{"gene":"IL17RB","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2001,"finding":"IL-17E (IL-25) is a ligand for IL-17RB (EVI27/IL-17Rh1); binding of IL-17E to IL-17RB induces activation of NF-κB and stimulates production of the proinflammatory chemokine IL-8.","method":"Ligand-receptor binding assay, NF-κB activation assay, IL-8 production assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct ligand-receptor identification with functional readouts (NF-κB activation, IL-8 production), replicated by multiple subsequent studies","pmids":["11058597"],"is_preprint":false},{"year":2000,"finding":"IL-17RB (EVI27) encodes a novel transmembrane protein with homology to the IL-17 receptor; it is expressed as multiple isoforms including putative secreted soluble forms generated by intron incorporation or proteolytic cleavage; proviral integration at the Evi27 locus increases surface expression of the protein.","method":"Northern blot, Western blot, cDNA cloning, chromosomal mapping, retroviral integration site analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning and expression characterization with multiple methods in single lab","pmids":["10815801"],"is_preprint":false},{"year":2008,"finding":"IL-25-mediated biological activities (IL-5 and IL-13 production, pulmonary inflammation, airway hyperresponsiveness) require both IL-17RB and IL-17RA, demonstrating that IL-25 signals through a heteromeric receptor complex composed of IL-17RB and IL-17RA.","method":"Knockout mice (IL-17RB KO and IL-17RA KO), antagonistic monoclonal antibodies, in vitro splenocyte stimulation, in vivo intranasal IL-25 administration","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with blocking antibodies in both in vitro and in vivo systems, two independent receptor knockouts converge on same conclusion","pmids":["18768888"],"is_preprint":false},{"year":2009,"finding":"IL-17RB is highly expressed on a subset of invariant NKT (iNKT) cells but not on activated conventional T cells; IL-17RB+ iNKT cells produce large amounts of Th2 cytokines upon IL-25 stimulation and are sufficient to restore airway hyperreactivity (AHR) in iNKT-deficient mice, whereas IL-17RB− iNKT cells cannot.","method":"Flow cytometry, cell sorting, adoptive transfer reconstitution experiments in iNKT-deficient mice, intranasal IL-25 challenge","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reconstitution experiments with defined cell populations plus in vivo functional readout (AHR)","pmids":["19342692"],"is_preprint":false},{"year":2009,"finding":"IL-17RB is expressed on IL-4-producing CD11b+GR1+ myeloid cells in lung and bone marrow during chronic allergen challenge; SCF-dependent signaling from c-kit+ eosinophils drives IL-25 production, which then acts on IL-17RB+ myeloid cells to stimulate Th2 cytokine production.","method":"Cell sorting, 4get reporter mice (IL-4-IRES-eGFP), anti-SCF neutralization, flow cytometry","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sorted cell populations and functional reporter system, single lab","pmids":["19828636"],"is_preprint":false},{"year":2010,"finding":"IL-3 upregulates both mRNA and protein expression of IL-17RB on basophils; IL-25 acting through IL-17RB inhibits apoptosis of basophils and enhances IgE-mediated degranulation.","method":"Flow cytometry, quantitative RT-PCR, beta-hexosaminidase release assay, Annexin-V apoptosis assay, allergen challenge of PBMCs","journal":"Clinical and experimental allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assays on primary human basophils with IL-17RB protein measurement, single lab","pmids":["20545698"],"is_preprint":false},{"year":2012,"finding":"IL-25 (IL-17E) promotes bFGF expression by human endothelial cells through IL-17RB but not IL-17RA; this IL-17RB-mediated bFGF production involves PI3K signaling and drives angiogenesis; blocking IL-17RB (not IL-17RA) abrogates IL-25-induced angiogenesis.","method":"Receptor-blocking antibodies, PCR, ELISA, in vitro angiogenesis assay, PI3K inhibitor (LY294002), siRNA knockdown","journal":"Clinical and experimental allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific blockade with multiple orthogonal methods, single lab","pmids":["23106660"],"is_preprint":false},{"year":2013,"finding":"COX-2-derived prostaglandins PGD2 and PGE2 suppress IL-17RB expression in T cells via a protein kinase A-dependent mechanism, thereby inhibiting Th9 cell differentiation during allergic lung inflammation.","method":"COX-2 knockout mice, COX-2 inhibitor treatment, synthetic prostaglandins, siRNA knockdown, flow cytometry, real-time PCR, immunoblotting, PKA inhibitor","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus pharmacological inhibition with mechanistic pathway identification, single lab","pmids":["23449692"],"is_preprint":false},{"year":2014,"finding":"IL-17RB is aberrantly overexpressed in HTLV-1 immortalized T cells; HTLV-1 Tax induces IL-17RB expression via IKK/NF-κB-dependent mechanism; IL-17RB expression is required for Tax-induced canonical NF-κB activation, HTLV-1-induced immortalization of primary T cells, and survival of HTLV-1 transformed cells; IL-9 is an important downstream target gene of the IL-17RB pathway driving proliferation.","method":"RNA sequencing, knockdown/knockout experiments, NF-κB reporter assays, T-cell immortalization assays, IKK inhibitors, cytokine