{"gene":"TLR7","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2004,"finding":"TLR7 recognizes single-stranded RNA (ssRNA) in endosomal compartments and signals through MyD88 to induce type I IFN and inflammatory cytokine production; ssRNA of non-viral origin also activates TLR7, identifying ssRNA as a TLR7 ligand.","method":"TLR7-deficient mice, MyD88-deficient mice, endosomal recognition assays with influenza genomic RNA and synthetic ssRNA","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO models with defined ligand and signaling readout, replicated across multiple ssRNA species, foundational paper widely confirmed","pmids":["14976261"],"is_preprint":false},{"year":2008,"finding":"TLR7 and TLR8 ectodomains sense RNA oligoribonucleotides (ORN) and imidazoquinolines through overlapping but non-identical recognition sites; RNA ORN versus imidazoquinoline binding produces ligand-specific differential phosphorylation and distinct transcriptional responses, suggesting TLR7 can signal in two different 'modes' depending on ligand class.","method":"Proteome- and genome-wide analysis, mutagenesis of ectodomain residues, primary human monocyte-derived DCs","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis and proteomics in primary cells, single lab, two orthogonal methods","pmids":["24813206"],"is_preprint":false},{"year":2015,"finding":"TLR7 senses guanosine (G), 2'-deoxyguanosine (dG), 7-methylguanosine, 8-hydroxyguanosine (8-OHG), and 8-hydroxydeoxyguanosine (8-OHdG) as endogenous small-molecule ligands when co-presented with an oligoribonucleotide (ORN); ORN strengthens TLR7 interaction with G/dG as measured by isothermal titration calorimetry.","method":"Cytokine production assays in mouse and human immune cells, isothermal titration calorimetry (ITC) binding assay, Unc93b1-mutant macrophages","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assay (ITC) plus functional cytokine assays, replicated in mouse and human cells with genetic controls","pmids":["26489884"],"is_preprint":false},{"year":2019,"finding":"Deoxyguanosine (dG) activates TLR7 independently of concurrent ssRNA provision; this signaling requires TLR7 and its adaptor MyD88 and depends on endosomal maturation, establishing dG as an RNA-independent TLR7 agonist.","method":"Cytokine production in TLR7-/- and MyD88-/- murine macrophages and pDCs, bafilomycin A1 endosomal acidification blockade, human PBMCs","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO validation with mechanistic endosomal requirement, replicated across cell types","pmids":["31608988"],"is_preprint":false},{"year":2024,"finding":"Lysosomal endonuclease RNase T2 generates guanosine 2',3'-cyclic monophosphate-terminated RNA fragments; PLD3/PLD4 exonucleases then release 2',3'-cGMP to engage TLR7 pocket 1 and generate pyrimidine-rich RNA fragments for TLR7 pocket 2, cooperatively producing both classes of TLR7 ligands. PLD enzymes form homodimers with two ligand-binding sites required for activity; disease-associated PLD mutants fail to form stable dimers.","method":"Biochemical assays, structural studies, loss-of-function studies in cell lines and primary cells, crystallography/cryo-EM of PLD homodimers","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution biochemistry, structural analysis, and cell-based loss-of-function, multiple orthogonal methods in one study","pmids":["38697119"],"is_preprint":false},{"year":2020,"finding":"TLR7 structural analysis by combined crystallography and cryo-EM reveals an equilibrium between open and closed receptor conformations; TLR7-specific antagonists bind a defined pocket and stabilize the open (inactive) conformation, providing the structural basis for TLR7 antagonism.","method":"X-ray crystallography, cryo-electron microscopy, structure-guided antagonist development, in vivo autoimmunity protection assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus cryo-EM with functional in vivo validation, multiple orthogonal methods","pmids":["33060576"],"is_preprint":false},{"year":2022,"finding":"A gain-of-function missense variant TLR7Y264H selectively increases TLR7 sensing of guanosine and 2',3'-cGMP and is sufficient to cause lupus when introduced into mice; downstream pathogenesis requires MyD88 (deficiency of MyD88 rescued all phenotypes), and TLR7Y264H drives cell-intrinsic aberrant survival of BCR-activated B cells and accumulation of CD11c+ age-associated B cells.","method":"Human genetic identification of de novo variant, knock-in mouse model, MyD88-deficient rescue epistasis, B cell functional assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — human variant with mouse knock-in plus epistasis rescue, replicated across cellular and serological readouts","pmids":["35477763"],"is_preprint":false},{"year":2019,"finding":"UNC93B1 specifically limits TLR7 (but not TLR9) signaling by recruiting syntenin-1, which facilitates sorting of TLR7 into intraluminal vesicles of multivesicular bodies to terminate signaling; this recruitment requires phosphorylation of UNC93B1. Mutations in UNC93B1 that disrupt syntenin-1 binding cause enhanced TLR7 signaling and TLR7-dependent autoimmunity in mice.","method":"Co-immunoprecipitation, UNC93B1 mutant mice, exosome fractionation, phosphorylation-dependent binding assays, in vivo autoimmunity models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic mouse models, subcellular fractionation, multiple orthogonal methods in one study","pmids":["31546246"],"is_preprint":false},{"year":2024,"finding":"The late endosomal BORC complex together with the small GTPase Arl8b controls intracellular TLR7 levels by regulating receptor turnover; this requires a direct interaction between TLR7-associated trafficking factor UNC93B1 and Arl8b. An UNC93B1 mutation causing reduced BORC interaction leads to endosomal TLR7 accumulation and childhood-onset lupus.","method":"Protein interaction studies (UNC93B1–Arl8b), patient-derived UNC93B1 mutant analysis, endosomal TLR7 level quantification, functional signaling assays","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction demonstrated, patient mutation with defined molecular consequence, multiple orthogonal