{"gene":"CD209","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2000,"finding":"DC-SIGN (CD209) binds HIV-1 envelope glycoprotein gp120 on dendritic cells and promotes efficient trans-infection of CD4+/chemokine receptor-expressing T cells without mediating viral entry into DCs themselves.","method":"Co-binding assays, trans-infection assays, antibody blocking experiments in primary DCs and transfected cell lines","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding and functional trans-infection assays replicated across multiple labs; foundational paper with multiple orthogonal methods","pmids":["10721995"],"is_preprint":false},{"year":2000,"finding":"DC-SIGN binds ICAM-2 on vascular endothelium and supports tethering and rolling of DC-SIGN-positive cells under shear flow, regulating chemokine-induced transmigration of dendritic cells across endothelium.","method":"Flow chamber assays under shear stress, antibody blocking, transfected cell lines expressing DC-SIGN","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional assay (shear flow rolling/tethering) with antibody blocking in both transfectants and primary DCs","pmids":["11017109"],"is_preprint":false},{"year":2000,"finding":"DC-SIGN and DC-SIGNR genes are located on chromosome 19p13 adjacent to CD23, share a similar genomic organization, and both encode proteins with tandem-repeat neck regions predicted to form coiled coils and mannose-binding C-type lectin domains.","method":"Genomic mapping, sequence analysis, expression studies in endometrium, placenta, and KG1 cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genomic and sequence characterization with expression data; structural inference from sequence without direct functional mutagenesis","pmids":["10975799"],"is_preprint":false},{"year":2002,"finding":"DC-SIGN is rapidly internalized upon soluble ligand binding via internalization motifs in its cytoplasmic tail; mutating a putative internalization motif reduces ligand-induced internalization. DC-SIGN-ligand complexes traffic to late endosomes/lysosomes, and ligands internalized by DC-SIGN are efficiently processed and presented to CD4+ T cells.","method":"Cytoplasmic tail mutagenesis, ratio fluorescence imaging, electron microscopy, antigen presentation assays to CD4+ T cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of internalization motif combined with imaging (fluorescence + EM) and functional antigen presentation readout in one study","pmids":["11859097"],"is_preprint":false},{"year":2003,"finding":"DC-SIGN captures and internalizes intact Mycobacterium bovis BCG through binding to the mycobacterial cell wall component ManLAM (mannose-capped lipoarabinomannan); anti-DC-SIGN antibodies block this infection. ManLAM binding to DC-SIGN prevents mycobacteria- or LPS-induced DC maturation, interfering with TLR-mediated signaling.","method":"Anti-DC-SIGN antibody blocking, DC infection assays, DC maturation assays (LPS stimulation), purified ManLAM binding experiments","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — antibody blocking, purified ligand, functional maturation readout; replicated across multiple labs","pmids":["12515809"],"is_preprint":false},{"year":2003,"finding":"DC-SIGN is the major M. tuberculosis receptor on human dendritic cells; mycobacterial lipoarabinomannan (LAM) was identified as a key ligand. Complement receptor 3 and mannose receptor played minor roles in mycobacterial binding to DCs.","method":"Anti-DC-SIGN antibody blocking, binding assays with purified LAM, comparison with CR3/MR-blocking antibodies in human monocyte-derived DCs","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct antibody-blocking and purified ligand experiments; independently confirmed by Geijtenbeek et al. in same journal issue","pmids":["12515819"],"is_preprint":false},{"year":2003,"finding":"DC-SIGN (CD209) mediates productive dengue virus infection of human dendritic cells; all four dengue serotypes use DC-SIGN to infect DCs. Transfection of DC-SIGN into THP-1 cells confers dengue susceptibility; anti-DC-SIGN antibodies block DC infection.","method":"DC-SIGN transfection into THP-1 cells, anti-DC-SIGN antibody blocking, dengue infection assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function transfection and loss-of-function antibody blocking; multiple serotypes tested","pmids":["12682107"],"is_preprint":false},{"year":2003,"finding":"DC-SIGN binds Ebola glycoproteins and greatly enhances transduction of primary cells (macrophages, dendritic cells) and endothelial cells by Ebola virus pseudotypes; DC-SIGN and DC-SIGNR do not directly mediate Ebola virus entry but act as attachment/enhancement factors.","method":"Ebola pseudotype transduction assays, primary cell infections, antibody blocking, transfected cell lines","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional pseudotype and replication-competent virus assays in primary cells; single lab study","pmids":["12504546"],"is_preprint":false},{"year":2003,"finding":"DC-SIGN is an antigen-uptake receptor for Candida albicans on dendritic cells; DC-SIGN internalizes C. albicans into DC-SIGN-enriched vesicles that are distinct from mannose receptor-containing vesicles, indicating separate endocytic routing.","method":"Binding assays in DC-SIGN transfectants and primary DCs, fluorescence microscopy showing DC-SIGN-enriched vesicles, comparison with mannose receptor compartments","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and internalization assays in both transfectants and primary DCs; single lab","pmids":["12645952"],"is_preprint":false},{"year":2003,"finding":"Hepatitis C virus E2 glycoprotein and E1/E2 pseudotypes bind DC-SIGN and DC-SIGNR expressed on cell lines and primary human endothelial cells; binding to immature MDDCs is dependent on DC-SIGN interactions.","method":"Binding assays with soluble E2 glycoprotein and HCV pseudotypes on DC-SIGN/DC-SIGNR transfectants and primary MDDCs; antibody-blocking experiments","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pseudotype binding and blocking assays in primary cells and transfectants; single lab","pmids":["12634366"],"is_preprint":false},{"year":2003,"finding":"DC-SIGN expression on B-cell lines dramatically enhances HIV-1 internalization; most captured virions are rapidly degraded in a lysosomal compartment, but a fraction is processed by the proteasome leading to MHC-I-restricted antigen presentation and activation of HIV-specific CTLs.","method":"DC-SIGN transfection into B-cell lines, HIV internalization assays, proteasome inhibitor experiments, CTL activation assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function transfection with multiple functional readouts (internalization, proteasome inhibition, CTL activation); single lab","pmids":["14576049"],"is_preprint":false},{"year":2004,"finding":"DC-SIGN-captured HCV pseudoviruses are internalized and trans-infect adjacent human liver cells; virus capture and transinfection require internalization of the SIGN-HCV pseudovirus complex.","method":"HCV pseudovirus transinfection assays, L-SIGN/DC-SIGN+ cell lines, internalization-dependent trans-infection assay","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional pseudovirus transinfection assay demonstrating internalization requirement; single lab","pmids":["15371595"],"is_preprint":false},{"year":2004,"finding":"DC-SIGN discriminates among Leishmania species and life cycle forms; it is a receptor for promastigote and amastigote stages of L. infantum and L. pifanoi but not for L. major metacyclic promastigotes. Leishmania binding to DC-SIGN is independent of lipophosphoglycan.","method":"Binding assays with different Leishmania species/stages on DC-SIGN-expressing cells; LPG-deficient parasite binding experiments","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comparative binding assays with multiple species and ligand-deficient parasites; single lab","pmids":["14707095"],"is_preprint":false},{"year":2006,"finding":"DC-SIGN engagement by specific antibodies induces ERK1/2 and Akt phosphorylation (without p38MAPK activation), PLCgamma phosphorylation, and transient intracellular calcium increases in DCs. A fraction of DC-SIGN partitions in lipid raft-enriched fractions and co-precipitates with tyrosine kinases Lyn and Syk. DC-SIGN cross-linking synergizes with TNF-α for IL-10 release and enhances LPS-induced IL-10.","method":"Antibody cross-linking, phosphorylation assays (ERK1/2, Akt, p38, PLCgamma), calcium flux assays, lipid raft fractionation, co-immunoprecipitation with Lyn and Syk, cytokine ELISA","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal signaling readouts (kinase phosphorylation, calcium flux, Co-IP, cytokine production) in primary DCs and transfectants","pmids":["16434485"],"is_preprint":false},{"year":2006,"finding":"DC-SIGN is a receptor for Human Herpesvirus 8 (HHV-8) on myeloid DCs and macrophages; HHV-8 binding and infection are blocked by anti-DC-SIGN mAb, soluble DC-SIGN, and mannan. HHV-8 infection via DC-SIGN leads to down-regulation of DC-SIGN itself, decreased endocytic activity, and inhibition of CD8+ T cell antigen stimulation.","method":"Anti-DC-SIGN antibody and soluble DC-SIGN blocking, mannan competition, DC-SIGN transfected cell line infection assays, T cell stimulation assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody/soluble receptor blocking and transfectant gain-of-function; multiple functional readouts; single lab","pmids":["16424204"],"is_preprint":false},{"year":2006,"finding":"DC-SIGN and CLEC-2 both contribute to HIV-1 capture by platelets; platelets express low levels of DC-SIGN and DC-SIGN-dependent capture of HIV-1 maintains virus in an infectious state over several days.","method":"Flow cytometry for DC-SIGN on platelets, antibody blocking with DC-SIGN and CLEC-2 inhibitors, HIV-1 infectivity assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combination inhibitor blocking experiments with infectivity readout; single lab","pmids":["16940507"],"is_preprint":false},{"year":2006,"finding":"DC-SIGN mediates recognition and phagocytosis of Neisseria gonorrhoeae by dendritic cells only for a specific lipooligosaccharide (LOS) mutant (lgtB); wild-type GC avoids DC-SIGN recognition through LOS variation. DC-SIGN-mediated phagocytosis is blocked by anti-DC-SIGN antibody.","method":"HeLa-DC-SIGN transfectants, GC lgtB mutant binding and phagocytosis assays, anti-DC-SIGN antibody blocking","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function transfection and mutant bacteria; antibody blocking; single lab","pmids":["16461738"],"is_preprint":false},{"year":2006,"finding":"Measles virus glycoproteins F and H are both DC-SIGN ligands; DC-SIGN does not support MV entry (does not confer susceptibility in CHO