells as an adhesion molecule in a trans configuration (PubMed:20172905). Acts as an inhibitory coreceptor on the surface of B-cells and inhibits B-cell receptor induced signaling, characterized by inhibition of the calcium mobilization and cellular activation. Mechanistically, the immunoreceptor tyrosine-based inhibitory motif domain is phosphorylated by the Src kinase LYN, which in turn leads to the recruitment of the protein tyrosine phosphatase 1/PTPN6, leading to the negative regulation of BCR signaling (PubMed:8627166). If this negative signaling from is of sufficient strength, apoptosis of the B-cell can be induced (PubMed:20516366)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P20273/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD22","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD22","total_profiled":1310},"omim":[{"mim_id":"606720","title":"ENDONUCLEASE, POLY(U)-SPECIFIC; ENDOU","url":"https://www.omim.org/entry/606720"},{"mim_id":"606572","title":"NADPH OXIDASE 5; NOX5","url":"https://www.omim.org/entry/606572"},{"mim_id":"604410","title":"SIALIC ACID-BINDING IMMUNOGLOBULIN-LIKE LECTIN 7; SIGLEC7","url":"https://www.omim.org/entry/604410"},{"mim_id":"603823","title":"FREE FATTY ACID RECEPTOR 2; FFAR2","url":"https://www.omim.org/entry/603823"},{"mim_id":"603822","title":"G PROTEIN-COUPLED RECEPTOR 42; GPR42","url":"https://www.omim.org/entry/603822"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":215.0},{"tissue":"ovary","ntpm":124.5}],"url":"https://www.proteinatlas.org/search/CD22"},"hgnc":{"alias_symbol":["SIGLEC-2","SIGLEC2"],"prev_symbol":[]},"alphafold":{"accession":"P20273","domains":[{"cath_id":"2.60.40.10","chopping":"23-138","consensus_level":"medium","plddt":84.4143,"start":23,"end":138},{"cath_id":"2.60.40.10","chopping":"145-237","consensus_level":"medium","plddt":92.4862,"start":145,"end":237},{"cath_id":"2.60.40.10","chopping":"244-329","consensus_level":"high","plddt":89.3405,"start":244,"end":329},{"cath_id":"2.60.40.10","chopping":"336-417","consensus_level":"medium","plddt":91.6539,"start":336,"end":417},{"cath_id":"2.60.40,2.60.40","chopping":"424-499","consensus_level":"medium","plddt":87.992,"start":424,"end":499},{"cath_id":"2.60.40.10","chopping":"510-588","consensus_level":"high","plddt":89.7551,"start":510,"end":588},{"cath_id":"2.60.40.10","chopping":"593-682","consensus_level":"high","plddt":90.257,"start":593,"end":682}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P20273","model_url":"https://alphafold.ebi.ac.uk/files/AF-P20273-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P20273-F1-predicted_aligned_error_v6.png","plddt_mean":79.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD22","jax_strain_url":"https://www.jax.org/strain/search?query=CD22"},"sequence":{"accession":"P20273","fasta_url":"https://rest.uniprot.org/uniprotkb/P20273.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P20273/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P20273"}},"corpus_meta":[{"pmid":"34312556","id":"PMC_34312556","title":"CAR 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CD45 was identified as the first CD22 ligand.\",\n      \"method\": \"Soluble CD22-Ig fusion protein binding assay, COS cell transfection with α2,6-sialyltransferase, periodate oxidation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro binding reconstitution with mutagenesis-equivalent (enzyme treatment) and transfection controls, replicated across multiple experimental approaches in one rigorous study\",\n      \"pmids\": [\"8463234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"CD22 mediates adhesion of monocytes and erythrocytes to B cells; CD22 shares structural homology with myelin-associated glycoprotein (MAG), placing it in the Ig superfamily as an adhesion molecule.\",\n      \"method\": \"Cell adhesion assay with CD22-transfected cells, structural analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional adhesion assay with transfected cells, single lab, two complementary approaches (adhesion assay + structural homology)\",\n      \"pmids\": [\"1691828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CD22 associates with the surface IgM-B cell antigen receptor (BCR) complex; CD22 is co-immunoprecipitated with the sIgM-BCR complex components (Igα/mb-1, Igβ/B29) maintained in digitonin, and CD22 undergoes rapid and striking tyrosine phosphorylation after sIgM crosslinking. CD22 contains the ARHI motif present in antigen receptor molecules.\",\n      \"method\": \"Co-immunoprecipitation in digitonin, in vitro kinase assay, immunoblot with anti-CD22 antiserum\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reciprocal co-IP with multiple BCR components, in vitro kinase assay, immunoblot validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"8475064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CD22 associates with the B cell antigen receptor (BCR) across multiple isotypes (IgM, IgD, IgG) in both Burkitt lymphoma lines and tonsil cells; the association is specific and stable but of low stoichiometry (0.2–2% of membrane immunoglobulin). CD22 becomes tyrosine phosphorylated within one minute after antigen-receptor cross-linking.\",\n      \"method\": \"In vitro kinase assay, Western blotting, co-immunoprecipitation with multiple BCR isotypes and cell types\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus co-IP across multiple isotypes and cell types, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"7684686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Tyrosine-phosphorylated CD22 binds and activates SHP (SHP-1), a protein tyrosine phosphatase that negatively regulates BCR signaling. Ligation of CD22 to prevent its co-aggregation with mIg lowers the threshold for mIg-mediated B cell activation by a factor of 100, establishing CD22 as a molecular switch for SHP.