methods","pmids":["38207015"],"is_preprint":false},{"year":2020,"finding":"TASL (encoded by CXorf21) interacts with endolysosomal transporter SLC15A4 and contains a pLxIS motif that mediates recruitment and activation of IRF5; loss of TASL specifically impairs the IRF pathway downstream of TLR7, TLR8, and TLR9 without affecting NF-κB or MAPK signaling, establishing TASL as a TLR7/8/9-to-IRF5 adaptor analogous to STING/MAVS/TRIF for IRF3.","method":"Protein interaction studies, TASL knockout in primary and transformed human immune cells, extensive mutagenesis of TASL pLxIS motif, signaling pathway dissection","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, mutagenesis, interaction studies, pathway epistasis; multiple orthogonal methods in one rigorous study","pmids":["32433612"],"is_preprint":false},{"year":2024,"finding":"UNC93B1 variants E92G and R336L cause selective TLR7 hyperactivation with constitutive type I IFN signaling; E92G causes UNC93B1 protein instability and reduced interaction with TLR7, demonstrating that UNC93B1 regulates TLR7 subtype-specific ligand recognition mechanisms.","method":"Patient-derived cells, mouse macrophages carrying UNC93B1 variants, TLR7/8/9 agonist stimulation assays, protein interaction studies","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — human patient variants validated in mouse macrophages with defined molecular interaction consequence, TLR subtype selectivity demonstrated","pmids":["38207055"],"is_preprint":false},{"year":2015,"finding":"TLR7 is present on the cell surface of immune cells (dendritic cells, macrophages, B cells) in addition to endolysosomes; an anti-TLR7 antibody is internalized with TLR7 into endolysosomes and inhibits TLR7 responses and in vivo cytokine production, demonstrating functional cell-surface TLR7.","method":"Anti-TLR7 antibody internalization assay, subcellular fractionation/immunofluorescence, in vivo cytokine production, Unc93b1 D34A/D34A autoimmune mouse model treatment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization with functional consequence demonstrated in vitro and in vivo with multiple cell types","pmids":["25648980"],"is_preprint":false},{"year":2021,"finding":"SHP2 promotes trafficking of TLR7 from the Golgi to the endosome in macrophages by dephosphorylating TLR7 at Tyr1024, which boosts TLR7 ubiquitination and NF-κB-mediated skin inflammation; TLR7 Tyr1024 point-mutant knock-in mice showed attenuated psoriasis-like phenotype.","method":"SHP2 allosteric inhibitor, TLR7 point-mutant knock-in mice, subcellular fractionation of TLR7, phosphorylation and ubiquitination assays, conditional SHP2 knockout mice","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphorylation site identified with KI mouse validation, TLR7 trafficking mechanistically linked to post-translational modification","pmids":["34936223"],"is_preprint":false},{"year":2009,"finding":"LL37 antimicrobial peptide binds self-RNA released by dying cells, protects it from extracellular degradation, and transports it into endosomal compartments where it activates TLR7 in plasmacytoid DCs to trigger IFN-α secretion.","method":"Co-culture and delivery assays, TLR7 reporter assays, IFN-α ELISA in pDCs, LL37-self-RNA complex characterization","journal":"Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanism of delivery and receptor activation established with TLR-specific readouts, multiple cell types validated","pmids":["19703986"],"is_preprint":false},{"year":2015,"finding":"TREML4 is an essential positive regulator of TLR7 signaling; TREML4-deficient macrophages are hyporesponsive to TLR7 agonists due to impaired STAT1 phosphorylation by p38 MAPK and decreased recruitment of adaptor MyD88 to TLR7.","method":"Genome-scale shRNA screen, Treml4-/- mice, TLR7 agonist stimulation assays, p38/STAT1 phosphorylation, MyD88 co-immunoprecipitation with TLR7","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined biochemical mechanism (MyD88 recruitment, p38/STAT1 axis), unbiased screen followed by mechanistic validation","pmids":["25848864"],"is_preprint":false},{"year":2010,"finding":"TLR9 suppresses TLR7-dependent RNA-associated autoantibody production in lupus-prone mice; TLR7-driven disease depends on MyD88; TLR7 and TLR9 act in parallel pathways on different autoantibody subsets with TLR9 also cross-regulating TLR7-dependent responses.","method":"Tlr7-/-, Tlr9-/-, double Tlr7/9-/-, and Myd88-/- MRL/lpr mice; autoantibody profiling; disease severity scoring","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple KO combinations in well-characterized lupus model, replicated phenotypes","pmids":["20089701"],"is_preprint":false},{"year":2007,"finding":"2'-O-methyl (2'OMe)-modified RNA acts as a potent antagonist of TLR7; it inhibits both RNA-mediated cytokine induction and the small-molecule TLR7 agonist loxoribine without requiring direct incorporation into the immunostimulatory RNA, acting in trans.","method":"Human PBMC and murine Flt3L DC cytokine assays, in vivo mouse treatment with loxoribine, 2'OMe antagonist competition assays","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional assays establishing antagonism mechanism, single lab","pmids":["17579574"],"is_preprint":false},{"year":2013,"finding":"Inosine incorporation into immunostimulatory ssRNA potentiates TLR7 activation; A-to-I RNA editing of viral ssRNA directly enhances mouse Tlr7 sensing, and inosine-mediated increase in ssRNA self-secondary structure enhances TLR7 (not TLR8)-dependent IFN-α production.","method":"TLR7 antagonist, Tlr7-deficient cells, human PBMCs with inosine-modified ssRNAs, influenza ssRNA editing analysis","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO cells with TLR7 antagonist confirmation, single lab, two orthogonal methods","pmids":["24227841"],"is_preprint":false},{"year":2008,"finding":"TLR7 and CD40 cooperate in B cells to synergistically produce IL-6 through enhanced JNK activity and increased AP-1 (cJun/cFos) activation; dual TLR7+CD40 stimulation markedly enhanced JNK activity and expanded AP-1 dimer species compared to single stimulation.","method":"Primary mouse and human B cell stimulation, kinase activity assays (JNK), AP-1 transcription factor analysis, IL-6 