cells) but functions as an attachment receptor enhancing CD46/CD150-mediated infection of immature DCs in cis.","method":"DC-SIGN transfection in CHO cells (entry assay), DC-SIGN inhibitor blocking of DC infection, MV glycoprotein binding experiments","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function transfection showing no entry plus blocking showing attachment role; two orthogonal approaches; single lab","pmids":["16537615"],"is_preprint":false},{"year":2007,"finding":"DC-SIGN neck region variants and the lectin domain both contribute to multimerization on the cell surface; glycosylation of the neck region negatively affects oligomer formation. Naturally occurring DC-SIGN neck variants differ in multimerization competence, exhibit altered sugar binding ability, but retain pathogen-interacting capacity.","method":"Structural analysis of neck variants, multimerization assays in transfected cells, sugar-binding assays, pathogen interaction assays with neck variant-expressing cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct structural and functional analysis of neck variants and glycosylation effects; single lab; multiple readouts","pmids":["18073208"],"is_preprint":false},{"year":2008,"finding":"DC-SIGN triggering by pathogens activates a signaling pathway with a central role for the serine/threonine kinase Raf-1; Raf-1 activation leads to acetylation of NF-κB subunit p65, which induces specific gene transcription profiles and modulates TLR-induced cytokine responses.","method":"Kinase activation assays, NF-κB p65 acetylation assays, gene transcription profiling; described as established across multiple pathogen studies","journal":"Cancer immunology, immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical signaling assays (Raf-1, NF-κB p65 acetylation) established across multiple pathogen studies; review synthesizing original data","pmids":["18998127"],"is_preprint":false},{"year":2009,"finding":"DC-SIGN hexamannosylated PIM6 (containing terminal α(1→2)-linked mannosyl residues identical to the ManLAM mannose cap) binds DC-SIGN with high affinity, whereas di- and tetramannosylated PIMs (PIM2 and PIM4) do not. However, a pimE deletion mutant M. bovis BCG lacking PIM6 binds DC-SIGN similarly to wild type, indicating PIM6 is a bona fide ligand but other unknown ligands dominate whole-mycobacterium-DC-SIGN interactions.","method":"Binding assay with synthetic and natural PIMs, M. bovis BCG pimE mutant and double-knockout (ΔpimE ΔcapA) binding assays to DC-SIGN and DCs, cytokine stimulation assays","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay with purified/synthetic ligands plus genetic mutant bacteria; multiple orthogonal approaches; single lab","pmids":["19651855"],"is_preprint":false},{"year":2009,"finding":"DC-SIGN exists in discrete nanoscale clusters on the plasma membrane of dendritic cells, is polarized to the leading edge of the lamellipod, and clusters exhibit two modes of lateral mobility: directed (at ~1420 nm/s toward lamellar sites of internalization) and non-directed. Endocytosis of DC-SIGN clusters occurs preferentially at lamellar sites posterior to the leading edge.","method":"Live-cell confocal microscopy, single particle tracking, fluorescence imaging in primary DCs and DC-SIGN transfectants","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live-cell imaging and single-particle tracking with quantitative mobility measurements; functional localization to endocytosis zones established","pmids":["18270264"],"is_preprint":false},{"year":2009,"finding":"Surface force measurements show DC-SIGN adopts an extended conformation and that glycan docking is associated with a conformational change that repositions carbohydrate-recognition domains during ligand binding. Lateral mobility of membrane-bound ligands enhances engagement of multiple CRDs in the DC-SIGN oligomer with appropriately spaced ligands.","method":"Surface force apparatus measurements between apposed lipid bilayers displaying DC-SIGN ectodomain and neoglycolipid ligands","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biophysical reconstitution (surface force measurements) with mechanistic conformational change readout; single lab","pmids":["19553201"],"is_preprint":false},{"year":2011,"finding":"Several phleboviruses (Rift Valley fever virus, Uukuniemi virus) exploit DC-SIGN as an authentic entry receptor via interactions with high-mannose N-glycans on viral glycoproteins; DC-SIGN is required for both virus internalization and infection. An endocytosis-defective DC-SIGN mutant cannot mediate virus uptake. After internalization, viruses separate from DC-SIGN and traffic to late endosomes.","method":"DC-SIGN endocytosis-defective mutant expression, live-cell imaging of virus-receptor interactions, antibody blocking, infection assays in DC-SIGN-expressing cells","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — endocytosis-defective mutant proving receptor requirement for internalization plus real-time imaging; multiple orthogonal methods","pmids":["21767814"],"is_preprint":false},{"year":2014,"finding":"NMR structural characterization of DC-SIGN CRD binding to Lewis X trisaccharide identified residues near the binding site and bound conformations distinct from those in crystal structures; the Le(X) binding mode differs from mannose-terminated saccharide binding.","method":"2D NMR (HSQC chemical shift perturbation), saturation transfer difference NMR, transferred NOE NMR, molecular docking using tetrameric DC-SIGN","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple NMR methods (HSQC, STD, trNOE) providing structural binding data with restraint-based modeling; single lab","pmids":["25121780"],"is_preprint":false},{"year":2014,"finding":"HHV-8 glycoprotein B (gB) binds DC-SIGN in a dose-dependent manner; gB has high-mannose carbohydrate structure. Key amino acids in the DC-SIGN carbohydrate recognition domain required for HHV-8 infection were identified and differ from the ICAM-2/3 and HIV-1 gp120 binding regions.","method":"Dose-dependent binding assays of gB to DC-SIGN, CRD mutagenesis, infection assays, glycan characterization of gB","journal":"Virus research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with mutagenesis of DC-SIGN CRD; single lab","pmids":["25018023"],"is_preprint":false},{"year":2015,"finding":"DC-SIGN-expressing macrophages mediate transplantation tolerance; simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling is required for immunoregulatory IL-10 production. Deletion of DC-SIGN-expressing macrophages or interference with DC-SIGN signaling abrogates tolerance.","method":"In vivo deletion of DC-SIGN+ macrophages, genetic/pharmacologic interference with DC-SIGN signaling, cytokine production assays, allograft survival experiments","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo deletion plus signaling interference with functional (allograft survival, Treg expansion, IL-10) readouts; mechanistic pathway established","pmids":["26070485"],"is_preprint":false},{"year":2015,"finding":"DC-SIGN-expressing macrophages within the follicular lymphoma (FL) microenvironment bind mannosylated IgM BCR on FL B cells, triggering delayed but long-lasting BCR aggregation and activation. M2 macrophages induce DC-SIGN-dependent adhesion of highly mannosylated IgM+ FL B cells and trigger BCR-associated kinase activation.","method":"DC-SIGN binding assays to FL B cell BCR, BCR signaling assays, macrophage-FL B cell co-culture assays, pharmacologic BCR inhibitor experiments","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and functional kinase activation assays with inhibitor validation; single lab","pmids":["26272216"],"is_preprint":false},{"year":2015,"finding":"LECT2 (leukocyte cell-derived chemotaxin 2) signals through CD209 (DC-SIGN) to promote JNK phosphorylation in human endothelial cells; CD209 siRNA knockdown abolishes LECT2-induced JNK phosphorylation, ICAM-1 upregulation, and pro-inflammatory cytokine induction.","method":"siRNA knockdown of CD209, JNK phosphorylation assays (Western blot), qPCR for ICAM-1 and cytokines, JNK inhibitor experiments in HUVECs and THP-1 cells","journal":"Metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with biochemical signaling readout; single lab, single method for knockdown confirmation","pmids":["26123523"],"is_preprint":false},{"year":2016,"finding":"DC-SIGN binds specifically to α-fucosylated human milk glycans (HMGs); 2'-fucosyllactose (2'-FL) and 3-fucosyllactose (3-FL) bind DC-SIGN with IC50 of ~1 mM for 2'-FL. No other C-type lectins tested bound HMGs.","method":"Glycan microarray screening (>200 HMGs), flow cytometry bead-binding assays with conjugated glycans, competition inhibition assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — glycan microarray plus confirmatory flow cytometry competition assay; single lab","pmids":["26976925"],"is_preprint":false},{"year":2015,"finding":"In human milk, MUC1 is the major glycoprotein binding to DC-SIGN via Lewis x-type oligosaccharides, and this interaction blocks DC-SIGN-pathogen interactions. This was specific for human milk; formula, bovine, and camel milk did not contain proteins interacting with DC-SIGN.","method":"Lectin domain binding assays with human milk fractions, identification of MUC1 as binding partner, competition with pathogens, specificity comparison across milk types","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding identification of MUC1 as DC-SIGN ligand with competitive blocking readout; single lab","pmids":["25821450"],"is_preprint":false},{"year":2019,"finding":"DC-SIGN-mediated antigen routing is determined by antigen physical properties: soluble glycopolymers are routed to early endosomes, while particulate (aggregated) antigens are diverted to surface-accessible invaginated pockets that also harbor HIV-1, thus avoiding degradation.","method":"ROMP-synthesized glycopolymers with varying length/size, confocal microscopy colocalization with endosomal markers, live-cell trafficking assays, comparison with HIV-1 routing","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — well-controlled synthetic antigen series with quantitative confocal colocalization; mechanistic comparison between soluble vs particulate routing; single lab with rigorous design","pmids":["31270240"],"is_preprint":false},{"year":2019,"finding":"DC-SIGN interacts physically with Lyn kinase; DC-SIGN activation recruits Lyn and p85 to form a DC-SIGN-Lyn-p85 complex, promoting CRC metastasis via PI3K/Akt/β-catenin signaling in a Lyn-dependent manner. This leads to MMP-9 and VEGF transcription and TCF1/LEF1-mediated suppression of miR-185.","method":"Co-immunoprecipitation (DC-SIGN-Lyn-p85 complex), gain-of-function/loss-of-function assays, PI3K/Akt/β-catenin pathway assays, miR-185 