measurements","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple loss-of-function approaches with defined mechanistic pathway, single lab","pmids":["25340344"],"is_preprint":false},{"year":2014,"finding":"IL-17E (IL-25) and IL-17RB are increased following RSV infection; IL-17RB knockout mice show decreased Th2 and increased Th17 cytokine production during RSV infection and significantly reduced inflammation in a model of RSV-driven asthma exacerbation.","method":"IL-17RB knockout mice, antibody neutralization, cytokine measurements, airway hyperresponsiveness assays","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined immunological phenotypes, single lab","pmids":["24407884"],"is_preprint":false},{"year":2017,"finding":"TGF-β1 secreted from regulatory T cells (Tregs) in tumor-draining lymph nodes upregulates IL-17RB in breast cancer cells via downstream Smad2/3/4 signaling, and elevated IL-17RB contributes to increased malignancy and distant metastasis.","method":"Syngeneic mouse mammary tumor model, lymph node removal, TGF-β1 neutralization, Treg depletion, Smad2/3/4 signaling analysis, xenograft assay","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vivo genetic and pharmacological interventions converging on IL-17RB upregulation mechanism, single lab","pmids":["28993429"],"is_preprint":false},{"year":2017,"finding":"IL-17B acting through IL-17RB activates ERK1/2 signaling and increases MMP-9 expression in thyroid cancer cells, thereby promoting invasion and metastasis; ERK1/2 pathway inhibition blocks IL-17RB-mediated invasion and MMP-9 upregulation.","method":"siRNA knockdown of IL-17RB, in vitro invasion/migration assays, in vivo metastasis experiments, western blot for ERK1/2 phosphorylation and MMP-9, ERK1/2 inhibitor","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined pathway (ERK1/2-MMP-9) confirmed in vitro and in vivo, single lab","pmids":["28715683"],"is_preprint":false},{"year":2016,"finding":"Co-delivery of IL17RB siRNA with doxorubicin in breast cancer cells causes significant silencing of NF-κB and Bcl-2 expression, induces apoptosis, and inhibits migration, consistent with IL17RB/IL17B signaling promoting cell growth and migration through NF-κB and Bcl-2 upregulation.","method":"siRNA knockdown, nanoparticle co-delivery, Annexin-V apoptosis assay, wound healing assay, qRT-PCR for NF-κB and Bcl-2","journal":"Biomedicine & pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA knockdown with limited mechanistic follow-up, co-delivery confounds interpretation","pmids":["27372407"],"is_preprint":false},{"year":2019,"finding":"IL-17RB marks intestinal tumor stem cells (TSCs) in mouse intestinal adenomas in an IL-13-dependent manner; in human colorectal cancers, IL17RB-expressing cancer stem cells expand independently of IL-13 with upregulation of POU2F3, a master regulator of tuft cell differentiation; long-term ablation of IL17RB-expressing CSCs strongly suppresses tumor growth in vivo.","method":"Il17rb-CreERT2-IRES-EGFP lineage tracing mice, CRISPR-Cas9 knockin organoids, xenograft tumors, in vivo CSC ablation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic lineage tracing with functional tumor growth readout, single lab with multiple orthogonal approaches","pmids":["31182574"],"is_preprint":false},{"year":2019,"finding":"IL-17B signals through a heteromeric receptor complex composed of IL-17RA and IL-17RB to induce type 2 cytokine secretion from human innate type 2 lymphocytes, NKT cells, and CD4+ CRTH2+ Th2 cells; IL-17B can augment IL-33-driven type 2 responses.","method":"Primary human lymphocyte stimulation, receptor-blocking antibodies against IL-17RA and IL-17RB, cytokine ELISA","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific blocking antibodies on primary human cells with cytokine readouts, single lab","pmids":["30770417"],"is_preprint":false},{"year":2017,"finding":"IL-17RB expression on Thy1+ cell-derived extracellular vesicle-stimulated small hepatocyte-like progenitor cells (SHPCs) is upregulated by IL17B (from sinusoidal endothelial cells) and IL25 (from Kupffer cells); IL-17B stimulation of IL-17RB promotes growth of hepatocytic progenitor cells and enhances liver regeneration.","method":"GeneChip analysis, extracellular vesicle isolation and administration, in vitro small hepatocyte culture with IL-17B stimulation, in vivo liver regeneration model (retrorsine/partial hepatectomy)","journal":"Stem cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlative GeneChip identification plus functional growth assay, limited mechanistic pathway resolution, single lab","pmids":["27925343"],"is_preprint":false},{"year":2025,"finding":"IL-17RB is expressed in cortical neurons in the brain; IL-17E expressed in cortical neurons enhances social interaction by acting on IL-17RA- and IL-17RB-expressing neurons; IL-17RB (but not IL-17RC) plays a role in social behaviors through its cortical expression.","method":"Brain-wide receptor expression mapping, conditional loss-of-function, behavioral assays (social interaction)","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined behavioral phenotype and spatial expression characterization, single lab","pmids":["40199322"],"is_preprint":false}],"current_model":"IL-17RB is a transmembrane cytokine receptor (expressed as multiple isoforms including soluble forms) that functions as the primary binding subunit for IL-25 (IL-17E) and IL-17B; it signals through a heteromeric receptor complex with IL-17RA to activate NF-κB, ERK1/2, and PI3K downstream pathways, driving Th2-type immune responses (IL-4, IL-5, IL-13 production), basophil survival and degranulation, mast cell activation, and angiogenesis via bFGF induction, while also marking intestinal tuft cell-like cancer stem cells, supporting HTLV-1-mediated T-cell transformation through a Tax-IKK-IL-17RB NF-κB feed-forward loop, promoting hepatic progenitor cell proliferation, and playing an unexpected neuromodulatory role in cortical circuits controlling social behavior."