cytokine ELISA","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase activity and transcription factor assays in primary cells, single lab","pmids":["18228247"],"is_preprint":false},{"year":2019,"finding":"TLR7 signaling in monocytes specifically increases expression of transcription factor FOSL1, which reduces IL-27 and TNFα production; TLR7 (but not TLR8) activation also stimulates Ca2+ flux in monocytes that prevents type I IFN responses, distinguishing TLR7 and TLR8 as activating distinct signaling cascades.","method":"siRNA knockdown of TLR7/TLR8, RNA virus infection of human monocytes, Ca2+ flux assays, cytokine profiling, FOSL1 gain/loss of function","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TLR-specific knockdown with defined signaling readouts in primary human cells, single lab, multiple orthogonal methods","pmids":["31662487"],"is_preprint":false},{"year":2015,"finding":"B cell autophagy is required for TLR7-dependent autoimmunity; B cell-specific deletion of Atg5 (autophagy gene) in TLR7-transgenic mice abolished antinuclear antibodies and inflammation, establishing that autophagy delivers RNA ligands to endosomal TLR7 in B cells.","method":"Cd19-Cre Atg5f/f × Tlr7 transgenic mice, ANA quantification, inflammatory cytokine measurement, survival analysis","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — B cell-specific genetic ablation of autophagy in TLR7 transgenic model with clear mechanistic pathway placement","pmids":["26120731"],"is_preprint":false},{"year":2019,"finding":"Chronic TLR7 signaling drives differentiation of inflammatory hemophagocytes (iHPCs) from Ly6Chi monocytes via IRF5; iHPCs are responsible for anemia and thrombocytopenia in TLR7-overexpressing mice. TLR7 signaling specifies monocyte fate through endosomal TLR/MyD88 signaling.","method":"TLR7-overexpressing mice, cell lineage tracing, IRF5-deficient mice, endosomal TLR/MyD88 genetic ablation, experimental malaria model","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic models with cell fate tracing and defined downstream transcription factor, replicated in two disease models","pmids":["30630901"],"is_preprint":false},{"year":2022,"finding":"Purine nucleoside phosphorylase (PNP) regulates TLR7 signaling in B lymphocytes and macrophages by controlling intracellular levels of (deoxy)guanosine nucleoside ligands for TLR7; PNP inactivation leads to accumulation of guanosine ligands, promoting germinal center formation and accelerating autoimmunity.","method":"PNP inhibitor/genetic inactivation, TLR7-dependent cytokine assays, mouse autoimmunity model, germinal center formation assays","journal":"Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological PNP inactivation with TLR7-specific mechanistic link, single lab","pmids":["35653193"],"is_preprint":false},{"year":2021,"finding":"RNase T2-dependent RNA degradation in endosomes/lysosomes positively regulates TLR7 responses in macrophages (and negatively regulates TLR3 responses); RNase T2 mutants (H122A, C188R) that impair RNA degradation also impair TLR7 responses, showing a direct mechanistic link between endosomal RNA processing and TLR7 activation.","method":"RNase T2-deficient macrophages, catalytic mutant rescue experiments, in vitro RNA degradation assays, endosomal colocalization studies","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO macrophages with mutagenesis rescue and in vitro enzymatic assays, single lab","pmids":["34161582"],"is_preprint":false},{"year":2018,"finding":"TLR7 escapes X chromosome inactivation in B lymphocytes, monocytes, and plasmacytoid DCs from women and Klinefelter syndrome males; biallelic B cells show higher TLR7 protein expression and greater than twofold increase in TLR7-driven IgG class switching and CD27+ plasma cell proliferation compared to monoallelic cells.","method":"Single-cell allelic expression analysis (SNP-based), TLR7 protein quantification by flow cytometry, B cell functional assays (class switching, plasma cell differentiation)","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — single-cell allelic resolution with matched functional B cell readouts, multiple primary cell types analyzed","pmids":["29374079"],"is_preprint":false},{"year":2016,"finding":"Structure-guided mutagenesis of human TLR7 identified specific ectodomain residues governing GS-9620 (TLR7 agonist) binding; TLR7 exists in a ligand-independent oligomeric state, and GS-9620 activation is associated with compound-induced conformational changes. Downstream, GS-9620 activates NF-κB and Akt pathways as immediate responses in pDCs.","method":"Structure-guided mutational analysis, subcellular distribution assays, NF-κB/Akt pathway activation in primary pDCs, oligomerization assay","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-guided mutagenesis with signaling readouts, single lab","pmids":["26784926"],"is_preprint":false},{"year":2020,"finding":"TLR7 activates B cell-intrinsic signaling to drive accelerated lupus in TLR9-deficient mice; B cell-specific TLR7 deletion (CD19-Cre) in TLR9-deficient MRL/lpr mice greatly improved disease, while TLR7 deficiency in CD11c+ cells had no impact, revealing a cis regulatory interaction between TLR7 and TLR9 within the B cell compartment.","method":"Conditional TLR7 floxed allele deletion (CD19-Cre and CD11c-Cre), bone marrow chimera strategy, MRL/lpr lupus-prone background","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with epistasis design, multiple genetic controls","pmids":["37606042"],"is_preprint":false},{"year":2023,"finding":"TLR7 in B cells promotes production of galactose-deficient IgA1 (Gd-IgA1) via the TLR7-GALNT2 axis in IgA nephropathy; TLR7 overexpression increases GALNT2 protein levels while TLR7 knockdown reduces them, and GALNT2 overexpression augments Gd-IgA1 production.","method":"TLR7 overexpression and knockdown in B cells, GALNT2 protein quantification, Gd-IgA1 ELISA, patient B cell functional assays","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain and loss of function with defined effector molecule, single lab, replicated in patient-derived cells","pmids":["32699192"],"is_preprint":false},{"year":2024,"finding":"Neuronal substance P induces death