expression, in vitro and in vivo metastasis assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing complex formation plus pathway inhibition; single lab; context is cancer cells, not canonical immune cells","pmids":["31217502"],"is_preprint":false},{"year":2021,"finding":"CD209 (DC-SIGN) interacts with the SARS-CoV-2 spike receptor-binding domain (S-RBD) and mediates SARS-CoV-2 entry into human endothelial cells; knockdown of CD209 or use of soluble CD209 inhibits virus entry. CD209 functions as an alternative receptor for SARS-CoV-2 in cells with low or absent ACE2.","method":"Biochemical binding assays (purified recombinant S-RBD and ectopically expressed CD209), siRNA knockdown, soluble CD209 inhibition, virus entry assays in human endothelial cells","journal":"ACS central science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple biochemical assays plus loss-of-function knockdown and soluble inhibitor; confirmed in disease-relevant primary human cells","pmids":["34341769"],"is_preprint":false},{"year":2010,"finding":"IL-4 is the primary inducer of DC-SIGN expression during monocyte-to-DC differentiation; GM-CSF cooperates with IL-4 for high-level expression. IFN-α, IFN-γ, TGF-β, and dexamethasone are negative regulators that prevent IL-4-dependent DC-SIGN induction and inhibit DC-SIGN-dependent HIV-1 binding.","method":"DC-SIGN-specific mAb detection, monocyte differentiation assays with various cytokines, mRNA quantification, HIV-1 binding inhibition assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cytokine manipulation with mRNA and protein readouts plus functional HIV binding assay; single lab","pmids":["11884427"],"is_preprint":false},{"year":2010,"finding":"IL-4 regulates DC-SIGN (CD209) expression on human Schwann cells; IL-4 increases CD209 expression and subsequent M. leprae binding to Schwann cells. Th1 cytokines do not induce CD209 on Schwann cells. CD209-positive Schwann cells show higher M. leprae binding than CD209-negative Schwann cells.","method":"Primary Schwann cell cultures, IL-4 treatment, M. leprae binding assays comparing CD209+ vs CD209- cells, immunohistochemistry on nerve biopsies","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional comparison of CD209+ vs CD209- Schwann cells with cytokine manipulation; supported by in situ biopsy data; single lab","pmids":["20713631"],"is_preprint":false},{"year":2014,"finding":"The neck domain of DC-SIGN, not the carbohydrate recognition domain (CRD), renders DC-SIGN higher binding affinity to HIV gp120 likely via tetramerization; DC-SIGN has better HIV-1 capture and transfer capability than DCIR.","method":"Soluble DC-SIGN/DCIR truncates and chimeras, comparative capture and transfer assays with a wide range of HIV-1 isolates, transfected cell lines","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chimeric domain-swap constructs with functional binding assays; single lab","pmids":["24928041"],"is_preprint":false},{"year":2021,"finding":"A secondary binding pocket remote from DC-SIGN's carbohydrate binding site can accommodate aromatic aglycone moieties of glycomimetics, and engagement of this pocket leads to allosteric enhancement of glycan recognition, enabling heteromultivalent cell targeting specific to DC-SIGN+ cells.","method":"NMR spectroscopy, molecular docking, molecular dynamics simulations, heteromultivalent liposome cell-binding assays in DC-SIGN+ vs Langerin+ cell lines","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR plus MD simulations with cell-based functional validation; secondary pocket is novel structural finding; single lab","pmids":["34748320"],"is_preprint":false},{"year":2019,"finding":"19F-NMR identifies a new binding mode where mannose coordinates a Ca2+ ion in the DC-SIGN CRD lectin carbohydrate recognition domain through axial OH-2 and equatorial OH-3 groups, mimicking the fucose/DC-SIGN binding architecture. Fucose binds with highest affinity among monosaccharides tested (Fuc > Man > Glc > Gal).","method":"19F-NMR competitive binding assays, 1H-STD-NMR, molecular dynamics simulations using purified DC-SIGN CRD","journal":"Molecules","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple NMR methods (19F and STD) with MD simulations; novel binding mode; single lab","pmids":["31242623"],"is_preprint":false}],"current_model":"CD209 (DC-SIGN) is a type II transmembrane C-type lectin expressed on dendritic cells and certain macrophages that functions as a multivalent pattern recognition receptor binding mannose- and fucose-containing glycans on pathogens (HIV-1 gp120, mycobacterial ManLAM/PIMs, dengue, Ebola, HCV, HHV-8 gB, SARS-CoV-2 spike RBD, and others) via its calcium-dependent carbohydrate recognition domain; upon ligand binding, DC-SIGN can act as an attachment/trans-infection factor (capturing virus and delivering it to T cells), an endocytic receptor trafficking cargo to late endosomes/lysosomes for antigen presentation on MHC-II or cross-presentation on MHC-I, or a signaling receptor that activates Raf-1, leading to NF-κB p65 acetylation, and also signals through Lyn, Syk, PLCgamma, and PI3K/Akt to modulate TLR-induced cytokine responses; its tetramerization via the neck domain enhances multivalent ligand binding, antigen physical properties determine intracellular routing, and DC-SIGN expression is positively regulated by IL-4/GM-CSF and negatively by IFN and TGF-β."},"narrative":{"mechanistic_narrative":"CD209 (DC-SIGN) is a calcium-dependent C-type lectin that operates as a multivalent pattern-recognition and adhesion receptor on dendritic cells and macrophages, recognizing mannose- and fucose-terminated glycans to capture pathogens and shape adaptive immunity [PMID:10721995, PMID:12515809, PMID:31242623]. Its carbohydrate-recognition domain coordinates a Ca2+ ion to engage mannose (via axial OH-2/equatorial OH-3) and fucose with highest affinity among monosaccharides, and accommodates Lewis X glycans in a binding mode distinct from mannose-terminated ligands [PMID:31242623, PMID:25121780]; high-avidity ligand engagement depends on neck-domain tetramerization, which confers strong binding to HIV-1 gp120, while neck glycosylation and natural neck variants tune oligomerization and sugar binding [PMID:24928041, PMID:18073208]. Through this glycan-recognition machinery DC-SIGN binds an exceptionally broad range of pathogens — HIV-1 gp120, mycobacterial ManLAM and hexamannosylated PIM6, dengue virus, Ebola and measles glycoproteins, HCV E2, HHV-8 gB, phlebovirus glycoproteins, and the SARS-CoV-2 spike RBD — as well as host ligands ICAM-2 and fucosylated milk glycans/MUC1 [PMID:10721995, PMID:12515809, PMID:19651855, PMID:12682107, PMID:16537615, PMID:12634366, PMID:25018023, PMID:21767814, PMID:34341769, PMID:11017109, PMID:25821450]. Functionally it acts in three modes: as an adhesion molecule supporting DC tethering and rolling on endothelial ICAM-2 under shear flow [PMID:11017109]; as an attachment/trans-infection factor that captures virus (HIV-1, HCV, measles) for delivery to susceptible target cells or, for phleboviruses, as an authentic endocytic entry receptor [PMID:10721995, PMID:15371595, PMID:16537615, PMID:21767814]; and as an endocytic antigen receptor whose cytoplasmic internalization motifs route ligand to late endosomes/lysosomes for MHC-II presentation, with particulate versus soluble antigen physical properties dictating intracellular routing and a fraction directed to proteasome-dependent MHC-I cross-presentation [PMID:11859097, PMID:31270240, PMID:14576049]. DC-SIGN is also a signaling receptor: ligation activates Raf-1 leading to NF-κB p65 acetylation that modulates TLR-induced cytokine output, and it couples to Lyn/Syk, PLCγ, ERK/Akt and calcium flux from lipid-raft-associated complexes [PMID:18998127, PMID:16434485]. In vivo, coordinate DC-SIGN and TLR4 engagement by fucosylated ligands drives immunoregulatory IL-10 and transplantation tolerance [PMID:26070485], while DC-SIGN nanoscale clusters polarized to the lamellipod and a conformational change upon glycan docking provide the spatial and biophysical basis for multivalent capture and endocytosis [PMID:18270264, PMID:19553201]. DC-SIGN expression is induced by IL-4 with GM-CSF and repressed by IFNs and TGF-β [PMID:11884427].","teleology":[{"year":2000,"claim":"Established DC-SIGN's founding function as a pathogen-capture receptor that promotes infection of bystander cells rather than its own host cell, defining the trans-infection paradigm.","evidence":"Co-binding and trans-infection assays of HIV-1 gp120 in primary DCs and transfectants","pmids":["10721995"],"confidence":"High","gaps":["Molecular basis of high-avidity gp120 binding not yet resolved","Did not address endocytic routing of captured virus"]},{"year":2000,"claim":"Showed DC-SIGN is also an adhesion receptor for endothelial ICAM-2, explaining how DC-SIGN+ cells tether, roll, and transmigrate, linking the lectin to leukocyte trafficking.","evidence":"Shear-flow chamber assays with antibody blocking in transfectants and primary DCs","pmids":["11017109"],"confidence":"High","gaps":["Glycan determinant on ICAM-2 not mapped here","Relationship between adhesion and pathogen-binding sites unresolved"]},{"year":2000,"claim":"Mapped the CD209/CD209L locus and predicted the tandem-repeat neck and mannose-binding lectin domain architecture from sequence, providing the structural framework for later function.","evidence":"Genomic mapping, sequence analysis, tissue expression studies","pmids":["10975799"],"confidence":"Medium","gaps":["Coiled-coil and lectin predictions not yet tested by mutagenesis","Functional consequences of neck repeats unestablished"]},{"year":2002,"claim":"Defined DC-SIGN as an endocytic antigen receptor by showing cytoplasmic internalization motifs drive ligand uptake to late endosomes/lysosomes and feed MHC-II antigen presentation.","evidence":"Cytoplasmic tail mutagenesis, fluorescence/EM imaging, CD4+ T cell presentation assays","pmids":["11859097"],"confidence":"High","gaps":["Adaptors recognizing the internalization motif not identified","Determinants of routing beyond the motif unexamined"]},{"year":2003,"claim":"Identified DC-SIGN as the major dendritic-cell receptor for mycobacteria through ManLAM/LAM, and showed ligation subverts TLR-driven DC maturation, establishing an immune-evasion role.","evidence":"Antibody blocking, purified ManLAM/LAM binding, DC maturation and infection assays","pmids":["12515809","12515819"],"confidence":"High","gaps":["Signaling pathway linking ManLAM to maturation block not yet defined","Other mycobacterial ligands not excluded"]},{"year":2003,"claim":"Broadened the ligand repertoire to demonstrate DC-SIGN serves as receptor or attachment factor for diverse pathogens (dengue, Ebola, HCV, Candida, Leishmania) and