\",\n      \"method\": \"Co-immunoprecipitation of phospho-CD22 with SHP, B cell activation threshold assay, CD22 ligation experiments\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical demonstration of phospho-CD22/SHP-1 interaction combined with functional activation threshold assay, highly cited and foundational\",\n      \"pmids\": [\"7618087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"BCR cross-linking causes PTP-1C (SHP-1) to translocate from cytosol to particulate fraction and associate with tyrosyl-phosphorylated CD22 (140–150 kDa). The association is mediated by the N-terminal SH2 domain of PTP-1C. CD22/PTP-1C/Syk/PLCγ1 complexes can be isolated from stimulated B cells. Binding of PLCγ1 and Syk to CD22 is mediated by the N-terminal SH2 domain of PLCγ1 and C-terminal SH2 domain of Syk respectively. In COS cells, wild-type PTP-1C dephosphorylates CD22, whereas null-mutant PTP-1C (PTP-1CM) does not.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting, COS cell transfection with wild-type and catalytically inactive PTP-1C, SH2 domain binding analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-IP of multi-protein complex, domain mapping with SH2 constructs, mutagenesis (null mutant PTP-1C) in COS cells, multiple orthogonal methods\",\n      \"pmids\": [\"8627166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CD22-deficient mice generated by targeted gene inactivation show normal B cell development but increased Ca2+ influx and increased apoptosis after BCR crosslinking in vitro, increased proliferative response to LPS, shorter B cell lifespan in vivo, impaired T-cell-independent immune responses, and absence of recirculating B cells from bone marrow. This establishes CD22 as a negative regulator of BCR signaling in vivo.\",\n      \"method\": \"Targeted gene inactivation (knockout mice), flow cytometry, Ca2+ flux assay, proliferation assays, immune response assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with multiple orthogonal phenotypic readouts (Ca2+ flux, apoptosis, proliferation, immune response), replicated across multiple assays\",\n      \"pmids\": [\"9016707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD22 is constitutively endocytosed by unstimulated B cell lines and subsequently degraded in an acidic intracellular compartment (presumably lysosomes) without detectable recycling to the cell surface. Ligation of CD22 with anti-CD22 mAbs markedly increases internalization but does not affect degradation rate. Internalization is not affected by phorbol ester or ligation of CD19 or sIgM.\",\n      \"method\": \"Flow cytometry, neuraminidase protection and neuraminidase shift assays, stimulation with phorbol esters and mAbs\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple direct biochemical assays of internalization and degradation kinetics under multiple conditions, rigorous controls\",\n      \"pmids\": [\"7722303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CD22 negatively regulates Vav tyrosine phosphorylation downstream of BCR crosslinking; in CD22-deficient B cells, Vav phosphorylation is uniquely augmented after BCR or CD19 crosslinking. Simultaneous crosslinking of CD19 with the BCR substantially decreases Vav phosphorylation when CD22 is expressed, revealing reciprocal regulation of BCR signaling thresholds by CD19 (positive) and CD22 (negative) via Vav.\",\n      \"method\": \"Immunoprecipitation and Western blot for phospho-Vav in CD22-deficient and CD19-deficient mice B cells, BCR and CD19 crosslinking\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — use of multiple genetic knockout mouse models (CD22-/- and CD19-/-) with direct biochemical readout (Vav phosphorylation), multiple conditions tested\",\n      \"pmids\": [\"9371816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD22 cytoplasmic domain contains two functionally distinct domains: (1) two C-terminal ITIM tyrosines (Tyr-843 and Tyr-863) required for efficient SHP-1 recruitment after BCR ligation, and (2) a separate tyrosine (Tyr-828) required for inducible Grb2 recruitment. Both Lyn and Syk are individually required for maximal CD22 tyrosine phosphorylation; together they account for all constitutive and induced phosphorylation.\",\n      \"method\": \"Mutagenesis of CD22 cytoplasmic tyrosines, co-immunoprecipitation of SHP-1 and Grb2, use of Src kinase inhibitor PP1, kinase-deficient cell experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis of multiple tyrosine residues with co-IP readout, pharmacological inhibitor validation, multiple orthogonal methods\",\n      \"pmids\": [\"11551923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD22 attenuates B cell Ca2+ signaling by potentiating plasma membrane calcium-ATPase (PMCA) activity. PMCA co-immunoprecipitates with CD22 in an activation-dependent manner. CD22 cytoplasmic tyrosine residues are required for PMCA association and enhanced Ca2+ efflux. CD22 regulation of Ca2+ efflux and the Ca2+ response also requires SHP-1. Disruption of PMCA4a/4b by homologous recombination attenuates CD22-mediated Ca2+ effects.\",\n      \"method\": \"Co-immunoprecipitation of PMCA with CD22, PMCA inhibition, homologous recombination knockout of PMCA4, CD22 cytoplasmic tyrosine mutants, Ca2+ flux assay\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution-level biochemistry (co-IP), mutagenesis of CD22 tyrosines, genetic knockout of PMCA, multiple complementary approaches in one study\",\n      \"pmids\": [\"15133509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mice deficient in both CD22 and the ST6Gal-I enzyme that synthesizes the CD22 α2,6-sialic acid ligand (Cd22-/- St6gal1-/- double knockouts) show restored BCR signaling compared to St6gal1-/- single knockouts, demonstrating that the suppressed BCR signaling in ligand-deficient B cells is mediated through CD22. B cells lacking ST6Gal-I show a net redistribution of BCR to clathrin-rich microdomains containing most CD22.