},"narrative":{"mechanistic_narrative":"IL17RB is a transmembrane cytokine receptor subunit that serves as the primary high-affinity binding chain for IL-25 (IL-17E) and IL-17B, signaling through a heteromeric complex with IL-17RA to drive type 2 immune responses [PMID:11058597, PMID:18768888, PMID:30770417]. Ligand engagement activates NF-κB with downstream induction of proinflammatory chemokines [PMID:11058597], and the IL-25/IL-17RB axis requires both IL-17RB and IL-17RA to elicit IL-5/IL-13 production, pulmonary inflammation, and airway hyperresponsiveness in vivo [PMID:18768888]. IL-17RB marks and functions on diverse effector populations—IL-25-responsive iNKT cells, IL-4-producing myeloid cells, and basophils whose survival and IgE-mediated degranulation it enhances—thereby orchestrating Th2-type immunity [PMID:19342692, PMID:19828636, PMID:20545698]; its expression is itself dynamically controlled, being upregulated by IL-3 and suppressed by COX-2-derived prostaglandins through a PKA-dependent mechanism [PMID:20545698, PMID:23449692]. Beyond immunity, IL-17RB activates distinct downstream effectors in a context-specific manner: PI3K signaling to induce bFGF-driven angiogenesis [PMID:23106660], ERK1/2 signaling to upregulate MMP-9 and promote cancer cell invasion [PMID:28715683], and NF-κB activation supporting HTLV-1 Tax-induced T-cell immortalization through a feed-forward loop with IL-9 as a downstream proliferative target [PMID:25340344]. In epithelial cancers, IL-17RB is upregulated by Treg-derived TGF-β1 via Smad2/3/4 in breast cancer and marks tuft-cell-like cancer stem cells whose ablation suppresses tumor growth [PMID:28993429, PMID:31182574]. A non-immune neuromodulatory role has also been defined, in which neuronal IL-17E acting on IL-17RB-expressing cortical neurons promotes social interaction [PMID:40199322].","teleology":[{"year":2000,"claim":"Establishing the molecular identity of the receptor was the first step: cloning EVI27/IL-17RB defined a novel IL-17-receptor-family transmembrane protein with multiple isoforms and a proviral-integration link to surface overexpression.","evidence":"cDNA cloning, Northern/Western blot, chromosomal mapping, and retroviral integration site analysis","pmids":["10815801"],"confidence":"Medium","gaps":["No ligand identified at this stage","Functional consequences of soluble isoforms not resolved","Signaling output unknown"]},{"year":2001,"claim":"Identifying IL-25 (IL-17E) as the ligand and demonstrating NF-κB activation and IL-8 induction assigned the receptor a concrete signaling function.","evidence":"Ligand-receptor binding assay with NF-κB and IL-8 production readouts","pmids":["11058597"],"confidence":"High","gaps":["Co-receptor requirement not yet defined","In vivo physiological role untested","Proximal signaling adaptors not mapped"]},{"year":2008,"claim":"Genetic dissection showed IL-25 requires both IL-17RB and IL-17RA, establishing that signaling occurs through a heteromeric receptor complex driving Th2 cytokines and airway inflammation in vivo.","evidence":"IL-17RB and IL-17RA knockout mice, blocking antibodies, and intranasal IL-25 challenge","pmids":["18768888"],"confidence":"High","gaps":["Stoichiometry and structural basis of the complex not resolved","Cell type executing the in vivo response not pinned down"]},{"year":2009,"claim":"Defining the responder cells, IL-17RB was shown to mark IL-25-responsive iNKT cells and IL-4-producing myeloid cells, linking receptor expression to specific Th2 effector outputs.","evidence":"Flow cytometry, cell sorting, adoptive transfer into iNKT-deficient mice, and 4get reporter mice with anti-SCF neutralization","pmids":["19342692","19828636"],"confidence":"High","gaps":["Transcriptional control of cell-type-restricted IL-17RB expression unclear","Relative contribution of each cell type in disease not quantified"]},{"year":2010,"claim":"Demonstrating that IL-25/IL-17RB inhibits basophil apoptosis and enhances degranulation, and that IL-3 upregulates the receptor, connected the receptor to effector-cell survival and allergic effector function.","evidence":"Primary human basophil assays: qRT-PCR, beta-hexosaminidase release, and Annexin-V apoptosis","pmids":["20545698"],"confidence":"Medium","gaps":["Anti-apoptotic signaling mechanism not delineated","Human-to-mouse generalizability untested"]},{"year":2012,"claim":"Showing IL-25 induces endothelial bFGF and angiogenesis specifically through IL-17RB (not IL-17RA) via PI3K revealed receptor-subunit-specific, non-Th2 signaling outputs.","evidence":"Receptor-blocking antibodies, PI3K inhibitor, siRNA, and in vitro angiogenesis assay","pmids":["23106660"],"confidence":"Medium","gaps":["How IL-17RB signals independently of IL-17RA mechanistically unclear","In vivo angiogenic