routes some cargo for MHC-I cross-presentation.","evidence":"Transfection gain-of-function, antibody blocking, pseudotype and binding assays, proteasome-inhibition/CTL assays across multiple pathogens","pmids":["12682107","12504546","12634366","12645952","14707095","14576049"],"confidence":"Medium","gaps":["Which pathogens use DC-SIGN for productive entry versus attachment-only varies and is not uniformly resolved","Distinct endocytic compartments for different cargo not fully characterized"]},{"year":2006,"claim":"Demonstrated DC-SIGN is a bona fide signaling receptor coupling to Lyn/Syk, PLCγ, ERK/Akt and calcium flux from lipid rafts to modulate cytokine responses.","evidence":"Antibody cross-linking, phosphorylation and calcium assays, raft fractionation, Co-IP with Lyn/Syk, cytokine ELISA","pmids":["16434485"],"confidence":"High","gaps":["Direct kinase–DC-SIGN interaction stoichiometry not defined","Link between proximal kinases and transcriptional output incomplete"]},{"year":2006,"claim":"Extended pathogen recognition to HHV-8, measles, Neisseria and platelet-mediated HIV capture, showing ligand-driven outcomes range from infection enhancement to receptor downregulation and immune suppression.","evidence":"Transfectant infection, soluble receptor/mannan blocking, glycan-mutant bacteria, platelet capture/infectivity assays","pmids":["16424204","16537615","16461738","16940507"],"confidence":"Medium","gaps":["Mechanism of HHV-8-induced DC-SIGN downregulation not defined","In vivo relevance of platelet capture untested"]},{"year":2008,"claim":"Defined Raf-1 as a central node downstream of pathogen-triggered DC-SIGN, with NF-κB p65 acetylation as the effector that tunes TLR-induced gene programs.","evidence":"Kinase and p65 acetylation assays, gene-transcription profiling synthesized across pathogen studies","pmids":["18998127"],"confidence":"Medium","gaps":["How distinct ligands selectively engage Raf-1 versus other pathways unclear","Connection between proximal Lyn/Syk and Raf-1 not bridged"]},{"year":2009,"claim":"Resolved the spatial and biophysical mechanics of multivalent capture: nanoscale clusters polarized to the lamellipod, directed lateral mobility to endocytic zones, and a glycan-docking conformational change repositioning the CRDs.","evidence":"Single-particle tracking live-cell imaging and surface-force measurements on DC-SIGN ectodomain/glycan bilayers","pmids":["18270264","19553201"],"confidence":"High","gaps":["Cytoskeletal machinery driving directed cluster transport not identified","Conformational change not visualized at atomic resolution"]},{"year":2009,"claim":"Dissected mycobacterial PIM ligands, showing hexamannosylated PIM6 is a high-affinity ligand but is dispensable for whole-bacterium binding, indicating redundant ligands.","evidence":"Synthetic/natural PIM binding and pimE-mutant BCG binding to DC-SIGN and DCs","pmids":["19651855"],"confidence":"High","gaps":["Dominant ligand on intact mycobacteria remains unidentified"]},{"year":2014,"claim":"Provided atomic-level glycan recognition detail, defining distinct Lewis X versus mannose binding modes and confirming the neck domain drives high-affinity gp120 binding via tetramerization.","evidence":"HSQC/STD/trNOE NMR with docking; domain-swap chimeras with HIV capture/transfer assays","pmids":["25121780","24928041"],"confidence":"High","gaps":["Functional consequence of distinct binding modes for antigen routing untested","Neck contribution to non-HIV ligands not generalized"]},{"year":2015,"claim":"Established an immunoregulatory, tolerogenic role in vivo where fucose-driven DC-SIGN signaling cooperates with TLR4 to produce IL-10 and sustain transplantation tolerance, and a pathological role in follicular lymphoma BCR triggering.","evidence":"In vivo macrophage deletion and signaling interference with allograft/IL-10 readouts; FL B-cell BCR aggregation and kinase activation assays","pmids":["26070485","26272216"],"confidence":"High","gaps":["Signaling branch distinguishing tolerogenic IL-10 from inflammatory output not fully mapped","FL findings from single lab and microenvironment-dependent"]},{"year":2019,"claim":"Showed antigen physical properties dictate intracellular routing — soluble glycopolymers to early endosomes, particulates to surface-accessible pockets shared with HIV-1 — explaining differential degradation versus retention.","evidence":"Defined synthetic glycopolymer series with quantitative confocal colocalization and trafficking","pmids":["31270240"],"confidence":"High","gaps":["Molecular sorting machinery distinguishing the routes unknown","Consequences for presentation efficiency not quantified"]},{"year":2019,"claim":"Refined the carbohydrate-recognition chemistry, defining mannose Ca2+ coordination via axial OH-2/equatorial OH-3 and the fucose>mannose affinity hierarchy.","evidence":"19F- and 1H-STD-NMR with molecular dynamics on purified CRD","pmids":["31242623"],"confidence":"Medium","gaps":["Single-lab in vitro CRD studies; cellular relevance of binding hierarchy not tested"]},{"year":2021,"claim":"Identified non-canonical activities: a SARS-CoV-2 spike-RBD entry-receptor role in ACE2-low endothelial cells, a druggable allosteric secondary pocket enhancing glycan recognition, and a Lyn/p85-dependent pro-metastatic signaling axis in colorectal cancer.","evidence":"S-RBD binding/siRNA/soluble-CD209 entry assays; NMR/MD with heteromultivalent liposome targeting; Co-IP and PI3K/Akt/β-catenin pathway and metastasis assays","pmids":["34341769","34748320","31217502"],"confidence":"High","gaps":["Physiological contribution of CD209 to SARS-CoV-2 infection in vivo unclear","Cancer signaling role from single lab in non-immune context"]},{"year":null,"claim":"How distinct ligands and antigen physical states selectively bias DC-SIGN between adhesion, trans-infection, endocytic presentation, and the Raf-1/NF-κB versus Lyn/Syk signaling outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model connecting ligand identity to signaling versus trafficking decisions","Adaptors linking cytoplasmic tail motifs to specific routes unidentified","In vivo physiological ligand spectrum incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[6,23,33]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[3,8,31]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[13,19,26]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[21,13]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3,31]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[3,10]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,13,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,6,33]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[19,13,32]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,23,31]}],"complexes":[],"partners":["ICAM2","LYN","SYK","PIK3R1","RAF1","LECT2","MUC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NNX6","full_name":"CD209 antigen","aliases":["C-type lectin domain family 4 member L","Dendritic cell-specific ICAM-3-grabbing non-integrin 1","DC-SIGN","DC-SIGN1"],"length_aa":404,"mass_kda":45.8,"function":"Pathogen-recognition receptor expressed on the surface of immature dendritic cells (DCs) and involved in initiation of primary immune response. Thought to mediate the endocytosis of pathogens which are subsequently degraded in lysosomal compartments. The receptor returns to the cell membrane surface and the pathogen-derived antigens are presented to resting T-cells via MHC class II proteins to initiate the adaptive immune response On dendritic cells (DCs) it is a high affinity receptor for ICAM2 and ICAM3 by binding to mannose-like carbohydrates (PubMed:10721994, PubMed:10721995, PubMed:11017109, PubMed:12574325). May act as a DC rolling receptor that mediates transendothelial migration of DC presursors from blood to tissues by binding endothelial ICAM2 (PubMed:11017109). Forms a first contact between DC and resting T cell, througth ICAM3 binding, facilitating the downstream DC-T cell clustering process and DC-induced proliferation of resting T Cells (PubMed:10721994, PubMed:10721995) (Microbial infection) Acts as an attachment receptor for HIV-1 and HIV-2 (Microbial infection) Acts as an attachment receptor for Ebolavirus (Microbial infection) Acts as an attachment receptor for Cytomegalovirus (Microbial infection) Acts as an attachment receptor for HCV (Microbial infection) Acts as an attachment receptor for Dengue virus (Microbial infection) Acts as an attachment receptor for Measles virus (Microbial infection) Acts as an attachment receptor for Herpes simplex virus 1 (Microbial infection) Acts as an attachment receptor for Influenzavirus A (Microbial infection) Acts as an attachment receptor for SARS-CoV (Microbial infection) Acts as an attachment receptor for Japanese encephalitis virus (Microbial infection) Acts as an attachment receptor for Lassa virus (PubMed:23966408). Acts as an attachment receptor for Marburg virusn (Microbial infection) Acts as an attachment receptor for Respiratory syncytial virus (Microbial infection) Acts as an attachment receptor for Rift valley fever virus and uukuniemi virus (Microbial infection) Acts as an attachment receptor for West-nile virus (Microbial infection) Probably recognizes in a calcium-dependent manner high mannose N-linked oligosaccharides in a variety of bacterial pathogen antigens, including Leishmania pifanoi LPG, Lewis-x antigen in Helicobacter pylori LPS, mannose in Klebsiella pneumonae LPS, di-mannose and tri-mannose in Mycobacterium tuberculosis ManLAM and Lewis-x antigen in Schistosoma mansoni SEA (PubMed:16379498). Recognition of M.tuberculosis by dendritic cells occurs partially via this molecule (PubMed:16092920, PubMed:21203928)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9NNX6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD209","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/CD209","total_profiled":1310},"omim":[{"mim_id":"616256","title":"C-TYPE LECTIN DOMAIN FAMILY 4, MEMBER G; CLEC4G","url":"https://www.omim.org/entry/616256"},{"mim_id":"614371","title":"DENGUE VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/614371"},{"mim_id":"609532","title":"HEPATITIS C VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609532"},{"mim_id":"609423","title":"HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609423"},{"mim_id":"608487","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 5; TRIM5","url":"https://www.omim.org/entry/608487"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":32.0},{"tissue":"placenta","ntpm":21.4}],"url":"https://www.proteinatlas.org/search/CD209"},"hgnc":{"alias_symbol":["DC-SIGN","hDC-SIGN","CDSIGN","DC-SIGN1","CLEC4L"],"prev_symbol":[]},"alphafold":{"accession":"Q9NNX6","domains":[{"cath_id":"1.20.1440,1.20.1480","chopping":"69-160","consensus_level":"high","plddt":64.5866,"start":69,"end":160},{"cath_id":"3.10.100.10","chopping":"261-381","consensus_level":"high","plddt":96.4601,"start":261,"end":381},{"cath_id":"1.20.1440","chopping":"164-253","consensus_level":"high","plddt":79.649,"start":164,"end":253}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NNX6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NNX6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NNX6-F1-predicted_aligned_error_v6.png","plddt_mean":71.