\",\n      \"method\": \"Double knockout mouse generation, Ca2+ flux assay, confocal microscopy/membrane microdomain fractionation\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double knockout mouse, Ca2+ flux readout, subcellular localization by confocal microscopy, clean mechanistic placement\",\n      \"pmids\": [\"16369536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ST6Gal-I deficiency (loss of CD22 α2,6-sialic acid ligands) induces constitutive IgM receptor endocytosis coincident with increased colocalization of BCR with CD22 and constitutive SHP-1 recruitment to CD22 independent of Lyn kinase. Co-deficiency with CD22 restores IgM receptor half-life at the cell surface and reverses membrane trafficking and signaling alterations, establishing a CD22-dependent mechanism.\",\n      \"method\": \"ST6Gal-I and CD22 double knockout mice, antigen receptor half-life and endocytosis assays, SHP-1 co-immunoprecipitation, Lyn kinase inhibitor studies\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic double knockout epistasis, multiple biochemical and cell biological readouts, direct causal link established\",\n      \"pmids\": [\"16782884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CD22 directly interacts with multiple isoforms of CD45 including CD45RO on T cells; cross-linking of CD3 and CD22 ligands together (anti-CD3 + soluble CD22) blocks anti-CD3-induced intracellular Ca2+ increase and inhibits tyrosine phosphorylation of PLCγ1 in T cells, indicating CD22 can modulate T cell signaling via CD45 engagement.\",\n      \"method\": \"Direct binding assay of CD22 with CD45 isoforms, Ca2+ flux assay in T cells, tyrosine phosphorylation Western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding plus functional Ca2+ and phosphorylation assays, single lab, two complementary methods\",\n      \"pmids\": [\"1438211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD22-mediated engagement of CD45 on T cells can modulate early T cell signals in antigen receptor/CD3-mediated stimulation. Addition of sialic acid by β-galactoside α-2,6-sialyltransferase to CD22 abrogates CD22-CD45 interactions, establishing that CD22-CD45 binding is sialic acid-dependent.\",\n      \"method\": \"Soluble CD22-Ig fusion protein binding to CD45-chimeric T cells, Ca2+ assay, enzymatic sialylation of CD22\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — soluble fusion protein binding assay with enzymatic modification, functional T cell signaling readout, single lab\",\n      \"pmids\": [\"7537381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Cross-linking of CD22 on primary B cells activates stress-activated protein kinases (SAPKs/JNKs) but not ERK-2, distinct from BCR ligation which activates ERK-2 without significant SAPK activation. CD22 ligation leads to increased nuclear AP-1 and c-jun levels and downregulation of anti-apoptotic Bcl-xL and Mcl-1, providing a mechanism for CD22-induced apoptosis in Burkitt lymphoma cells.\",\n      \"method\": \"SAPK/JNK and ERK kinase activity assays, nuclear extract AP-1 EMSA, Western blot for Bcl-2 family members, primary B cell and B cell line experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (kinase assays, EMSA, Western blot) in primary cells and lines, single lab\",\n      \"pmids\": [\"10438726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD22 interacts with AP50, the medium chain subunit of the clathrin adaptor AP-2 complex, via tyrosine-based internalization motifs in its cytoplasmic domain. Tyr-843 is the primary binding site for AP50 with Tyr-863 sufficient for mAb-mediated internalization. This interaction mediates clathrin-dependent endocytosis of CD22.\",\n      \"method\": \"Yeast two-hybrid analysis, co-precipitation of α-adaptin with CD22 mutants, transfectant Jurkat cell internalization assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — yeast two-hybrid identification confirmed by co-precipitation and functional internalization assays with specific tyrosine mutants, multiple orthogonal methods\",\n      \"pmids\": [\"12646615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD22 cis-ligand binding domain is crucial for regulating BCR signaling by controlling CD22 association with the BCR. Mice with mutated CD22 ligand-binding domain show strongly reduced Ca2+ signaling. Conversely, mice with mutated CD22 ITIM motifs have increased B cell Ca2+ responses, increased B cell turnover, and impaired B cell survival. Thus the ligand-binding and signaling domains of CD22 reciprocally regulate BCR Ca2+ signaling.\",\n      \"method\": \"Knockin mice with mutated CD22 ligand-binding domain or ITIM motifs, Ca2+ flux assay, B cell survival assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — dual knockin mouse genetic approach with domain-specific mutations, Ca2+ flux readout, multiple orthogonal assays in one study\",\n      \"pmids\": [\"23836650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sialylated multivalent antigens engage CD22 in trans and inhibit BCR signaling and B cell activation. Exposure of B cells to sialylated antigens inhibits key steps in BCR signaling, revealing that trans interactions (CD22 bound by antigen-displayed sialic acid ligands) are sufficient to suppress B cell activation.\",\n      \"method\": \"Sialylated multivalent antigen synthesis, BCR signaling assays (Ca2+ flux, phosphorylation), B cell activation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay with defined synthetic ligands, Ca2+ and signaling readouts, single lab\",\n      \"pmids\": [\"19202057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD22 is organized into highly mobile nanodomains in naïve B cells, as revealed by super-resolution microscopy and single-particle tracking. CD22 lateral diffusion is perturbed in the absence of CD45 or when the CD22 lectin domain is mutated. Brownian dynamic simulations and ex vivo experiments suggest CD22's inhibitory function is enabled by its fast diffusion providing 'global BCR surveillance' at the plasma membrane. The cortical cytoskeleton cooperates with CD22 to restrain BCR signaling.