of TACR1high cancer cells, releasing extracellular ssRNAs that activate TLR7 in neighboring tumor cells to non-canonically activate a prometastatic gene expression program, driving breast cancer metastasis.","method":"3D co-cultures, in vivo mouse mammary tumor models, TLR7-deficient cancer cells, TACR1 antagonist treatment, gene expression profiling","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific TLR7 loss-of-function with defined ligand (extracellular ssRNA) and downstream gene expression program, multiple in vivo models","pmids":["39112700"],"is_preprint":false},{"year":2024,"finding":"TLR7 gain-of-function interface mutations at the dimerization interface (F507S and L528I) cause systemic and neuroinflammatory disease; the mutations are predicted to enhance TLR7 homodimerization, which enhances TLR7 signaling.","method":"Human patient variant identification, structural modeling of dimerization interface, functional signaling assays in patient-derived cells","journal":"Journal of clinical immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — human variants with structural modeling and functional validation, single lab; dimerization mechanism is partly computational","pmids":["38324161"],"is_preprint":false},{"year":2008,"finding":"TLR7 and TLR8 activation in human CD34-derived DCs induces DC maturation via JNK and NF-κB; TLR7 (but not TLR8) activation additionally engages the Jak/STAT signaling pathway to drive CD40 expression and cytokine production, while p38MAPK plays a positive role downstream of TLR7 but inhibitory role downstream of TLR8.","method":"Selective TLR7 (imiquimod) and TLR8 (3M002) agonists, kinase inhibitor panel, primary human CD34-DCs, cytokine ELISA","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection in primary human cells with two orthogonal agonists, single lab","pmids":["19164127"],"is_preprint":false},{"year":2023,"finding":"TLR7 in dendritic cells promotes neutrophil activation and migration in pustular psoriasis via a TLR7-MyD88-DC-CXCL16 axis; TLR7 induces DC secretion of CXCL16, which activates neutrophils expressing its receptor CXCR6, and this was confirmed in Cd11c-Cre Myd88f/f conditional knockout mice.","method":"Conditional MyD88 KO (Cd11c-Cre), Mrp8-Cre Cxcr6f/f KO mice, imiquimod psoriasis model, DC-neutrophil co-culture with TLR7 inhibitor/agonist","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mice with defined pathway, single lab","pmids":["37160878"],"is_preprint":false},{"year":2023,"finding":"TLR7 signaling in B cells promotes germinal center formation, affinity maturation, IgG2b/2c isotype switching, and BCR repertoire diversity upon VLP immunization in a B cell-intrinsic manner; chimeric mice lacking TLR7 exclusively in B cells failed to show these enhanced IgG responses.","method":"TLR7-deficient chimeric mice with B cell-specific TLR7 deletion, VLP immunization, deep BCR repertoire sequencing, germinal center analysis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — B cell-intrinsic KO with BCR deep sequencing and GC analysis, single lab","pmids":["35126381"],"is_preprint":false},{"year":2023,"finding":"TLR7/8 sensing of lysosomal nucleosides drives histiocytosis in SLC29A3-deficient mice; TLR7 increases phagocyte numbers by driving Ly6Chi monocyte proliferation and maturation, requiring downstream FcRγ and DAP10 for monocyte proliferation.","method":"Slc29a3-/- × Tlr7-/- mice, monocyte lineage analysis, FcRγ and DAP10-deficient mice, patient-derived monocyte assays","journal":"Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple KO combinations, defined downstream signaling molecules, replicated in patient-derived cells","pmids":["37462944"],"is_preprint":false},{"year":2023,"finding":"TLR7 promotes smoke-induced emphysema and COPD through mast cell activity; TLR7 deficiency reduces emphysema severity, TLR7 agonist inhalation alone induces emphysema that is prevented by mast cell stabilizer or mast cell protease-6 (Mcpt6) deficiency, establishing a TLR7→mast cell tryptase pathway in lung damage.","method":"TLR7-deficient mice, Mcpt6-deficient mice, imiquimod inhalation model, cromolyn mast cell stabilizer, anti-TLR7 monoclonal antibody treatment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KO models plus pharmacological interventions establishing pathway, replicated in human COPD tissue","pmids":["37963864"],"is_preprint":false},{"year":2024,"finding":"Tlr7 (X-linked) regulates sex-specific type I interferon responses to myelin; Tlr7 deletion dampens sex differences and protects against demyelination in mouse models of aging and Alzheimer's disease-related tau pathology, with XY sex chromosomes heightening IFN response through Tlr7.","method":"Single-nuclei transcriptomics, Tlr7-knockout mice, sex chromosome manipulation (Four Core Genotypes approach), demyelination mouse model, TLR7 inhibitor treatment","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with single-cell transcriptomics and pharmacological confirmation, sex-chromosome-specific mechanism demonstrated","pmids":["39607927"],"is_preprint":false}],"current_model":"TLR7 is an endosomal (and cell-surface) single-stranded RNA sensor that recognizes two classes of ligands in two binding pockets—guanosine/deoxyguanosine nucleosides (pocket 1, generated by PLD3/PLD4 from RNase T2-processed RNA) and short pyrimidine-rich RNA fragments (pocket 2)—and signals through MyD88 to activate NF-κB, MAPK, and IRF5 (via the TASL–SLC15A4 adaptor complex) to produce inflammatory cytokines and type I interferons; TLR7 trafficking and signaling threshold are controlled by UNC93B1 (which recruits syntenin-1 to sort TLR7 into multivesicular bodies) and by SHP2-mediated dephosphorylation of TLR7-Tyr1024 (which promotes Golgi-to-endosome trafficking), while its endosomal abundance is regulated by the BORC–Arl8b–UNC93B1 axis; gain-of-function variants (TLR7Y264H, F507S, L528I) or X-chromosome escape from inactivation increase TLR7 dosage and drive B cell-intrinsic autoimmunity through MyD88-dependent pathways, whereas TLR9 cross-regulates TLR7-dependent responses within B cells."