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD209","jax_strain_url":"https://www.jax.org/strain/search?query=CD209"},"sequence":{"accession":"Q9NNX6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NNX6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NNX6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NNX6"}},"corpus_meta":[{"pmid":"10721995","id":"PMC_10721995","title":"DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells.","date":"2000","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/10721995","citation_count":1890,"is_preprint":false},{"pmid":"12515809","id":"PMC_12515809","title":"Mycobacteria target DC-SIGN to suppress dendritic cell function.","date":"2003","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12515809","citation_count":797,"is_preprint":false},{"pmid":"12949494","id":"PMC_12949494","title":"DC-SIGN: escape mechanism for pathogens.","date":"2003","source":"Nature reviews. 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lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells.","date":"2003","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12645952","citation_count":296,"is_preprint":false},{"pmid":"12634366","id":"PMC_12634366","title":"Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR.","date":"2003","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12634366","citation_count":294,"is_preprint":false},{"pmid":"11884427","id":"PMC_11884427","title":"DC-SIGN (CD209) expression is IL-4 dependent and is negatively regulated by IFN, TGF-beta, and anti-inflammatory agents.","date":"2002","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11884427","citation_count":225,"is_preprint":false},{"pmid":"10975799","id":"PMC_10975799","title":"DC-SIGN; a related gene, DC-SIGNR; and CD23 form a cluster on 19p13.","date":"2000","source":"Journal of immunology 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\"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding and functional trans-infection assays replicated across multiple labs; foundational paper with multiple orthogonal methods\",\n      \"pmids\": [\"10721995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"DC-SIGN binds ICAM-2 on vascular endothelium and supports tethering and rolling of DC-SIGN-positive cells under shear flow, regulating chemokine-induced transmigration of dendritic cells across endothelium.\",\n      \"method\": \"Flow chamber assays under shear stress, antibody blocking, transfected cell lines expressing DC-SIGN\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional assay (shear flow rolling/tethering) with antibody blocking in both transfectants and primary DCs\",\n      \"pmids\": [\"11017109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"DC-SIGN and DC-SIGNR genes are located on chromosome 19p13 adjacent to CD23, share a similar genomic organization, and both encode proteins with tandem-repeat neck regions predicted to form coiled coils and mannose-binding C-type lectin domains.\",\n      \"method\": \"Genomic mapping, sequence analysis, expression studies in endometrium, placenta, and KG1 cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genomic and sequence characterization with expression data; structural inference from sequence without direct functional mutagenesis\",\n      \"pmids\": [\"10975799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DC-SIGN is rapidly internalized upon soluble ligand binding via internalization motifs in its cytoplasmic tail; mutating a putative internalization motif reduces ligand-induced internalization. DC-SIGN-ligand complexes traffic to late endosomes/lysosomes, and ligands internalized by DC-SIGN are efficiently processed and presented to CD4+ T cells.\",\n      \"method\": \"Cytoplasmic tail mutagenesis, ratio fluorescence imaging, electron microscopy, antigen presentation assays to CD4+ T cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of internalization motif combined with imaging (fluorescence + EM) and functional antigen presentation readout in one study\",\n      \"pmids\": [\"11859097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"DC-SIGN captures and internalizes intact Mycobacterium bovis BCG through binding to the mycobacterial cell wall component ManLAM (mannose-capped lipoarabinomannan); anti-DC-SIGN antibodies block this infection. ManLAM binding to DC-SIGN prevents mycobacteria- or LPS-induced DC maturation, interfering with TLR-mediated signaling.\",\n      \"method\": \"Anti-DC-SIGN antibody blocking, DC infection assays, DC maturation assays (LPS stimulation), purified ManLAM binding experiments\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — antibody blocking, purified ligand, functional maturation readout; replicated across multiple labs\",\n      \"pmids\": [\"12515809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"DC-SIGN is the major M. tuberculosis receptor on human dendritic cells; mycobacterial lipoarabinomannan (LAM) was identified as a key ligand. Complement receptor 3 and mannose receptor played minor roles in mycobacterial binding to DCs.\",\n      \"method\": \"Anti-DC-SIGN antibody blocking, binding assays with purified LAM, comparison with CR3/MR-blocking antibodies in human monocyte-derived DCs\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct antibody-blocking and purified ligand experiments; independently confirmed by Geijtenbeek et al. in same journal issue\",\n      \"pmids\": [\"12515819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"DC-SIGN (CD209) mediates productive dengue virus infection of human dendritic cells; all four dengue serotypes use DC-SIGN to infect DCs. Transfection of DC-SIGN into THP-1 cells confers dengue susceptibility; anti-DC-SIGN antibodies block DC infection.\",\n      \"method\": \"DC-SIGN transfection into THP-1 cells, anti-DC-SIGN antibody blocking, dengue infection assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function transfection and loss-of-function antibody blocking; multiple serotypes tested\",\n      \"pmids\": [\"12682107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"DC-SIGN binds Ebola glycoproteins and greatly enhances transduction of primary cells (macrophages, dendritic cells) and endothelial cells by Ebola virus pseudotypes; DC-SIGN and DC-SIGNR do not directly mediate Ebola virus entry but act as attachment/enhancement factors.\",\n      \"method\": \"Ebola pseudotype transduction assays, primary cell infections, antibody blocking, transfected cell lines\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional pseudotype and replication-competent virus assays in primary cells; single lab study\",\n      \"pmids\": [\"12504546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"DC-SIGN is an antigen-uptake receptor for Candida albicans on dendritic cells; DC-SIGN internalizes C. albicans into DC-SIGN-enriched vesicles that are distinct from mannose receptor-containing vesicles, indicating separate endocytic routing.\",\n      \"method\": \"Binding assays in DC-SIGN transfectants and primary DCs, fluorescence microscopy showing DC-SIGN-enriched vesicles, comparison with mannose receptor compartments\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and internalization assays in both transfectants and primary DCs; single lab\",\n      \"pmids\": [\"12645952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Hepatitis C virus E2 glycoprotein and E1/E2 pseudotypes bind DC-SIGN and DC-SIGNR expressed on cell lines and primary human endothelial cells; binding to immature MDDCs is dependent on DC-SIGN interactions.\",\n      \"method\": \"Binding assays with soluble E2 glycoprotein and HCV pseudotypes on DC-SIGN/DC-SIGNR transfectants and primary MDDCs; antibody-blocking experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pseudotype binding and blocking assays in primary cells and transfectants; single lab\",\n      \"pmids\": [\"12634366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"DC-SIGN expression on B-cell lines dramatically enhances HIV-1 internalization; most captured virions are rapidly degraded in a lysosomal compartment, but a fraction is processed by the proteasome leading to MHC-I-restricted antigen presentation and activation of HIV-specific CTLs.\",\n      \"method\": \"DC-SIGN transfection into B-cell lines, HIV internalization assays, proteasome inhibitor experiments, CTL activation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function transfection with multiple functional readouts (internalization, proteasome inhibition, CTL activation); single lab\",\n      \"pmids\": [\"14576049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DC-SIGN-captured HCV pseudoviruses are internalized and trans-infect adjacent human liver cells; virus capture and transinfection require internalization of the SIGN-HCV pseudovirus complex.\",\n      \"method\": \"HCV pseudovirus transinfection assays, L-SIGN/DC-SIGN+ cell lines, internalization-dependent trans-infection assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional pseudovirus transinfection assay demonstrating internalization requirement; single lab\",\n      \"pmids\": [\"15371595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DC-SIGN discriminates among Leishmania species and life cycle forms; it is a receptor for promastigote and amastigote stages of L. infantum and L. pifanoi but not for L. major metacyclic promastigotes. Leishmania binding to DC-SIGN is independent of lipophosphoglycan.\",\n      \"method\": \"Binding assays with different Leishmania species/stages on DC-SIGN-expressing cells; LPG-deficient parasite binding experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comparative binding assays with multiple species and ligand-deficient parasites; single lab\",\n      \"pmids\": [\"14707095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DC-SIGN engagement by specific antibodies induces ERK1/2 and Akt phosphorylation (without p38MAPK activation), PLCgamma phosphorylation, and transient intracellular calcium increases in DCs. A fraction of DC-SIGN partitions in lipid raft-enriched fractions and co-precipitates with tyrosine kinases Lyn and Syk. DC-SIGN cross-linking synergizes with TNF-α for IL-10 release and enhances LPS-induced IL-10.