\",\n      \"method\": \"Super-resolution microscopy (STORM/PALM), single-particle tracking, Brownian dynamic simulations, CD22 lectin-domain mutant B cells, CD45-deficient B cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — super-resolution imaging plus single-particle tracking plus genetic mutants plus computational simulation, multiple orthogonal methods\",\n      \"pmids\": [\"26671981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of human CD22 ectodomain solved at 2.1 Å resolution, revealing that specificity for α2-6 sialic acid ligands is dictated by a pre-formed β-hairpin unique among Siglec family members. The CD22 ectodomain adopts an extended conformation facilitating CD22 nanocluster formation on B cells and trans ligand binding. The structure of CD22 with therapeutic antibody epratuzumab was determined at 3.1 Å, delineating the epratuzumab binding site and revealing a critical role for N-linked glycosylation in antibody engagement.\",\n      \"method\": \"X-ray crystallography (2.1 Å and 3.1 Å structures), structural analysis of ligand-binding β-hairpin, glycosylation site mapping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at high resolution with functional validation of ligand specificity determinant and antibody epitope, single rigorous study with multiple structural datasets\",\n      \"pmids\": [\"28970495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD22 is upregulated on aged microglia and mediates the anti-phagocytic effect of α2,6-linked sialic acid; CD22 was identified as a negative regulator of microglial phagocytosis by CRISPR-Cas9 knockout screens. Inhibition of CD22 promotes clearance of myelin debris, amyloid-β oligomers, and α-synuclein fibrils in vivo. Long-term CNS delivery of a CD22-blocking antibody reprograms microglia toward a homeostatic transcriptional state and improves cognitive function in aged mice.\",\n      \"method\": \"CRISPR-Cas9 knockout screen, RNA sequencing, in vivo antibody blockade, phagocytosis assays, cognitive behavioral testing\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen identification confirmed by in vivo antibody blockade with multiple phagocytosis substrates and cognitive readouts, multiple orthogonal methods\",\n      \"pmids\": [\"30944478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD45 regulates tyrosine phosphorylation of CD22 and its association with SHP-1; cross-linking of CD45 induces physical sequestration from CD22, leading to increased CD22 tyrosine phosphorylation and SHP-1 recruitment. In CD45-deficient B cells, CD22 shows increased basal and inducible tyrosine phosphorylation and enhanced SHP-1 recruitment. Expression of catalytically inactive SHP-1 in CD45-deficient cells restored intracellular Ca2+ mobilization.\",\n      \"method\": \"CD45-deficient B cell line, CD45 cross-linking and capping, co-immunoprecipitation of SHP-1 with CD22, expression of catalytically inactive SHP-1, Ca2+ flux assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (CD45-deficient cells) plus dominant-negative SHP-1 approach, co-IP, and functional Ca2+ readout, multiple orthogonal methods\",\n      \"pmids\": [\"10228003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD22 phosphorylation upon BCR ligation is not uniform: Y762 undergoes the most rapid phosphorylation, and ultimately all four tyrosine motifs (Y762, Y807, Y822, Y842) are phosphorylated at ~35% of CD22 molecules. Anti-CD40 stimulation specifically upregulates BCR-induced phosphorylation of ITIM tyrosines Y762 and Y842, but not Y807 (Grb2 site), revealing qualitative differences in CD22 phosphorylation patterns depending on stimulus.\",\n      \"method\": \"Phospho-specific polyclonal antibodies to four CD22 tyrosine motifs, flow cytometry, Western blot, anti-IgM and anti-CD40 stimulation\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific phospho-antibodies for four residues, multiple stimulation conditions, single lab\",\n      \"pmids\": [\"16393971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD22-deficient mice show hyperactivation to TLR3, TLR4, and TLR9 ligands, and this hyperactivation is associated with impaired induction of SOCS1 and SOCS3 (suppressors of cytokine signaling). Antibody-mediated CD22 sequestration on wild-type B cells augments TLR-induced proliferation. Ectopic CD22 expression in CD22-deficient B cell lines blunts TLR responses. CD22 expression in a TLR4 reporter cell line inhibits LPS-induced NF-κB transcription. This establishes CD22 as a negative regulator of TLR signaling in addition to BCR signaling.\",\n      \"method\": \"CD22 knockout mice, TLR ligand stimulation proliferation assays, SOCS1/3 expression analysis, ectopic CD22 expression in knockout B cell line, TLR4-NF-κB reporter assay\",\n      \"journal\": \"Journal of innate immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus rescue by ectopic expression plus reporter assay, multiple TLR ligands tested, multiple cell systems\",\n      \"pmids\": [\"21178327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD22 serves as a receptor for soluble IgM (sIgM); CD22 is efficiently activated in trans by complexes of antigen and sIgM due to the presence of α2,6-sialic acid glycan ligands on sIgM, establishing sIgM as a natural trans ligand for CD22 and implicating a negative feedback loop for B cell activation analogous to FcγRIIB.