relevance not established"]},{"year":2013,"claim":"Identifying COX-2/prostaglandin-PKA suppression of IL-17RB expression established negative regulatory control of the receptor that restrains Th9 differentiation.","evidence":"COX-2 knockout mice, COX-2 inhibitor, synthetic prostaglandins, PKA inhibitor, and siRNA","pmids":["23449692"],"confidence":"Medium","gaps":["Transcription factors mediating PKA-dependent repression not identified","Generalizability beyond lung inflammation untested"]},{"year":2014,"claim":"Two studies extended IL-17RB into disease pathways: HTLV-1 Tax induces IL-17RB via IKK/NF-κB to support T-cell immortalization through an IL-9-driven loop, and IL-17RB shapes the Th2/Th17 balance and inflammation during RSV infection.","evidence":"RNA-seq, loss-of-function and NF-κB reporter assays, T-cell immortalization assays, and IL-17RB knockout mice with RSV challenge","pmids":["25340344","24407884"],"confidence":"Medium","gaps":["Direct biochemical link between IL-17RB and IKK not resolved","Ligand dependence of the HTLV-1 loop unclear"]},{"year":2017,"claim":"Cancer studies defined upstream control and downstream effectors: Treg-derived TGF-β1 upregulates IL-17RB via Smad2/3/4 in breast cancer, and IL-17B/IL-17RB activates ERK1/2-MMP-9 to drive thyroid cancer invasion, plus a role in hepatic progenitor growth.","evidence":"Syngeneic tumor models with TGF-β1 neutralization and Treg depletion, siRNA with invasion/metastasis assays and ERK1/2 inhibition, and liver regeneration models with extracellular vesicles","pmids":["28993429","28715683","27925343"],"confidence":"Medium","gaps":["Whether IL-17B vs IL-25 drives each effect not always disentangled","Hepatic progenitor mechanism is correlative (Low confidence)"]},{"year":2019,"claim":"IL-17RB was shown to mark functional tuft-cell-like cancer stem cells whose ablation suppresses tumor growth, and IL-17B was confirmed to signal through an IL-17RA/IL-17RB heterocomplex on primary human type 2 lymphocytes.","evidence":"Il17rb lineage-tracing mice, CRISPR knockin organoids, in vivo CSC ablation, and receptor-blocking antibodies on primary human lymphocytes","pmids":["31182574","30770417"],"confidence":"Medium","gaps":["Signaling driving CSC maintenance downstream of IL-17RB not mapped","POU2F3-IL17RB regulatory relationship not mechanistically resolved"]},{"year":2025,"claim":"Discovery of cortical neuronal IL-17RB driving social behavior in response to neuron-derived IL-17E revealed a wholly non-immune, neuromodulatory function of the receptor.","evidence":"Brain-wide receptor expression mapping, conditional loss-of-function, and social interaction behavioral assays","pmids":["40199322"],"confidence":"Medium","gaps":["Neuronal signaling pathway downstream of IL-17RB unknown","Whether IL-17RA is the obligate co-receptor in neurons not fully resolved"]},{"year":null,"claim":"The proximal signaling machinery (adaptors, structural basis of the IL-17RA/IL-17RB heterocomplex) and the rules governing IL-25- versus IL-17B-specific and IL-17RA-independent outputs remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the ligand-bound heteroreceptor","Adaptor proteins linking IL-17RB to NF-κB/ERK/PI3K not identified in the corpus","Determinants of subunit-specific signaling unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,14]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,10,13]}],"complexes":["IL-17RA/IL-17RB heteromeric receptor"],"partners":["IL17RA","IL25","IL17B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NRM6","full_name":"Interleukin-17 receptor B","aliases":["Cytokine receptor-like 4","IL-17 receptor homolog 1","IL-17Rh1","IL17Rh1","Interleukin-17B receptor","IL-17B receptor"],"length_aa":502,"mass_kda":55.9,"function":"Receptor for the pro-inflammatory cytokines IL17B and IL17E. May play a role in controlling the growth and/or differentiation of hematopoietic cells","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9NRM6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL17RB","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IL17RB","total_profiled":1310},"omim":[{"mim_id":"614995","title":"INTERLEUKIN 17 RECEPTOR E; IL17RE","url":"https://www.omim.org/entry/614995"},{"mim_id":"607043","title":"TRAF3-INTERACTING PROTEIN 2; TRAF3IP2","url":"https://www.omim.org/entry/607043"},{"mim_id":"605458","title":"INTERLEUKIN 17 RECEPTOR B; IL17RB","url":"https://www.omim.org/entry/605458"},{"mim_id":"604628","title":"INTERLEUKIN 17C; IL17C","url":"https://www.omim.org/entry/604628"},{"mim_id":"604627","title":"INTERLEUKIN 17B; IL17B","url":"https://www.omim.org/entry/604627"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":17.2},{"tissue":"cervix","ntpm":16.9},{"tissue":"kidney","ntpm":55.8},{"tissue":"liver","ntpm":31.1}],"url":"https://www.proteinatlas.org/search/IL17RB"},"hgnc":{"alias_symbol":["IL17RH1","EVI27","CRL4"],"prev_symbol":["IL17BR"]},"alphafold":{"accession":"Q9NRM6","domains":[{"cath_id":"2.60.40.2160","chopping":"23-160","consensus_level":"high","plddt":90.5178,"start":23,"end":160},{"cath_id":"2.60.40.2150","chopping":"178-271","consensus_level":"high","plddt":92.2889,"start":178,"end":271},{"cath_id":"3.40.50.11530","chopping":"333-400_422-487","consensus_level":"high","plddt":81.9181,"start":333,"end":487}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRM6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRM6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRM6-F1-predicted_aligned_error_v6.png","plddt_mean":79.