\",\n      \"method\": \"Antibody cross-linking, phosphorylation assays (ERK1/2, Akt, p38, PLCgamma), calcium flux assays, lipid raft fractionation, co-immunoprecipitation with Lyn and Syk, cytokine ELISA\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal signaling readouts (kinase phosphorylation, calcium flux, Co-IP, cytokine production) in primary DCs and transfectants\",\n      \"pmids\": [\"16434485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DC-SIGN is a receptor for Human Herpesvirus 8 (HHV-8) on myeloid DCs and macrophages; HHV-8 binding and infection are blocked by anti-DC-SIGN mAb, soluble DC-SIGN, and mannan. HHV-8 infection via DC-SIGN leads to down-regulation of DC-SIGN itself, decreased endocytic activity, and inhibition of CD8+ T cell antigen stimulation.\",\n      \"method\": \"Anti-DC-SIGN antibody and soluble DC-SIGN blocking, mannan competition, DC-SIGN transfected cell line infection assays, T cell stimulation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody/soluble receptor blocking and transfectant gain-of-function; multiple functional readouts; single lab\",\n      \"pmids\": [\"16424204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DC-SIGN and CLEC-2 both contribute to HIV-1 capture by platelets; platelets express low levels of DC-SIGN and DC-SIGN-dependent capture of HIV-1 maintains virus in an infectious state over several days.\",\n      \"method\": \"Flow cytometry for DC-SIGN on platelets, antibody blocking with DC-SIGN and CLEC-2 inhibitors, HIV-1 infectivity assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combination inhibitor blocking experiments with infectivity readout; single lab\",\n      \"pmids\": [\"16940507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DC-SIGN mediates recognition and phagocytosis of Neisseria gonorrhoeae by dendritic cells only for a specific lipooligosaccharide (LOS) mutant (lgtB); wild-type GC avoids DC-SIGN recognition through LOS variation. DC-SIGN-mediated phagocytosis is blocked by anti-DC-SIGN antibody.\",\n      \"method\": \"HeLa-DC-SIGN transfectants, GC lgtB mutant binding and phagocytosis assays, anti-DC-SIGN antibody blocking\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function transfection and mutant bacteria; antibody blocking; single lab\",\n      \"pmids\": [\"16461738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Measles virus glycoproteins F and H are both DC-SIGN ligands; DC-SIGN does not support MV entry (does not confer susceptibility in CHO cells) but functions as an attachment receptor enhancing CD46/CD150-mediated infection of immature DCs in cis.\",\n      \"method\": \"DC-SIGN transfection in CHO cells (entry assay), DC-SIGN inhibitor blocking of DC infection, MV glycoprotein binding experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function transfection showing no entry plus blocking showing attachment role; two orthogonal approaches; single lab\",\n      \"pmids\": [\"16537615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DC-SIGN neck region variants and the lectin domain both contribute to multimerization on the cell surface; glycosylation of the neck region negatively affects oligomer formation. Naturally occurring DC-SIGN neck variants differ in multimerization competence, exhibit altered sugar binding ability, but retain pathogen-interacting capacity.\",\n      \"method\": \"Structural analysis of neck variants, multimerization assays in transfected cells, sugar-binding assays, pathogen interaction assays with neck variant-expressing cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct structural and functional analysis of neck variants and glycosylation effects; single lab; multiple readouts\",\n      \"pmids\": [\"18073208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DC-SIGN triggering by pathogens activates a signaling pathway with a central role for the serine/threonine kinase Raf-1; Raf-1 activation leads to acetylation of NF-κB subunit p65, which induces specific gene transcription profiles and modulates TLR-induced cytokine responses.\",\n      \"method\": \"Kinase activation assays, NF-κB p65 acetylation assays, gene transcription profiling; described as established across multiple pathogen studies\",\n      \"journal\": \"Cancer immunology, immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical signaling assays (Raf-1, NF-κB p65 acetylation) established across multiple pathogen studies; review synthesizing original data\",\n      \"pmids\": [\"18998127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DC-SIGN hexamannosylated PIM6 (containing terminal α(1→2)-linked mannosyl residues identical to the ManLAM mannose cap) binds DC-SIGN with high affinity, whereas di- and tetramannosylated PIMs (PIM2 and PIM4) do not. However, a pimE deletion mutant M. bovis BCG lacking PIM6 binds DC-SIGN similarly to wild type, indicating PIM6 is a bona fide ligand but other unknown ligands dominate whole-mycobacterium-DC-SIGN interactions.\",\n      \"method\": \"Binding assay with synthetic and natural PIMs, M. bovis BCG pimE mutant and double-knockout (ΔpimE ΔcapA) binding assays to DC-SIGN and DCs, cytokine stimulation assays\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay with purified/synthetic ligands plus genetic mutant bacteria; multiple orthogonal approaches; single lab\",\n      \"pmids\": [\"19651855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DC-SIGN exists in discrete nanoscale clusters on the plasma membrane of dendritic cells, is polarized to the leading edge of the lamellipod, and clusters exhibit two modes of lateral mobility: directed (at ~1420 nm/s toward lamellar sites of internalization) and non-directed. Endocytosis of DC-SIGN clusters occurs preferentially at lamellar sites posterior to the leading edge.\",\n      \"method\": \"Live-cell confocal microscopy, single particle tracking, fluorescence imaging in primary DCs and DC-SIGN transfectants\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live-cell imaging and single-particle tracking with quantitative mobility measurements; functional localization to endocytosis zones established\",\n      \"pmids\": [\"18270264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Surface force measurements show DC-SIGN adopts an extended conformation and that glycan docking is associated with a conformational change that repositions carbohydrate-recognition domains during ligand binding. Lateral mobility of membrane-bound ligands enhances engagement of multiple CRDs in the DC-SIGN oligomer with appropriately spaced ligands.\",\n      \"method\": \"Surface force apparatus measurements between apposed lipid bilayers displaying DC-SIGN ectodomain and neoglycolipid ligands\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biophysical reconstitution (surface force measurements) with mechanistic conformational change readout; single lab\",\n      \"pmids\": [\"19553201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Several phleboviruses (Rift Valley fever virus, Uukuniemi virus) exploit DC-SIGN as an authentic entry receptor via interactions with high-mannose N-glycans on viral glycoproteins; DC-SIGN is required for both virus internalization and infection. An endocytosis-defective DC-SIGN mutant cannot mediate virus uptake. After internalization, viruses separate from DC-SIGN and traffic to late endosomes.\",\n      \"method\": \"DC-SIGN endocytosis-defective mutant expression, live-cell imaging of virus-receptor interactions, antibody blocking, infection assays in DC-SIGN-expressing cells\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — endocytosis-defective mutant proving receptor requirement for internalization plus real-time imaging; multiple orthogonal methods\",\n      \"pmids\": [\"21767814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NMR structural characterization of DC-SIGN CRD binding to Lewis X trisaccharide identified residues near the binding site and bound conformations distinct from those in crystal structures; the Le(X) binding mode differs from mannose-terminated saccharide binding.\",\n      \"method\": \"2D NMR (HSQC chemical shift perturbation), saturation transfer difference NMR, transferred NOE NMR, molecular docking using tetrameric DC-SIGN\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple NMR methods (HSQC, STD, trNOE) providing structural binding data with restraint-based modeling; single lab\",\n      \"pmids\": [\"25121780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HHV-8 glycoprotein B (gB) binds DC-SIGN in a dose-dependent manner; gB has high-mannose carbohydrate structure. Key amino acids in the DC-SIGN carbohydrate recognition domain required for HHV-8 infection were identified and differ from the ICAM-2/3 and HIV-1 gp120 binding regions.\",\n      \"method\": \"Dose-dependent binding assays of gB to DC-SIGN, CRD mutagenesis, infection assays, glycan characterization of gB\",\n      \"journal\": \"Virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with mutagenesis of DC-SIGN CRD; single lab\",\n      \"pmids\": [\"25018023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DC-SIGN-expressing macrophages mediate transplantation tolerance; simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling is required for immunoregulatory IL-10 production. Deletion of DC-SIGN-expressing macrophages or interference with DC-SIGN signaling abrogates tolerance.\",\n      \"method\": \"In vivo deletion of DC-SIGN+ macrophages, genetic/pharmacologic interference with DC-SIGN signaling, cytokine production assays, allograft survival experiments\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo deletion plus signaling interference with functional (allograft survival, Treg expansion, IL-10) readouts; mechanistic pathway established\",\n      \"pmids\": [\"26070485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DC-SIGN-expressing macrophages within the follicular lymphoma (FL) microenvironment bind mannosylated IgM BCR on FL B cells, triggering delayed but long-lasting BCR aggregation and activation. M2 macrophages induce DC-SIGN-dependent adhesion of highly mannosylated IgM+ FL B cells and trigger BCR-associated kinase activation.\",\n      \"method\": \"DC-SIGN binding assays to FL B cell BCR, BCR signaling assays, macrophage-FL B cell co-culture assays, pharmacologic BCR inhibitor experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and functional kinase activation assays with inhibitor validation; single lab\",\n      \"pmids\": [\"26272216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LECT2 (leukocyte cell-derived chemotaxin 2) signals through CD209 (DC-SIGN) to promote JNK phosphorylation in human endothelial cells; CD209 siRNA knockdown abolishes LECT2-induced JNK phosphorylation, ICAM-1 upregulation, and pro-inflammatory cytokine induction.