\",\n      \"method\": \"Trans activation assay with sIgM-antigen complexes, glycan ligand analysis, Ca2+ signaling readout\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional demonstration of trans activation by sIgM complexes, single lab, mechanistic link to glycan ligands shown\",\n      \"pmids\": [\"21956693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Immature but not mature dendritic cells (DCs) inhibit BCR-induced B cell proliferation in a contact-dependent manner that requires CD22 but is independent of the ST6Gal-I-generated α2,6-sialic acid CD22 ligand. A second, distinct CD22 ligand is expressed on DCs that is resistant to neuraminidase and sodium metaperiodate, indicating a non-sialylated DC-associated CD22 ligand mediates CD22-dependent DC-B cell inhibitory interaction.\",\n      \"method\": \"Co-culture of bone marrow-derived DCs with B cells, CD22 knockout and ST6Gal-I knockout mice, neuraminidase and periodate treatment, proliferation assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic knockouts with direct co-culture functional assay, enzyme-resistance controls identify second ligand, single lab\",\n      \"pmids\": [\"18354178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD22 associates in a sialic acid-dependent manner with integrin β7 on B cell surfaces, and recruits intracellular Shp1 to β7, restraining β7 endocytosis and enhancing surface α4β7 display. B cells lacking CD22, expressing CD22 with mutated Shp1-binding domains, or mutated carbohydrate-binding domains show reduced surface α4β7 and impaired homing to gut-associated lymphoid tissue (GALT). This establishes a CD22-Shp1-integrin β7 axis controlling B cell trafficking in mucosal immunity.\",\n      \"method\": \"CD22 knockout mice, CD22 domain-specific mutant knockin mice, co-immunoprecipitation of CD22 with β7 integrin, flow cytometry of surface α4β7, B cell homing assay to GALT, Shp1-conditional knockout\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple knockin/knockout genetic models with domain-specific mutations, co-IP, direct homing assay, multiple orthogonal methods\",\n      \"pmids\": [\"33589816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Soluble CD22 (sCD22) binds to insulin-like growth factor 2 receptor (IGF2R) on human myeloid cells as identified by unbiased genetic and proteomic screens. sCD22 docks near mannose 6-phosphate-binding domains of IGF2R and disrupts lysosomal protein trafficking. CD22 blocking antibodies ameliorate lysosome dysfunction in human NPC1 mutant iPSC-derived microglia-like cells.\",\n      \"method\": \"Unbiased genetic screen, proteomic screen, IGF2R targeted truncation, lysosomal trafficking assays in iPSC-derived microglia, CD22 blocking antibody treatment\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased genome-wide screens confirmed by domain truncation experiment and functional lysosomal trafficking assay, multiple orthogonal methods\",\n      \"pmids\": [\"34851695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Notch1 signaling in regulatory T cells (Tregs) induces CD22 expression, which destabilizes Tregs in an mTORC1-dependent manner and promotes systemic inflammation. Dominant-negative mutations in Notch1 regulators NUMB and NUMBL in MIS-C patients lead to Notch1 upregulation and downstream CD22 induction. This Notch1/CD22 signaling axis disrupts Treg function.\",\n      \"method\": \"Genetic analysis of patient variants (NUMB/NUMBL mutations), Notch1 signaling perturbation in Tregs, CD22 expression analysis, mTORC1 pathway assays, functional Treg stability assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic patient variant analysis combined with Notch1/CD22/mTORC1 pathway mechanistic experiments, single study\",\n      \"pmids\": [\"36282598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human B lymphocytes express α2-6-sialylated 6-sulfo-N-acetyllactosamine (6-sulfo-LacNAc) as a preferred endogenous ligand for CD22; NaClO3 inhibition of cellular sulfation and a mAb specific to this determinant almost completely abrogates human B cell binding to CD22, establishing that both α2-6-sialylation and 6-GlcNAc-sulfation are required for optimal CD22 ligand recognition.\",\n      \"method\": \"Sulfation inhibition (NaClO3), blocking mAb to sulfo-LacNAc determinant, B cell-CD22 binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition of sulfation plus specific mAb blocking with direct binding assay, single lab\",\n      \"pmids\": [\"17728258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Proximity labeling of CD22 cis-ligands on B cell surface reveals that CD22, CD45, and IgM associate with CD22 through α2,6-sialic acid-dependent lectin-glycan interactions in cis; these molecules are absent from CD22 proximity in ST6GalI-/- B cells lacking α2,6 sialic acids, but are already located at relative proximity through non-lectin-glycan interactions.\",\n      \"method\": \"Biotin-tyramide proximity labeling on living B cells, ST6GalI-/- and Cmah-/- knockout mice, mass spectrometry identification of labeled proteins\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling with genetic controls, direct identification of cis-ligands in situ, single lab\",\n      \"pmids\": [\"29146181\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD22 (Siglec-2) is a B cell-restricted inhibitory co-receptor that functions as a sialic acid-binding lectin recognizing α2,6-linked sialic acid ligands; upon BCR crosslinking, CD22 is rapidly tyrosine-phosphorylated by Lyn and Syk kinases, recruits SHP-1 via ITIM motifs to dephosphorylate BCR signaling components and PMCA to enhance Ca2+ efflux, while separately recruiting Grb2 (via Tyr-828) and controlling clathrin-mediated endocytosis via AP-2 adaptor binding; cis sialic acid interactions regulate CD22 nanocluster organization and BCR co-localization, whereas trans ligand engagement strongly inhibits BCR signaling; CD22 also negatively regulates TLR signaling via SOCS1/3 induction, controls integrin β7 display in mucosal B cell homing via a CD22-Shp1-β7 axis, and in microglia/aged brain cells acts as a negative regulator of