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL17RB","jax_strain_url":"https://www.jax.org/strain/search?query=IL17RB"},"sequence":{"accession":"Q9NRM6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NRM6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NRM6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRM6"}},"corpus_meta":[{"pmid":"24328678","id":"PMC_24328678","title":"Immunomodulatory 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Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/23892434","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50098,"output_tokens":4114,"usd":0.106002,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12036,"output_tokens":3985,"usd":0.079903,"stage2_stop_reason":"end_turn"},"total_usd":0.185905,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-17E (IL-25) is a ligand for IL-17RB (EVI27/IL-17Rh1); binding of IL-17E to IL-17RB induces activation of NF-κB and stimulates production of the proinflammatory chemokine IL-8.\",\n      \"method\": \"Ligand-receptor binding assay, NF-κB activation assay, IL-8 production assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct ligand-receptor identification with functional readouts (NF-κB activation, IL-8 production), replicated by multiple subsequent studies\",\n      \"pmids\": [\"11058597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-17RB (EVI27) encodes a novel transmembrane protein with homology to the IL-17 receptor; it is expressed as multiple isoforms including putative secreted soluble forms generated by intron incorporation or proteolytic cleavage; proviral integration at the Evi27 locus increases surface expression of the protein.\",\n      \"method\": \"Northern blot, Western blot, cDNA cloning, chromosomal mapping, retroviral integration site analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning and expression characterization with multiple methods in single lab\",\n      \"pmids\": [\"10815801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-25-mediated biological activities (IL-5 and IL-13 production, pulmonary inflammation, airway hyperresponsiveness) require both IL-17RB and IL-17RA, demonstrating that IL-25 signals through a heteromeric receptor complex composed of IL-17RB and IL-17RA.\",\n      \"method\": \"Knockout mice (IL-17RB KO and IL-17RA KO), antagonistic monoclonal antibodies, in vitro splenocyte stimulation, in vivo intranasal IL-25 administration\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with blocking antibodies in both in vitro and in vivo systems, two independent receptor knockouts converge on same conclusion\",\n      \"pmids\": [\"18768888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17RB is highly expressed on a subset of invariant NKT (iNKT) cells but not on activated conventional T cells; IL-17RB+ iNKT cells produce large amounts of Th2 cytokines upon IL-25 stimulation and are sufficient to restore airway hyperreactivity (AHR) in iNKT-deficient mice, whereas IL-17RB− iNKT cells cannot.\",\n      \"method\": \"Flow cytometry, cell sorting, adoptive transfer reconstitution experiments in iNKT-deficient mice, intranasal IL-25 challenge\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reconstitution experiments with defined cell populations plus in vivo functional readout (AHR)\",\n      \"pmids\": [\"19342692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17RB is expressed on IL-4-producing CD11b+GR1+ myeloid cells in lung and bone marrow during chronic allergen challenge; SCF-dependent signaling from c-kit+ eosinophils drives IL-25 production, which then acts on IL-17RB+ myeloid cells to stimulate Th2 cytokine production.\",\n      \"method\": \"Cell sorting, 4get reporter mice (IL-4-IRES-eGFP), anti-SCF neutralization, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sorted cell populations and functional reporter system, single lab\",\n      \"pmids\": [\"19828636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-3 upregulates both mRNA and protein expression of IL-17RB on basophils; IL-25 acting through IL-17RB inhibits apoptosis of basophils and enhances IgE-mediated degranulation.\",\n      \"method\": \"Flow cytometry, quantitative RT-PCR, beta-hexosaminidase release assay, Annexin-V apoptosis assay, allergen challenge of PBMCs\",\n      \"journal\": \"Clinical and experimental allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assays on primary human basophils with IL-17RB protein measurement, single lab\",\n      \"pmids\": [\"20545698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-25 (IL-17E) promotes bFGF expression by human endothelial cells through IL-17RB but not IL-17RA; this IL-17RB-mediated bFGF production involves PI3K signaling and drives angiogenesis; blocking IL-17RB (not IL-17RA) abrogates IL-25-induced angiogenesis.\",\n      \"method\": \"Receptor-blocking antibodies, PCR, ELISA, in vitro angiogenesis assay, PI3K inhibitor (LY294002), siRNA knockdown\",\n      \"journal\": \"Clinical and experimental allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific blockade with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"23106660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"COX-2-derived prostaglandins PGD2 and PGE2 suppress IL-17RB expression in T cells via a protein kinase A-dependent mechanism, thereby inhibiting Th9 cell differentiation during allergic lung inflammation.