},"narrative":{"mechanistic_narrative":"TLR7 is an endosomal single-stranded RNA sensor of innate immunity that signals through MyD88 to drive type I interferon and inflammatory cytokine production [PMID:14976261]. Rather than recognizing intact RNA, TLR7 detects degradation products generated within the endolysosome: lysosomal RNase T2 cleaves RNA, and the exonucleases PLD3/PLD4 release guanosine-derived 2',3'-cGMP for one binding pocket and pyrimidine-rich fragments for a second pocket, so that both ligand classes are produced cooperatively from RNA processing [PMID:38697119, PMID:34161582]. Consistent with this, TLR7 senses free guanosine, deoxyguanosine and oxidized guanosine nucleosides, with oligoribonucleotide co-presentation strengthening nucleoside binding [PMID:26489884, PMID:31608988], and the nucleoside salvage enzyme PNP limits ligand availability by clearing (deoxy)guanosine [PMID:35653193]. Structurally TLR7 cycles between open (inactive) and closed (active) conformations and exists as a ligand-independent oligomer, with antagonists stabilizing the open state [PMID:33060576, PMID:26784926]. Downstream of receptor engagement TLR7 recruits MyD88 to activate NF-κB, MAPK/JNK and Jak/STAT cascades [PMID:25848864, PMID:19164127], and engages the SLC15A4-associated adaptor TASL through its pLxIS motif to activate IRF5 specifically along the IRF branch [PMID:32433612]. TLR7 abundance, localization and signaling threshold are set by trafficking machinery: UNC93B1 recruits syntenin-1 to sort TLR7 into multivesicular bodies and terminate signaling [PMID:31546246] and interacts with the BORC–Arl8b axis to control endosomal receptor turnover [PMID:38207015], while SHP2-mediated dephosphorylation of TLR7-Tyr1024 promotes Golgi-to-endosome trafficking and ubiquitination [PMID:34936223]. Excess TLR7 dosage or activity drives B cell-intrinsic autoimmunity: gain-of-function variants (Y264H; dimerization-interface F507S/L528I) cause lupus and neuroinflammatory disease in a MyD88-dependent manner [PMID:35477763, PMID:38324161], escape from X-chromosome inactivation raises biallelic TLR7 expression and amplifies B cell responses [PMID:29374079], and UNC93B1 mutations that disrupt TLR7 trafficking cause childhood-onset lupus [PMID:38207015, PMID:38207055]. Chronic TLR7 signaling also specifies pathogenic monocyte fates via IRF5 [PMID:30630901] and contributes to histiocytosis, psoriasis, emphysema, demyelination, and breast cancer metastasis through tissue-specific effector pathways [PMID:39112700, PMID:37462944, PMID:37963864, PMID:39607927].","teleology":[{"year":2004,"claim":"Established the founding identity of TLR7 as an endosomal ssRNA sensor coupled to MyD88, defining both ligand class and signaling adaptor.","evidence":"TLR7- and MyD88-deficient mice with viral and synthetic ssRNA in endosomal recognition assays","pmids":["14976261"],"confidence":"High","gaps":["Did not define the precise molecular feature of RNA recognized","Did not resolve how RNA reaches the endosomal receptor"]},{"year":2008,"claim":"Showed TLR7 ectodomain residues distinguish RNA versus imidazoquinoline ligands and that ligand class dictates distinct phosphorylation and transcriptional outputs, hinting at dual recognition modes.","evidence":"Ectodomain mutagenesis and proteome/genome-wide analysis in primary human monocyte-derived DCs","pmids":["24813206"],"confidence":"Medium","gaps":["Binding sites inferred from mutagenesis, not direct structure","Mechanistic link between ligand class and downstream output not fully resolved"]},{"year":2015,"claim":"Identified guanosine-family nucleosides as endogenous TLR7 ligands whose binding is enhanced by oligoribonucleotides, reframing TLR7 as a sensor of RNA degradation products rather than intact RNA.","evidence":"ITC binding assays plus cytokine readouts in mouse and human cells with Unc93b1 controls","pmids":["26489884"],"confidence":"High","gaps":["Did not establish the enzymatic source of nucleoside ligands","Two-pocket structural basis not yet defined"]},{"year":2015,"claim":"Demonstrated functional cell-surface TLR7 in addition to endolysosomal pools, expanding the receptor's localization and showing surface receptor can be targeted therapeutically.","evidence":"Anti-TLR7 antibody internalization, fractionation/immunofluorescence and in vivo treatment of Unc93b1 D34A autoimmune mice","pmids":["25648980"],"confidence":"High","gaps":["Relative contribution of surface versus endosomal TLR7 to physiologic signaling unclear","Trafficking route between surface and endosome not defined here"]},{"year":2019,"claim":"Established that deoxyguanosine activates TLR7 independently of supplied ssRNA but still requires MyD88 and endosomal maturation, confirming nucleosides as bona fide RNA-independent agonists.","evidence":"Cytokine assays in TLR7-/- and MyD88-/- macrophages/pDCs with bafilomycin A1 blockade","pmids":["31608988"],"confidence":"High","gaps":["Did not show which pocket dG occupies","Source of endogenous dG in vivo not addressed"]},{"year":2019,"claim":"Defined UNC93B1–syntenin-1 sorting into multivesicular bodies as the mechanism that selectively terminates TLR7 signaling, linking receptor trafficking to autoimmunity.","evidence":"Reciprocal Co-IP, phosphorylation-dependent binding, exosome fractionation and UNC93B1 mutant autoimmune mice","pmids":["31546246"],"confidence":"High","gaps":["Kinase phosphorylating UNC93B1 not identified","TLR9 selectivity mechanism not fully explained"]},{"year":2020,"claim":"Provided the structural framework of TLR7 conformational equilibrium and a defined antagonist pocket, enabling rational stabilization of the inactive open state.","evidence":"X-ray crystallography, cryo-EM and structure-guided antagonist with in vivo autoimmunity protection","pmids":["33060576"],"confidence":"High","gaps":["Did not capture full active dimer with both physiologic ligands","Conformational dynamics during signaling not resolved in cells"]},{"year":2020,"claim":"Identified TASL as the SLC15A4-bound, pLxIS-motif adaptor that specifically couples endosomal TLRs to IRF5, defining the IRF branch of TLR7 signaling distinct from NF-κB/MAPK.","evidence":"TASL knockout, pLxIS mutagenesis and pathway dissection in human immune cells","pmids":["32433612"],"confidence":"High","gaps":["Structural