\",\n      \"method\": \"siRNA knockdown of CD209, JNK phosphorylation assays (Western blot), qPCR for ICAM-1 and cytokines, JNK inhibitor experiments in HUVECs and THP-1 cells\",\n      \"journal\": \"Metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with biochemical signaling readout; single lab, single method for knockdown confirmation\",\n      \"pmids\": [\"26123523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DC-SIGN binds specifically to α-fucosylated human milk glycans (HMGs); 2'-fucosyllactose (2'-FL) and 3-fucosyllactose (3-FL) bind DC-SIGN with IC50 of ~1 mM for 2'-FL. No other C-type lectins tested bound HMGs.\",\n      \"method\": \"Glycan microarray screening (>200 HMGs), flow cytometry bead-binding assays with conjugated glycans, competition inhibition assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — glycan microarray plus confirmatory flow cytometry competition assay; single lab\",\n      \"pmids\": [\"26976925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In human milk, MUC1 is the major glycoprotein binding to DC-SIGN via Lewis x-type oligosaccharides, and this interaction blocks DC-SIGN-pathogen interactions. This was specific for human milk; formula, bovine, and camel milk did not contain proteins interacting with DC-SIGN.\",\n      \"method\": \"Lectin domain binding assays with human milk fractions, identification of MUC1 as binding partner, competition with pathogens, specificity comparison across milk types\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding identification of MUC1 as DC-SIGN ligand with competitive blocking readout; single lab\",\n      \"pmids\": [\"25821450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DC-SIGN-mediated antigen routing is determined by antigen physical properties: soluble glycopolymers are routed to early endosomes, while particulate (aggregated) antigens are diverted to surface-accessible invaginated pockets that also harbor HIV-1, thus avoiding degradation.\",\n      \"method\": \"ROMP-synthesized glycopolymers with varying length/size, confocal microscopy colocalization with endosomal markers, live-cell trafficking assays, comparison with HIV-1 routing\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — well-controlled synthetic antigen series with quantitative confocal colocalization; mechanistic comparison between soluble vs particulate routing; single lab with rigorous design\",\n      \"pmids\": [\"31270240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DC-SIGN interacts physically with Lyn kinase; DC-SIGN activation recruits Lyn and p85 to form a DC-SIGN-Lyn-p85 complex, promoting CRC metastasis via PI3K/Akt/β-catenin signaling in a Lyn-dependent manner. This leads to MMP-9 and VEGF transcription and TCF1/LEF1-mediated suppression of miR-185.\",\n      \"method\": \"Co-immunoprecipitation (DC-SIGN-Lyn-p85 complex), gain-of-function/loss-of-function assays, PI3K/Akt/β-catenin pathway assays, miR-185 expression, in vitro and in vivo metastasis assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing complex formation plus pathway inhibition; single lab; context is cancer cells, not canonical immune cells\",\n      \"pmids\": [\"31217502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD209 (DC-SIGN) interacts with the SARS-CoV-2 spike receptor-binding domain (S-RBD) and mediates SARS-CoV-2 entry into human endothelial cells; knockdown of CD209 or use of soluble CD209 inhibits virus entry. CD209 functions as an alternative receptor for SARS-CoV-2 in cells with low or absent ACE2.\",\n      \"method\": \"Biochemical binding assays (purified recombinant S-RBD and ectopically expressed CD209), siRNA knockdown, soluble CD209 inhibition, virus entry assays in human endothelial cells\",\n      \"journal\": \"ACS central science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple biochemical assays plus loss-of-function knockdown and soluble inhibitor; confirmed in disease-relevant primary human cells\",\n      \"pmids\": [\"34341769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-4 is the primary inducer of DC-SIGN expression during monocyte-to-DC differentiation; GM-CSF cooperates with IL-4 for high-level expression. IFN-α, IFN-γ, TGF-β, and dexamethasone are negative regulators that prevent IL-4-dependent DC-SIGN induction and inhibit DC-SIGN-dependent HIV-1 binding.\",\n      \"method\": \"DC-SIGN-specific mAb detection, monocyte differentiation assays with various cytokines, mRNA quantification, HIV-1 binding inhibition assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cytokine manipulation with mRNA and protein readouts plus functional HIV binding assay; single lab\",\n      \"pmids\": [\"11884427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-4 regulates DC-SIGN (CD209) expression on human Schwann cells; IL-4 increases CD209 expression and subsequent M. leprae binding to Schwann cells. Th1 cytokines do not induce CD209 on Schwann cells. CD209-positive Schwann cells show higher M. leprae binding than CD209-negative Schwann cells.\",\n      \"method\": \"Primary Schwann cell cultures, IL-4 treatment, M. leprae binding assays comparing CD209+ vs CD209- cells, immunohistochemistry on nerve biopsies\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional comparison of CD209+ vs CD209- Schwann cells with cytokine manipulation; supported by in situ biopsy data; single lab\",\n      \"pmids\": [\"20713631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The neck domain of DC-SIGN, not the carbohydrate recognition domain (CRD), renders DC-SIGN higher binding affinity to HIV gp120 likely via tetramerization; DC-SIGN has better HIV-1 capture and transfer capability than DCIR.\",\n      \"method\": \"Soluble DC-SIGN/DCIR truncates and chimeras, comparative capture and transfer assays with a wide range of HIV-1 isolates, transfected cell lines\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimeric domain-swap constructs with functional binding assays; single lab\",\n      \"pmids\": [\"24928041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A secondary binding pocket remote from DC-SIGN's carbohydrate binding site can accommodate aromatic aglycone moieties of glycomimetics, and engagement of this pocket leads to allosteric enhancement of glycan recognition, enabling heteromultivalent cell targeting specific to DC-SIGN+ cells.\",\n      \"method\": \"NMR spectroscopy, molecular docking, molecular dynamics simulations, heteromultivalent liposome cell-binding assays in DC-SIGN+ vs Langerin+ cell lines\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR plus MD simulations with cell-based functional validation; secondary pocket is novel structural finding; single lab\",\n      \"pmids\": [\"34748320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"19F-NMR identifies a new binding mode where mannose coordinates a Ca2+ ion in the DC-SIGN CRD lectin carbohydrate recognition domain through axial OH-2 and equatorial OH-3 groups, mimicking the fucose/DC-SIGN binding architecture. Fucose binds with highest affinity among monosaccharides tested (Fuc > Man > Glc > Gal).\",\n      \"method\": \"19F-NMR competitive binding assays, 1H-STD-NMR, molecular dynamics simulations using purified DC-SIGN CRD\",\n      \"journal\": \"Molecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple NMR methods (19F and STD) with MD simulations; novel binding mode; single lab\",\n      \"pmids\": [\"31242623\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD209 (DC-SIGN) is a type II transmembrane C-type lectin expressed on dendritic cells and certain macrophages that functions as a multivalent pattern recognition receptor binding mannose- and fucose-containing glycans on pathogens (HIV-1 gp120, mycobacterial ManLAM/PIMs, dengue, Ebola, HCV, HHV-8 gB, SARS-CoV-2 spike RBD, and others) via its calcium-dependent carbohydrate recognition domain; upon ligand binding, DC-SIGN can act as an attachment/trans-infection factor (capturing virus and delivering it to T cells), an endocytic receptor trafficking cargo to late endosomes/lysosomes for antigen presentation on MHC-II or cross-presentation on MHC-I, or a signaling receptor that activates Raf-1, leading to NF-κB p65 acetylation, and also signals through Lyn, Syk, PLCgamma, and PI3K/Akt to modulate TLR-induced cytokine responses; its tetramerization via the neck domain enhances multivalent ligand binding, antigen physical properties determine intracellular routing, and DC-SIGN expression is positively regulated by IL-4/GM-CSF and negatively by IFN and TGF-β.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD209 (DC-SIGN) is a calcium-dependent C-type lectin that operates as a multivalent pattern-recognition and adhesion receptor on dendritic cells and macrophages, recognizing mannose- and fucose-terminated glycans to capture pathogens and shape adaptive immunity [#0, #4, #38]. Its carbohydrate-recognition domain coordinates a Ca2+ ion to engage mannose (via axial OH-2/equatorial OH-3) and fucose with highest affinity among monosaccharides, and accommodates Lewis X glycans in a binding mode distinct from mannose-terminated ligands [#38, #24]; high-avidity ligand engagement depends on neck-domain tetramerization, which confers strong binding to HIV-1 gp120, while neck glycosylation and natural neck variants tune oligomerization and sugar binding [#36, #18]. Through this glycan-recognition machinery DC-SIGN binds an exceptionally broad range of pathogens — HIV-1 gp120, mycobacterial ManLAM and hexamannosylated PIM6, dengue virus, Ebola and measles glycoproteins, HCV E2, HHV-8 gB, phlebovirus glycoproteins, and the SARS-CoV-2 spike RBD — as well as host ligands ICAM-2 and fucosylated milk glycans/MUC1 [#0, #4, #20, #6, #17, #9, #25, #23, #33, #1, #30]. Functionally it acts in three modes: as an adhesion molecule supporting DC tethering and rolling on endothelial ICAM-2 under shear flow [#1]; as an attachment/trans-infection factor that captures virus (HIV-1, HCV, measles) for delivery to susceptible target cells or, for phleboviruses, as an authentic endocytic entry receptor [#0, #11, #17, #23]; and as an endocytic antigen receptor whose cytoplasmic internalization motifs route ligand to late endosomes/lysosomes for MHC-II presentation, with particulate versus soluble antigen physical properties dictating intracellular routing and a fraction directed to proteasome-dependent MHC-I cross-presentation [#3, #31, #10]. DC-SIGN is also a signaling receptor: ligation activates Raf-1 leading to NF-κB p65 acetylation that modulates TLR-induced cytokine output, and it couples to Lyn/Syk, PLCγ, ERK/Akt and calcium flux from lipid-raft-associated complexes [#19, #13]. In vivo, coordinate DC-SIGN and TLR4 engagement by fucosylated ligands drives immunoregulatory IL-10 and transplantation tolerance [#26], while DC-SIGN nanoscale clusters polarized to the lamellipod and a conformational change upon glycan docking provide the spatial and biophysical basis for multivalent capture and endocytosis [#21, #22]. DC-SIGN expression is induced by IL-4 with GM-CSF and repressed by IFNs and TGF-β [#34].