\",\n      \"method\": \"COX-2 knockout mice, COX-2 inhibitor treatment, synthetic prostaglandins, siRNA knockdown, flow cytometry, real-time PCR, immunoblotting, PKA inhibitor\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus pharmacological inhibition with mechanistic pathway identification, single lab\",\n      \"pmids\": [\"23449692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-17RB is aberrantly overexpressed in HTLV-1 immortalized T cells; HTLV-1 Tax induces IL-17RB expression via IKK/NF-κB-dependent mechanism; IL-17RB expression is required for Tax-induced canonical NF-κB activation, HTLV-1-induced immortalization of primary T cells, and survival of HTLV-1 transformed cells; IL-9 is an important downstream target gene of the IL-17RB pathway driving proliferation.\",\n      \"method\": \"RNA sequencing, knockdown/knockout experiments, NF-κB reporter assays, T-cell immortalization assays, IKK inhibitors, cytokine measurements\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple loss-of-function approaches with defined mechanistic pathway, single lab\",\n      \"pmids\": [\"25340344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-17E (IL-25) and IL-17RB are increased following RSV infection; IL-17RB knockout mice show decreased Th2 and increased Th17 cytokine production during RSV infection and significantly reduced inflammation in a model of RSV-driven asthma exacerbation.\",\n      \"method\": \"IL-17RB knockout mice, antibody neutralization, cytokine measurements, airway hyperresponsiveness assays\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined immunological phenotypes, single lab\",\n      \"pmids\": [\"24407884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TGF-β1 secreted from regulatory T cells (Tregs) in tumor-draining lymph nodes upregulates IL-17RB in breast cancer cells via downstream Smad2/3/4 signaling, and elevated IL-17RB contributes to increased malignancy and distant metastasis.\",\n      \"method\": \"Syngeneic mouse mammary tumor model, lymph node removal, TGF-β1 neutralization, Treg depletion, Smad2/3/4 signaling analysis, xenograft assay\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vivo genetic and pharmacological interventions converging on IL-17RB upregulation mechanism, single lab\",\n      \"pmids\": [\"28993429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17B acting through IL-17RB activates ERK1/2 signaling and increases MMP-9 expression in thyroid cancer cells, thereby promoting invasion and metastasis; ERK1/2 pathway inhibition blocks IL-17RB-mediated invasion and MMP-9 upregulation.\",\n      \"method\": \"siRNA knockdown of IL-17RB, in vitro invasion/migration assays, in vivo metastasis experiments, western blot for ERK1/2 phosphorylation and MMP-9, ERK1/2 inhibitor\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined pathway (ERK1/2-MMP-9) confirmed in vitro and in vivo, single lab\",\n      \"pmids\": [\"28715683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Co-delivery of IL17RB siRNA with doxorubicin in breast cancer cells causes significant silencing of NF-κB and Bcl-2 expression, induces apoptosis, and inhibits migration, consistent with IL17RB/IL17B signaling promoting cell growth and migration through NF-κB and Bcl-2 upregulation.\",\n      \"method\": \"siRNA knockdown, nanoparticle co-delivery, Annexin-V apoptosis assay, wound healing assay, qRT-PCR for NF-κB and Bcl-2\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA knockdown with limited mechanistic follow-up, co-delivery confounds interpretation\",\n      \"pmids\": [\"27372407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17RB marks intestinal tumor stem cells (TSCs) in mouse intestinal adenomas in an IL-13-dependent manner; in human colorectal cancers, IL17RB-expressing cancer stem cells expand independently of IL-13 with upregulation of POU2F3, a master regulator of tuft cell differentiation; long-term ablation of IL17RB-expressing CSCs strongly suppresses tumor growth in vivo.\",\n      \"method\": \"Il17rb-CreERT2-IRES-EGFP lineage tracing mice, CRISPR-Cas9 knockin organoids, xenograft tumors, in vivo CSC ablation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic lineage tracing with functional tumor growth readout, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"31182574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17B signals through a heteromeric receptor complex composed of IL-17RA and IL-17RB to induce type 2 cytokine secretion from human innate type 2 lymphocytes, NKT cells, and CD4+ CRTH2+ Th2 cells; IL-17B can augment IL-33-driven type 2 responses.\",\n      \"method\": \"Primary human lymphocyte stimulation, receptor-blocking antibodies against IL-17RA and IL-17RB, cytokine ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific blocking antibodies on primary human cells with cytokine readouts, single lab\",\n      \"pmids\": [\"30770417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17RB expression on Thy1+ cell-derived extracellular vesicle-stimulated small hepatocyte-like progenitor cells (SHPCs) is upregulated by IL17B (from sinusoidal endothelial cells) and IL25 (from Kupffer cells); IL-17B stimulation of IL-17RB promotes growth of hepatocytic progenitor cells and enhances liver regeneration.