basis of TASL–IRF5 engagement not resolved here","How signal selectivity between TLR7/8/9 is achieved unclear"]},{"year":2021,"claim":"Linked endosomal RNA processing to TLR7 activation by showing RNase T2 catalytic activity is required to generate TLR7-activating ligands, oppositely regulating TLR3.","evidence":"RNase T2-deficient macrophages with catalytic mutant rescue and in vitro degradation assays","pmids":["34161582"],"confidence":"Medium","gaps":["Did not define the exact RNase T2 product engaging TLR7","Single lab; ligand chemistry resolved only later"]},{"year":2021,"claim":"Defined SHP2-mediated dephosphorylation of TLR7-Tyr1024 as a post-translational switch promoting Golgi-to-endosome trafficking and ubiquitination, tuning inflammatory output.","evidence":"SHP2 inhibitor, conditional SHP2 KO, TLR7 Tyr1024 point-mutant knock-in mice and fractionation","pmids":["34936223"],"confidence":"High","gaps":["Kinase adding the Tyr1024 phosphate not identified","Generalizability beyond macrophage skin inflammation untested here"]},{"year":2022,"claim":"Proved a single human gain-of-function variant (Y264H) increasing nucleoside sensing is sufficient to cause lupus and that pathology is entirely MyD88-dependent and B cell-intrinsic.","evidence":"Human de novo variant, knock-in mouse, MyD88-deficient rescue epistasis and B cell assays","pmids":["35477763"],"confidence":"High","gaps":["Did not map the contribution of non-B-cell TLR7","Structural effect of Y264H on the binding pocket not directly visualized"]},{"year":2022,"claim":"Showed PNP controls TLR7 by limiting intracellular guanosine ligand levels, identifying nucleoside metabolism as a tunable upstream determinant of TLR7-driven autoimmunity.","evidence":"PNP genetic/pharmacologic inactivation with TLR7-dependent cytokine and germinal center assays","pmids":["35653193"],"confidence":"Medium","gaps":["Single lab","Quantitative relationship between PNP activity and TLR7 threshold not defined"]},{"year":2024,"claim":"Resolved the enzymatic two-step generation of both TLR7 ligand classes, showing RNase T2 then PLD3/PLD4 homodimers produce 2',3'-cGMP for pocket 1 and pyrimidine fragments for pocket 2.","evidence":"Reconstitution biochemistry, PLD homodimer crystallography/cryo-EM and cell-based loss-of-function","pmids":["38697119"],"confidence":"High","gaps":["In vivo stoichiometry of the two pockets during physiologic signaling unclear","How disease PLD mutants alter human TLR7 thresholds quantitatively not defined"]},{"year":2024,"claim":"Established the BORC–Arl8b–UNC93B1 axis as a controller of endosomal TLR7 turnover, with a patient UNC93B1 mutation causing TLR7 accumulation and childhood-onset lupus.","evidence":"UNC93B1–Arl8b interaction studies, patient-derived mutant analysis and endosomal TLR7 quantification","pmids":["38207015"],"confidence":"High","gaps":["Full BORC subunit requirements not dissected","How turnover defect translates to specific B cell autoimmunity not detailed"]},{"year":2024,"claim":"Showed UNC93B1 missense variants confer selective TLR7 hyperactivation via protein instability and altered TLR7 interaction, demonstrating UNC93B1 controls TLR7 subtype-specific recognition.","evidence":"Patient cells and UNC93B1-variant mouse macrophages with TLR7/8/9 agonist and interaction assays","pmids":["38207055"],"confidence":"High","gaps":["Mechanism of TLR7-versus-TLR9 selectivity at residue level incomplete","Structural consequence of variants not solved"]},{"year":2024,"claim":"Identified dimerization-interface gain-of-function variants (F507S, L528I) that enhance TLR7 homodimerization to cause systemic and neuroinflammatory disease, extending the GOF allelic series beyond ligand sensing.","evidence":"Human patient variants, structural modeling and functional signaling in patient cells","pmids":["38324161"],"confidence":"Medium","gaps":["Dimerization enhancement is partly computational","Direct structural confirmation of altered dimer interface lacking"]},{"year":2024,"claim":"Revealed a non-canonical TLR7 role in cancer: tumor-cell TLR7 senses extracellular ssRNA released by substance-P-killed cells to drive a prometastatic program, extending TLR7 beyond immune cells.","evidence":"3D co-cultures, TLR7-deficient cancer cells, TACR1 antagonism and in vivo mammary tumor models","pmids":["39112700"],"confidence":"High","gaps":["Adaptor usage for the prometastatic program not defined","Whether canonical MyD88/IRF pathways are involved unclear"]},{"year":null,"claim":"How the two ligand pockets, conformational equilibrium, trafficking checkpoints and adaptor choice (MyD88/NF-κB vs TASL/IRF5) are integrated to set quantitative signaling thresholds across distinct cell types and diseases remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of the active TLR7 dimer bound to both physiologic ligands","Cell-type-specific determinants of NF-κB versus IRF5 branch selection undefined","Mechanism distinguishing protective immunity from pathogenic autoimmunity at a single threshold unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,4,17]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,9,14]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,13]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,7,8,23]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[3,23,33]},{"term_id":"GO:0005886","term_label":"plasma 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with influenza genomic RNA and synthetic ssRNA\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO models with defined ligand and signaling readout, replicated across multiple ssRNA species, foundational paper widely confirmed\",\n      \"pmids\": [\"14976261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TLR7 and TLR8 ectodomains sense RNA oligoribonucleotides (ORN) and imidazoquinolines through overlapping but non-identical recognition sites; RNA ORN versus imidazoquinoline binding produces ligand-specific differential phosphorylation and distinct transcriptional responses, suggesting TLR7 can signal in two different 'modes' depending on ligand class.