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established DC-SIGN's founding function as a pathogen-capture receptor that promotes infection of bystander cells rather than its own host cell, defining the trans-infection paradigm.\",\n      \"evidence\": \"Co-binding and trans-infection assays of HIV-1 gp120 in primary DCs and transfectants\",\n      \"pmids\": [\"10721995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of high-avidity gp120 binding not yet resolved\", \"Did not address endocytic routing of captured virus\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed DC-SIGN is also an adhesion receptor for endothelial ICAM-2, explaining how DC-SIGN+ cells tether, roll, and transmigrate, linking the lectin to leukocyte trafficking.\",\n      \"evidence\": \"Shear-flow chamber assays with antibody blocking in transfectants and primary DCs\",\n      \"pmids\": [\"11017109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycan determinant on ICAM-2 not mapped here\", \"Relationship between adhesion and pathogen-binding sites unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapped the CD209/CD209L locus and predicted the tandem-repeat neck and mannose-binding lectin domain architecture from sequence, providing the structural framework for later function.\",\n      \"evidence\": \"Genomic mapping, sequence analysis, tissue expression studies\",\n      \"pmids\": [\"10975799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Coiled-coil and lectin predictions not yet tested by mutagenesis\", \"Functional consequences of neck repeats unestablished\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined DC-SIGN as an endocytic antigen receptor by showing cytoplasmic internalization motifs drive ligand uptake to late endosomes/lysosomes and feed MHC-II antigen presentation.\",\n      \"evidence\": \"Cytoplasmic tail mutagenesis, fluorescence/EM imaging, CD4+ T cell presentation assays\",\n      \"pmids\": [\"11859097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptors recognizing the internalization motif not identified\", \"Determinants of routing beyond the motif unexamined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified DC-SIGN as the major dendritic-cell receptor for mycobacteria through ManLAM/LAM, and showed ligation subverts TLR-driven DC maturation, establishing an immune-evasion role.\",\n      \"evidence\": \"Antibody blocking, purified ManLAM/LAM binding, DC maturation and infection assays\",\n      \"pmids\": [\"12515809\", \"12515819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway linking ManLAM to maturation block not yet defined\", \"Other mycobacterial ligands not excluded\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Broadened the ligand repertoire to demonstrate DC-SIGN serves as receptor or attachment factor for diverse pathogens (dengue, Ebola, HCV, Candida, Leishmania) and routes some cargo for MHC-I cross-presentation.\",\n      \"evidence\": \"Transfection gain-of-function, antibody blocking, pseudotype and binding assays, proteasome-inhibition/CTL assays across multiple pathogens\",\n      \"pmids\": [\"12682107\", \"12504546\", \"12634366\", \"12645952\", \"14707095\", \"14576049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which pathogens use DC-SIGN for productive entry versus attachment-only varies and is not uniformly resolved\", \"Distinct endocytic compartments for different cargo not fully characterized\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated DC-SIGN is a bona fide signaling receptor coupling to Lyn/Syk, PLCγ, ERK/Akt and calcium flux from lipid rafts to modulate cytokine responses.\",\n      \"evidence\": \"Antibody cross-linking, phosphorylation and calcium assays, raft fractionation, Co-IP with Lyn/Syk, cytokine ELISA\",\n      \"pmids\": [\"16434485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase–DC-SIGN interaction stoichiometry not defined\", \"Link between proximal kinases and transcriptional output incomplete\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended pathogen recognition to HHV-8, measles, Neisseria and platelet-mediated HIV capture, showing ligand-driven outcomes range from infection enhancement to receptor downregulation and immune suppression.\",\n      \"evidence\": \"Transfectant infection, soluble receptor/mannan blocking, glycan-mutant bacteria, platelet capture/infectivity assays\",\n      \"pmids\": [\"16424204\", \"16537615\", \"16461738\", \"16940507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of HHV-8-induced DC-SIGN downregulation not defined\", \"In vivo relevance of platelet capture untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined Raf-1 as a central node downstream of pathogen-triggered DC-SIGN, with NF-κB p65 acetylation as the effector that tunes TLR-induced gene programs.\",\n      \"evidence\": \"Kinase and p65 acetylation assays, gene-transcription profiling synthesized across pathogen studies\",\n      \"pmids\": [\"18998127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How distinct ligands selectively engage Raf-1 versus other pathways unclear\", \"Connection between proximal Lyn/Syk and Raf-1 not bridged\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the spatial and biophysical mechanics of multivalent capture: nanoscale clusters polarized to the lamellipod, directed lateral mobility to endocytic zones, and a glycan-docking conformational change repositioning the CRDs.\",\n      \"evidence\": \"Single-particle tracking live-cell imaging and surface-force measurements on DC-SIGN ectodomain/glycan bilayers\",\n      \"pmids\": [\"18270264\", \"19553201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoskeletal machinery driving directed cluster transport not identified\", \"Conformational change not visualized at atomic resolution\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Dissected mycobacterial PIM ligands, showing hexamannosylated PIM6 is a high-affinity ligand but is dispensable for whole-bacterium binding, indicating redundant ligands.\",\n      \"evidence\": \"Synthetic/natural PIM binding and pimE-mutant BCG binding to DC-SIGN and DCs\",\n      \"pmids\": [\"19651855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dominant ligand on intact mycobacteria remains unidentified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided atomic-level glycan recognition detail, defining distinct Lewis X versus mannose binding modes and confirming the neck domain drives high-affinity gp120 binding via tetramerization.\",\n      \"evidence\": \"HSQC/STD/trNOE NMR with docking; domain-swap chimeras with HIV capture/transfer assays\",\n      \"pmids\": [\"25121780\", \"24928041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of distinct binding modes for antigen routing untested\", \"Neck contribution to non-HIV ligands not generalized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established an immunoregulatory, tolerogenic role in vivo where fucose-driven DC-SIGN signaling cooperates with TLR4 to produce IL-10 and sustain transplantation tolerance, and a pathological role in follicular lymphoma BCR triggering.\",\n      \"evidence\": \"In vivo macrophage deletion and signaling interference with allograft/IL-10 readouts; FL B-cell BCR aggregation and kinase activation assays\",\n      \"pmids\": [\"26070485\", \"26272216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling branch distinguishing tolerogenic IL-10 from inflammatory output not fully mapped\", \"FL findings from single lab and microenvironment-dependent\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed antigen physical properties dictate intracellular routing — soluble glycopolymers to early endosomes, particulates to surface-accessible pockets shared with HIV-1 — explaining differential degradation versus retention.\",\n      \"evidence\": \"Defined synthetic glycopolymer series with quantitative confocal colocalization and trafficking\",\n      \"pmids\": [\"31270240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sorting machinery distinguishing the routes unknown\", \"Consequences for presentation efficiency not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Refined the carbohydrate-recognition chemistry, defining mannose Ca2+ coordination via axial OH-2/equatorial OH-3 and the fucose>mannose affinity hierarchy.\",\n      \"evidence\": \"19F- and 1H-STD-NMR with molecular dynamics on purified CRD\",\n      \"pmids\": [\"31242623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab in vitro CRD studies; cellular relevance of binding hierarchy not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified non-canonical activities: a SARS-CoV-2 spike-RBD entry-receptor role in ACE2-low endothelial cells, a druggable allosteric secondary pocket enhancing glycan recognition, and a Lyn/p85-dependent pro-metastatic signaling axis in colorectal cancer.\",\n      \"evidence\": \"S-RBD binding/siRNA/soluble-CD209 entry assays; NMR/MD with heteromultivalent liposome targeting; Co-IP and PI3K/Akt/β-catenin pathway and metastasis assays\",\n      \"pmids\": [\"34341769\", \"34748320\", \"31217502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contribution of CD209 to SARS-CoV-2 infection in vivo unclear\", \"Cancer signaling role from single lab in non-immune context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct ligands and antigen physical states selectively bias DC-SIGN between adhesion, trans-infection, endocytic presentation, and the Raf-1/NF-κB versus Lyn/Syk signaling outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model connecting ligand identity to signaling versus trafficking decisions\", \"Adaptors linking cytoplasmic tail motifs to specific routes unidentified\", \"In vivo physiological ligand spectrum incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [6, 23, 33]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [3, 8, 31]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [13, 19, 26]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [21, 13]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3, 31]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 13, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 6, 33]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [19, 13, 32]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 23, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ICAM2\", \"LYN\", \"SYK\", \"PIK3R1\", \"RAF1\", \"LECT2\", \"MUC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}