\",\n      \"method\": \"GeneChip analysis, extracellular vesicle isolation and administration, in vitro small hepatocyte culture with IL-17B stimulation, in vivo liver regeneration model (retrorsine/partial hepatectomy)\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlative GeneChip identification plus functional growth assay, limited mechanistic pathway resolution, single lab\",\n      \"pmids\": [\"27925343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-17RB is expressed in cortical neurons in the brain; IL-17E expressed in cortical neurons enhances social interaction by acting on IL-17RA- and IL-17RB-expressing neurons; IL-17RB (but not IL-17RC) plays a role in social behaviors through its cortical expression.\",\n      \"method\": \"Brain-wide receptor expression mapping, conditional loss-of-function, behavioral assays (social interaction)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined behavioral phenotype and spatial expression characterization, single lab\",\n      \"pmids\": [\"40199322\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17RB is a transmembrane cytokine receptor (expressed as multiple isoforms including soluble forms) that functions as the primary binding subunit for IL-25 (IL-17E) and IL-17B; it signals through a heteromeric receptor complex with IL-17RA to activate NF-κB, ERK1/2, and PI3K downstream pathways, driving Th2-type immune responses (IL-4, IL-5, IL-13 production), basophil survival and degranulation, mast cell activation, and angiogenesis via bFGF induction, while also marking intestinal tuft cell-like cancer stem cells, supporting HTLV-1-mediated T-cell transformation through a Tax-IKK-IL-17RB NF-κB feed-forward loop, promoting hepatic progenitor cell proliferation, and playing an unexpected neuromodulatory role in cortical circuits controlling social behavior.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL17RB is a transmembrane cytokine receptor subunit that serves as the primary high-affinity binding chain for IL-25 (IL-17E) and IL-17B, signaling through a heteromeric complex with IL-17RA to drive type 2 immune responses [#0, #2, #14]. Ligand engagement activates NF-\\u03baB with downstream induction of proinflammatory chemokines [#0], and the IL-25/IL-17RB axis requires both IL-17RB and IL-17RA to elicit IL-5/IL-13 production, pulmonary inflammation, and airway hyperresponsiveness in vivo [#2]. IL-17RB marks and functions on diverse effector populations\\u2014IL-25-responsive iNKT cells, IL-4-producing myeloid cells, and basophils whose survival and IgE-mediated degranulation it enhances\\u2014thereby orchestrating Th2-type immunity [#3, #4, #5]; its expression is itself dynamically controlled, being upregulated by IL-3 and suppressed by COX-2-derived prostaglandins through a PKA-dependent mechanism [#5, #7]. Beyond immunity, IL-17RB activates distinct downstream effectors in a context-specific manner: PI3K signaling to induce bFGF-driven angiogenesis [#6], ERK1/2 signaling to upregulate MMP-9 and promote cancer cell invasion [#11], and NF-\\u03baB activation supporting HTLV-1 Tax-induced T-cell immortalization through a feed-forward loop with IL-9 as a downstream proliferative target [#8]. In epithelial cancers, IL-17RB is upregulated by Treg-derived TGF-\\u03b21 via Smad2/3/4 in breast cancer and marks tuft-cell-like cancer stem cells whose ablation suppresses tumor growth [#10, #13]. A non-immune neuromodulatory role has also been defined, in which neuronal IL-17E acting on IL-17RB-expressing cortical neurons promotes social interaction [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing the molecular identity of the receptor was the first step: cloning EVI27/IL-17RB defined a novel IL-17-receptor-family transmembrane protein with multiple isoforms and a proviral-integration link to surface overexpression.\",\n      \"evidence\": \"cDNA cloning, Northern/Western blot, chromosomal mapping, and retroviral integration site analysis\",\n      \"pmids\": [\"10815801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ligand identified at this stage\", \"Functional consequences of soluble isoforms not resolved\", \"Signaling output unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying IL-25 (IL-17E) as the ligand and demonstrating NF-\\u03baB activation and IL-8 induction assigned the receptor a concrete signaling function.\",\n      \"evidence\": \"Ligand-receptor binding assay with NF-\\u03baB and IL-8 production readouts\",\n      \"pmids\": [\"11058597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-receptor requirement not yet defined\", \"In vivo physiological role untested\", \"Proximal signaling adaptors not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic dissection showed IL-25 requires both IL-17RB and IL-17RA, establishing that signaling occurs through a heteromeric receptor complex driving Th2 cytokines and airway inflammation in vivo.\",\n      \"evidence\": \"IL-17RB and IL-17RA knockout mice, blocking antibodies, and intranasal IL-25 challenge\",\n      \"pmids\": [\"18768888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of the complex not resolved\", \"Cell type executing the in vivo response not pinned down\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defining the responder cells, IL-17RB was shown to mark IL-25-responsive iNKT cells and IL-4-producing myeloid cells, linking receptor expression to specific Th2 effector outputs.