\",\n      \"method\": \"Proteome- and genome-wide analysis, mutagenesis of ectodomain residues, primary human monocyte-derived DCs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis and proteomics in primary cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"24813206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TLR7 senses guanosine (G), 2'-deoxyguanosine (dG), 7-methylguanosine, 8-hydroxyguanosine (8-OHG), and 8-hydroxydeoxyguanosine (8-OHdG) as endogenous small-molecule ligands when co-presented with an oligoribonucleotide (ORN); ORN strengthens TLR7 interaction with G/dG as measured by isothermal titration calorimetry.\",\n      \"method\": \"Cytokine production assays in mouse and human immune cells, isothermal titration calorimetry (ITC) binding assay, Unc93b1-mutant macrophages\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assay (ITC) plus functional cytokine assays, replicated in mouse and human cells with genetic controls\",\n      \"pmids\": [\"26489884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Deoxyguanosine (dG) activates TLR7 independently of concurrent ssRNA provision; this signaling requires TLR7 and its adaptor MyD88 and depends on endosomal maturation, establishing dG as an RNA-independent TLR7 agonist.\",\n      \"method\": \"Cytokine production in TLR7-/- and MyD88-/- murine macrophages and pDCs, bafilomycin A1 endosomal acidification blockade, human PBMCs\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO validation with mechanistic endosomal requirement, replicated across cell types\",\n      \"pmids\": [\"31608988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lysosomal endonuclease RNase T2 generates guanosine 2',3'-cyclic monophosphate-terminated RNA fragments; PLD3/PLD4 exonucleases then release 2',3'-cGMP to engage TLR7 pocket 1 and generate pyrimidine-rich RNA fragments for TLR7 pocket 2, cooperatively producing both classes of TLR7 ligands. PLD enzymes form homodimers with two ligand-binding sites required for activity; disease-associated PLD mutants fail to form stable dimers.\",\n      \"method\": \"Biochemical assays, structural studies, loss-of-function studies in cell lines and primary cells, crystallography/cryo-EM of PLD homodimers\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution biochemistry, structural analysis, and cell-based loss-of-function, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38697119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TLR7 structural analysis by combined crystallography and cryo-EM reveals an equilibrium between open and closed receptor conformations; TLR7-specific antagonists bind a defined pocket and stabilize the open (inactive) conformation, providing the structural basis for TLR7 antagonism.\",\n      \"method\": \"X-ray crystallography, cryo-electron microscopy, structure-guided antagonist development, in vivo autoimmunity protection assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus cryo-EM with functional in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"33060576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A gain-of-function missense variant TLR7Y264H selectively increases TLR7 sensing of guanosine and 2',3'-cGMP and is sufficient to cause lupus when introduced into mice; downstream pathogenesis requires MyD88 (deficiency of MyD88 rescued all phenotypes), and TLR7Y264H drives cell-intrinsic aberrant survival of BCR-activated B cells and accumulation of CD11c+ age-associated B cells.\",\n      \"method\": \"Human genetic identification of de novo variant, knock-in mouse model, MyD88-deficient rescue epistasis, B cell functional assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human variant with mouse knock-in plus epistasis rescue, replicated across cellular and serological readouts\",\n      \"pmids\": [\"35477763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UNC93B1 specifically limits TLR7 (but not TLR9) signaling by recruiting syntenin-1, which facilitates sorting of TLR7 into intraluminal vesicles of multivesicular bodies to terminate signaling; this recruitment requires phosphorylation of UNC93B1. Mutations in UNC93B1 that disrupt syntenin-1 binding cause enhanced TLR7 signaling and TLR7-dependent autoimmunity in mice.\",\n      \"method\": \"Co-immunoprecipitation, UNC93B1 mutant mice, exosome fractionation, phosphorylation-dependent binding assays, in vivo autoimmunity models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic mouse models, subcellular fractionation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31546246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The late endosomal BORC complex together with the small GTPase Arl8b controls intracellular TLR7 levels by regulating receptor turnover; this requires a direct interaction between TLR7-associated trafficking factor UNC93B1 and Arl8b. An UNC93B1 mutation causing reduced BORC interaction leads to endosomal TLR7 accumulation and childhood-onset lupus.\",\n      \"method\": \"Protein interaction studies (UNC93B1–Arl8b), patient-derived UNC93B1 mutant analysis, endosomal TLR7 level quantification, functional signaling assays\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction demonstrated, patient mutation with defined molecular consequence, multiple orthogonal methods\",\n      \"pmids\": [\"38207015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TASL (encoded by CXorf21) interacts with endolysosomal transporter SLC15A4 and contains a pLxIS motif that mediates recruitment and activation of IRF5; loss of TASL specifically impairs the IRF pathway downstream of TLR7, TLR8, and TLR9 without affecting NF-κB or MAPK signaling, establishing TASL as a TLR7/8/9-to-IRF5 adaptor analogous to STING/MAVS/TRIF for IRF3.\",\n      \"method\": \"Protein interaction studies, TASL knockout in primary and transformed human immune cells, extensive mutagenesis of TASL pLxIS motif, signaling pathway dissection\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, mutagenesis, interaction studies, pathway epistasis; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"32433612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UNC93B1 variants E92G and R336L cause selective TLR7 hyperactivation with constitutive type I IFN signaling; E92G causes UNC93B1 protein instability and reduced interaction with TLR7, demonstrating that UNC93B1 regulates TLR7 subtype-specific ligand recognition mechanisms.