phagocytosis whose blockade restores homeostatic function partly through the sCD22-IGF2R lysosomal trafficking pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD22 (Siglec-2) is a B cell-restricted inhibitory co-receptor that sets the threshold for B cell antigen receptor (BCR) signaling by recognizing α2,6-linked sialic acid glycans through its N-terminal lectin domain [#0, #20]. It associates with the BCR complex across multiple immunoglobulin isotypes and becomes rapidly tyrosine-phosphorylated by Lyn and Syk within a minute of receptor crosslinking [#2, #3, #9]. Phosphorylation of its cytoplasmic ITIM tyrosines recruits and activates the phosphatase SHP-1, which dephosphorylates BCR signaling components and raises the activation threshold, while a separate tyrosine (Tyr-828/Y807) recruits Grb2 [#4, #5, #9]. Through this SHP-1 axis CD22 attenuates downstream Vav phosphorylation and dampens calcium signaling, in part by activation-dependent association with and potentiation of the plasma membrane calcium-ATPase (PMCA) to enhance Ca2+ efflux [#8, #10]. CD22-deficient mice exhibit heightened Ca2+ flux, increased BCR-induced apoptosis, shortened B cell lifespan, and impaired T-independent responses, establishing its role as a negative regulator of B cell activation in vivo [#6, #17]. CD22's ligand-binding and signaling domains act reciprocally: cis engagement by α2,6-sialylated ligands (including CD45, IgM, and the preferred 6-sulfo-LacNAc determinant) organizes CD22 into mobile nanodomains controlling its proximity to the BCR, whereas trans engagement by sialylated multivalent antigens or soluble IgM strongly inhibits BCR signaling [#11, #17, #18, #19, #25, #30, #31]. CD22 also directs its own clathrin-mediated endocytosis via tyrosine-based motifs that bind the AP-2 adaptor subunit AP50 [#7, #16]. Beyond B cells, CD22 negatively regulates TLR signaling through induction of SOCS1/3 [#24], controls B cell mucosal homing via a CD22-SHP1-integrin β7 axis [#27], and acts as a negative regulator of microglial phagocytosis in the aged brain whose blockade restores homeostatic function, with soluble CD22 engaging IGF2R to disrupt lysosomal trafficking [#21, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established CD22 as an Ig-superfamily adhesion molecule before its signaling role was known, placing it structurally among MAG-related proteins.\",\n      \"evidence\": \"Cell adhesion assay with CD22-transfected cells and structural homology analysis\",\n      \"pmids\": [\"1691828\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the molecular nature of the adhesion ligand\", \"No link to signaling function\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Defined the molecular basis of CD22 ligand recognition as a sialic acid-binding lectin specific for α2,6-linked sialic acids, identifying CD45 as the first ligand.\",\n      \"evidence\": \"Soluble CD22-Ig fusion binding assays, sialyltransferase transfection, and periodate oxidation\",\n      \"pmids\": [\"8463234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve cis versus trans ligand biology\", \"Endogenous physiological ligands not yet defined\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Showed CD22 physically associates with the BCR complex and is rapidly tyrosine-phosphorylated on receptor crosslinking, linking it to BCR signaling.\",\n      \"evidence\": \"Co-immunoprecipitation with Igα/Igβ in digitonin and in vitro kinase assays across multiple BCR isotypes\",\n      \"pmids\": [\"8475064\", \"7684686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Low stoichiometry of association left functional consequence unclear\", \"Kinases responsible not yet identified\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identified SHP-1 as the effector recruited by phospho-CD22 and demonstrated functionally that CD22 raises the BCR activation threshold ~100-fold, defining it as an inhibitory switch.\",\n      \"evidence\": \"Co-IP of phospho-CD22 with SHP and B cell activation threshold assays\",\n      \"pmids\": [\"7618087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ITIM residues mediating recruitment not yet mapped\", \"Downstream substrates of SHP-1 not delineated\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Resolved the inhibitory complex architecture, showing SHP-1 binds CD22 via its N-terminal SH2 domain within CD22/SHP-1/Syk/PLCγ1 assemblies and dephosphorylates CD22.\",\n      \"evidence\": \"Co-IP of multiprotein complex, SH2 domain mapping, and COS-cell reconstitution with catalytically inactive PTP-1C\",\n      \"pmids\": [\"8627166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of complex not established at this stage\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed CD22 is constitutively endocytosed and degraded in an acidic compartment, establishing trafficking behavior independent of BCR or CD19 signaling.\",\n      \"evidence\": \"Flow cytometry and neuraminidase shift/protection assays under multiple stimulation conditions\",\n      \"pmids\": [\"7722303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endocytic machinery not identified\", \"Functional role of constitutive turnover unclear\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Genetic knockout established CD22 as a bona fide negative regulator of BCR signaling in vivo, with effects on Ca2+ flux, apoptosis, B cell lifespan, and immune responses.\",\n      \"evidence\": \"CD22-deficient mice with Ca2+ flux, proliferation, and immune response assays\",\n      \"pmids\": [\"9016707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway linking CD22 loss to phenotypes not fully resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identified Vav as a regulated node and revealed reciprocal CD19 (positive) / CD22 (negative) control of BCR signaling thresholds.