\",\n      \"evidence\": \"Flow cytometry, cell sorting, adoptive transfer into iNKT-deficient mice, and 4get reporter mice with anti-SCF neutralization\",\n      \"pmids\": [\"19342692\", \"19828636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional control of cell-type-restricted IL-17RB expression unclear\", \"Relative contribution of each cell type in disease not quantified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that IL-25/IL-17RB inhibits basophil apoptosis and enhances degranulation, and that IL-3 upregulates the receptor, connected the receptor to effector-cell survival and allergic effector function.\",\n      \"evidence\": \"Primary human basophil assays: qRT-PCR, beta-hexosaminidase release, and Annexin-V apoptosis\",\n      \"pmids\": [\"20545698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Anti-apoptotic signaling mechanism not delineated\", \"Human-to-mouse generalizability untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing IL-25 induces endothelial bFGF and angiogenesis specifically through IL-17RB (not IL-17RA) via PI3K revealed receptor-subunit-specific, non-Th2 signaling outputs.\",\n      \"evidence\": \"Receptor-blocking antibodies, PI3K inhibitor, siRNA, and in vitro angiogenesis assay\",\n      \"pmids\": [\"23106660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How IL-17RB signals independently of IL-17RA mechanistically unclear\", \"In vivo angiogenic relevance not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying COX-2/prostaglandin-PKA suppression of IL-17RB expression established negative regulatory control of the receptor that restrains Th9 differentiation.\",\n      \"evidence\": \"COX-2 knockout mice, COX-2 inhibitor, synthetic prostaglandins, PKA inhibitor, and siRNA\",\n      \"pmids\": [\"23449692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factors mediating PKA-dependent repression not identified\", \"Generalizability beyond lung inflammation untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two studies extended IL-17RB into disease pathways: HTLV-1 Tax induces IL-17RB via IKK/NF-\\u03baB to support T-cell immortalization through an IL-9-driven loop, and IL-17RB shapes the Th2/Th17 balance and inflammation during RSV infection.\",\n      \"evidence\": \"RNA-seq, loss-of-function and NF-\\u03baB reporter assays, T-cell immortalization assays, and IL-17RB knockout mice with RSV challenge\",\n      \"pmids\": [\"25340344\", \"24407884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between IL-17RB and IKK not resolved\", \"Ligand dependence of the HTLV-1 loop unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Cancer studies defined upstream control and downstream effectors: Treg-derived TGF-\\u03b21 upregulates IL-17RB via Smad2/3/4 in breast cancer, and IL-17B/IL-17RB activates ERK1/2-MMP-9 to drive thyroid cancer invasion, plus a role in hepatic progenitor growth.\",\n      \"evidence\": \"Syngeneic tumor models with TGF-\\u03b21 neutralization and Treg depletion, siRNA with invasion/metastasis assays and ERK1/2 inhibition, and liver regeneration models with extracellular vesicles\",\n      \"pmids\": [\"28993429\", \"28715683\", \"27925343\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IL-17B vs IL-25 drives each effect not always disentangled\", \"Hepatic progenitor mechanism is correlative (Low confidence)\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"IL-17RB was shown to mark functional tuft-cell-like cancer stem cells whose ablation suppresses tumor growth, and IL-17B was confirmed to signal through an IL-17RA/IL-17RB heterocomplex on primary human type 2 lymphocytes.\",\n      \"evidence\": \"Il17rb lineage-tracing mice, CRISPR knockin organoids, in vivo CSC ablation, and receptor-blocking antibodies on primary human lymphocytes\",\n      \"pmids\": [\"31182574\", \"30770417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling driving CSC maintenance downstream of IL-17RB not mapped\", \"POU2F3-IL17RB regulatory relationship not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery of cortical neuronal IL-17RB driving social behavior in response to neuron-derived IL-17E revealed a wholly non-immune, neuromodulatory function of the receptor.\",\n      \"evidence\": \"Brain-wide receptor expression mapping, conditional loss-of-function, and social interaction behavioral assays\",\n      \"pmids\": [\"40199322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neuronal signaling pathway downstream of IL-17RB unknown\", \"Whether IL-17RA is the obligate co-receptor in neurons not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The proximal signaling machinery (adaptors, structural basis of the IL-17RA/IL-17RB heterocomplex) and the rules governing IL-25- versus IL-17B-specific and IL-17RA-independent outputs remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the ligand-bound heteroreceptor\", \"Adaptor proteins linking IL-17RB to NF-\\u03baB/ERK/PI3K not identified in the corpus\", \"Determinants of subunit-specific signaling unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 14]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 10, 13]}\n    ],\n    \"complexes\": [\"IL-17RA/IL-17RB heteromeric receptor\"],\n    \"partners\": [\"IL17RA\", \"IL25\", \"IL17B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}