\",\n      \"evidence\": \"Phospho-Vav immunoblotting in CD22- and CD19-deficient mouse B cells under BCR/CD19 crosslinking\",\n      \"pmids\": [\"9371816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting SHP-1 to Vav not directly demonstrated\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Connected CD22 to apoptotic outcome by showing CD22 ligation activates SAPK/JNK and downregulates Bcl-xL/Mcl-1, distinct from BCR-driven ERK activation.\",\n      \"evidence\": \"Kinase activity assays, AP-1 EMSA, and Bcl-2 family Western blots in primary and lymphoma B cells\",\n      \"pmids\": [\"10438726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pathway analysis without genetic confirmation\", \"Relevance to physiological CD22 ligation unclear\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Placed CD45 upstream of CD22 phosphorylation, showing CD45 sequestration enhances CD22 phosphorylation and SHP-1 recruitment to restrain Ca2+ signaling.\",\n      \"evidence\": \"CD45-deficient B cells, CD45 capping, SHP-1 co-IP, and dominant-negative SHP-1 rescue of Ca2+ flux\",\n      \"pmids\": [\"10228003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD45 acts via lectin-glycan or phosphatase activity not fully separated\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapped distinct cytoplasmic modules — ITIM tyrosines for SHP-1 versus Tyr-828 for Grb2 — and assigned Lyn and Syk as the kinases driving CD22 phosphorylation.\",\n      \"evidence\": \"Systematic tyrosine mutagenesis, SHP-1/Grb2 co-IP, and PP1 inhibitor in kinase-deficient cells\",\n      \"pmids\": [\"11551923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of Grb2 recruitment to CD22 not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified AP50/AP-2 binding to CD22 tyrosine-based motifs as the basis for clathrin-mediated endocytosis, explaining the earlier observed constitutive internalization.\",\n      \"evidence\": \"Yeast two-hybrid, α-adaptin co-precipitation with CD22 mutants, and internalization assays in Jurkat transfectants\",\n      \"pmids\": [\"12646615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between AP-2 endocytic motif (Tyr-843) and ITIM signaling not fully separated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed a non-SHP-1 mechanism of Ca2+ control: CD22 associates with and potentiates PMCA in an activation- and tyrosine-dependent manner to enhance Ca2+ efflux.\",\n      \"evidence\": \"PMCA/CD22 co-IP, CD22 tyrosine mutants, and PMCA4 knockout with Ca2+ flux assays\",\n      \"pmids\": [\"15133509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus SHP-1-bridged nature of CD22-PMCA association not fully resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Used genetic epistasis to prove that suppressed BCR signaling in ST6Gal-I-deficient B cells is mediated through CD22 and linked ligand loss to BCR redistribution into clathrin-rich microdomains.\",\n      \"evidence\": \"Cd22-/- St6gal1-/- double knockout mice, Ca2+ flux, and membrane microdomain analysis\",\n      \"pmids\": [\"16369536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ligand-controlled CD22-BCR positioning not yet at molecular resolution\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed that loss of α2,6-sialic acid ligands drives constitutive IgM endocytosis and Lyn-independent SHP-1 recruitment to CD22, all reversed by CD22 co-deficiency.\",\n      \"evidence\": \"ST6Gal-I/CD22 double knockouts, receptor half-life and endocytosis assays, SHP-1 co-IP, Lyn inhibition\",\n      \"pmids\": [\"16782884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lyn-independent phosphorylation mechanism left unexplained\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated heterogeneous, stimulus-dependent phosphorylation of CD22 tyrosines, with Y762 fastest and CD40 selectively boosting ITIM phosphorylation.\",\n      \"evidence\": \"Site-specific phospho-antibodies to four CD22 motifs with anti-IgM and anti-CD40 stimulation\",\n      \"pmids\": [\"16393971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab phospho-antibody data\", \"Functional consequence of differential site phosphorylation not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the preferred human endogenous CD22 ligand as α2,6-sialylated 6-sulfo-LacNAc, adding sulfation as a recognition determinant.\",\n      \"evidence\": \"Sulfation inhibition (NaClO3) and blocking mAb in B cell-CD22 binding assays\",\n      \"pmids\": [\"17728258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab biochemical study\", \"In vivo requirement for sulfation not tested genetically\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified a non-sialylated, DC-associated CD22 ligand that mediates contact-dependent inhibition of B cell proliferation by immature dendritic cells.\",\n      \"evidence\": \"DC-B cell co-culture, CD22 and ST6Gal-I knockouts, neuraminidase/periodate resistance controls\",\n      \"pmids\": [\"18354178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular identity of the second ligand unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that trans engagement of CD22 by sialylated multivalent antigens is itself sufficient to suppress BCR signaling and B cell activation.\",\n      \"evidence\": \"Synthetic sialylated multivalent antigens with Ca2+ flux and activation assays\",\n      \"pmids\": [\"19202057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding using synthetic ligands\", \"Physiological source of trans ligands not addressed here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified soluble IgM as a natural α2,6-sialylated trans ligand activating CD22, implicating a negative feedback loop on B cell activation.\",\n      \"evidence\": \"Trans activation assays with sIgM-antigen complexes and Ca2+ signaling readouts\",\n      \"pmids\": [\"21956693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo contribution of sIgM-CD22 feedback not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended CD22's inhibitory role beyond the BCR by showing it negatively regulates TLR3/4/9 signaling via SOCS1/3 induction.\",\n      \"evidence\": \"CD22 knockout mice, ectopic CD22 rescue, TLR ligand proliferation assays, and TLR4-NF-κB reporter\",\n      \"pmids\": [\"21178327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between CD22 and SOCS induction not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that the ligand-binding and ITIM signaling domains of CD22 reciprocally regulate BCR Ca2+ signaling using domain-specific knockin mice.\",\n      \"evidence\": \"Knockin mice with mutated ligand-binding domain or ITIM motifs, Ca2+ flux and survival assays\",\n      \"pmids\": [\"23836650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial mechanism by which cis ligand controls CD22-BCR association not directly imaged here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed that CD22 organizes into highly mobile nanodomains whose fast diffusion, dependent on CD45 and the lectin domain, enables 'global BCR surveillance' in cooperation with the cortical cytoskeleton.\",\n      \"evidence\": \"Super-resolution microscopy, single-particle tracking, Brownian dynamics simulation, and lectin/CD45 mutants\",\n      \"pmids\": [\"26671981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular bridge between CD22 and the cortical cytoskeleton not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Solved the CD22 ectodomain crystal structure, attributing α2,6-sialic acid specificity to a pre-formed β-hairpin and an extended conformation favoring nanocluster formation and trans binding, plus defining the epratuzumab epitope.\",\n      \"evidence\": \"X-ray crystallography at 2.1 Å and 3.1 Å with glycosylation site mapping\",\n      \"pmids\": [\"28970495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length receptor and cytoplasmic signaling module not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Used in situ proximity labeling to define CD22 cis-ligands (CD45, IgM) as α2,6-sialic acid-dependent partners that are already pre-positioned near CD22.\",\n      \"evidence\": \"Biotin-tyramide proximity labeling on living B cells with ST6GalI-/- and Cmah-/- controls and mass spectrometry\",\n      \"pmids\": [\"29146181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab method\", \"Functional consequence of each cis interaction not dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a CD22-SHP1-integrin β7 axis in which sialic acid-dependent CD22-β7 association restrains β7 endocytosis to enhance α4β7 display and mucosal B cell homing.\",\n      \"evidence\": \"Domain-specific knockin/knockout mice, CD22-β7 co-IP, surface α4β7 flow cytometry, and GALT homing assays\",\n      \"pmids\": [\"33589816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this axis operates in human mucosal immunity not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified CD22 as a negative regulator of microglial phagocytosis upregulated in the aged brain, with blockade restoring clearance of myelin, amyloid-β, and α-synuclein and improving cognition.\",\n      \"evidence\": \"CRISPR-Cas9 knockout screen, RNA-seq, in vivo CD22-blocking antibody, phagocytosis and cognitive assays\",\n      \"pmids\": [\"30944478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling mediating anti-phagocytic effect in microglia not fully defined here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified IGF2R as a receptor for soluble CD22 in myeloid cells, with sCD22 docking near mannose-6-phosphate-binding domains to disrupt lysosomal trafficking, linking CD22 to lysosomal dysfunction.\",\n      \"evidence\": \"Unbiased genetic and proteomic screens, IGF2R truncation, and lysosomal trafficking assays in NPC1 iPSC-microglia with CD22 blockade\",\n      \"pmids\": [\"34851695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How sCD22 is generated in vivo not established\", \"Relationship to membrane CD22 anti-phagocytic function unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed CD22 downstream of Notch1 in regulatory T cells, where it destabilizes Tregs via mTORC1 and promotes inflammation, with relevance to MIS-C patient variants.\",\n      \"evidence\": \"Patient NUMB/NUMBL variant analysis, Notch1 perturbation, CD22 expression and mTORC1 assays, Treg stability assays\",\n      \"pmids\": [\"36282598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"Mechanism by which CD22 engages mTORC1 in Tregs not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD22's biochemically defined inhibitory signaling modules are mechanistically repurposed across distinct cell types — B cell, microglial, and Treg contexts — and whether common downstream effectors unify these roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying signaling model linking BCR, TLR, phagocytic, and Treg functions\", \"Mechanism connecting CD22 to SOCS and mTORC1 not defined\", \"Generation and physiological role of soluble CD22 unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 20, 30]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 6, 17, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 9, 16]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [7, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 19, 27, 31]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7, 16]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [7, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 6, 24, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 9, 10, 17]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [7, 16]}\n    ],\n    \"complexes\": [\"BCR complex\", \"CD22/SHP-1/Syk/PLCγ1 inhibitory complex\"],\n    \"partners\": [\"SHP-1 (PTPN6)\", \"Lyn\", \"Syk\", \"Grb2\", \"CD45\", \"PMCA (ATP2B4)\", \"AP50 (AP2M1)\", \"ITGB7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}