\",\n      \"method\": \"Patient-derived cells, mouse macrophages carrying UNC93B1 variants, TLR7/8/9 agonist stimulation assays, protein interaction studies\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human patient variants validated in mouse macrophages with defined molecular interaction consequence, TLR subtype selectivity demonstrated\",\n      \"pmids\": [\"38207055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TLR7 is present on the cell surface of immune cells (dendritic cells, macrophages, B cells) in addition to endolysosomes; an anti-TLR7 antibody is internalized with TLR7 into endolysosomes and inhibits TLR7 responses and in vivo cytokine production, demonstrating functional cell-surface TLR7.\",\n      \"method\": \"Anti-TLR7 antibody internalization assay, subcellular fractionation/immunofluorescence, in vivo cytokine production, Unc93b1 D34A/D34A autoimmune mouse model treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization with functional consequence demonstrated in vitro and in vivo with multiple cell types\",\n      \"pmids\": [\"25648980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SHP2 promotes trafficking of TLR7 from the Golgi to the endosome in macrophages by dephosphorylating TLR7 at Tyr1024, which boosts TLR7 ubiquitination and NF-κB-mediated skin inflammation; TLR7 Tyr1024 point-mutant knock-in mice showed attenuated psoriasis-like phenotype.\",\n      \"method\": \"SHP2 allosteric inhibitor, TLR7 point-mutant knock-in mice, subcellular fractionation of TLR7, phosphorylation and ubiquitination assays, conditional SHP2 knockout mice\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphorylation site identified with KI mouse validation, TLR7 trafficking mechanistically linked to post-translational modification\",\n      \"pmids\": [\"34936223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LL37 antimicrobial peptide binds self-RNA released by dying cells, protects it from extracellular degradation, and transports it into endosomal compartments where it activates TLR7 in plasmacytoid DCs to trigger IFN-α secretion.\",\n      \"method\": \"Co-culture and delivery assays, TLR7 reporter assays, IFN-α ELISA in pDCs, LL37-self-RNA complex characterization\",\n      \"journal\": \"Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanism of delivery and receptor activation established with TLR-specific readouts, multiple cell types validated\",\n      \"pmids\": [\"19703986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TREML4 is an essential positive regulator of TLR7 signaling; TREML4-deficient macrophages are hyporesponsive to TLR7 agonists due to impaired STAT1 phosphorylation by p38 MAPK and decreased recruitment of adaptor MyD88 to TLR7.\",\n      \"method\": \"Genome-scale shRNA screen, Treml4-/- mice, TLR7 agonist stimulation assays, p38/STAT1 phosphorylation, MyD88 co-immunoprecipitation with TLR7\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined biochemical mechanism (MyD88 recruitment, p38/STAT1 axis), unbiased screen followed by mechanistic validation\",\n      \"pmids\": [\"25848864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TLR9 suppresses TLR7-dependent RNA-associated autoantibody production in lupus-prone mice; TLR7-driven disease depends on MyD88; TLR7 and TLR9 act in parallel pathways on different autoantibody subsets with TLR9 also cross-regulating TLR7-dependent responses.\",\n      \"method\": \"Tlr7-/-, Tlr9-/-, double Tlr7/9-/-, and Myd88-/- MRL/lpr mice; autoantibody profiling; disease severity scoring\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple KO combinations in well-characterized lupus model, replicated phenotypes\",\n      \"pmids\": [\"20089701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"2'-O-methyl (2'OMe)-modified RNA acts as a potent antagonist of TLR7; it inhibits both RNA-mediated cytokine induction and the small-molecule TLR7 agonist loxoribine without requiring direct incorporation into the immunostimulatory RNA, acting in trans.\",\n      \"method\": \"Human PBMC and murine Flt3L DC cytokine assays, in vivo mouse treatment with loxoribine, 2'OMe antagonist competition assays\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional assays establishing antagonism mechanism, single lab\",\n      \"pmids\": [\"17579574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Inosine incorporation into immunostimulatory ssRNA potentiates TLR7 activation; A-to-I RNA editing of viral ssRNA directly enhances mouse Tlr7 sensing, and inosine-mediated increase in ssRNA self-secondary structure enhances TLR7 (not TLR8)-dependent IFN-α production.\",\n      \"method\": \"TLR7 antagonist, Tlr7-deficient cells, human PBMCs with inosine-modified ssRNAs, influenza ssRNA editing analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO cells with TLR7 antagonist confirmation, single lab, two orthogonal methods\",\n      \"pmids\": [\"24227841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TLR7 and CD40 cooperate in B cells to synergistically produce IL-6 through enhanced JNK activity and increased AP-1 (cJun/cFos) activation; dual TLR7+CD40 stimulation markedly enhanced JNK activity and expanded AP-1 dimer species compared to single stimulation.\",\n      \"method\": \"Primary mouse and human B cell stimulation, kinase activity assays (JNK), AP-1 transcription factor analysis, IL-6 cytokine ELISA\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase activity and transcription factor assays in primary cells, single lab\",\n      \"pmids\": [\"18228247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TLR7 signaling in monocytes specifically increases expression of transcription factor FOSL1, which reduces IL-27 and TNFα production; TLR7 (but not TLR8) activation also stimulates Ca2+ flux in monocytes that prevents type I IFN responses, distinguishing TLR7 and TLR8 as activating distinct signaling cascades.\",\n      \"method\": \"siRNA knockdown of TLR7/TLR8, RNA virus infection of human monocytes, Ca2+ flux assays, cytokine profiling, FOSL1 gain/loss of function\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TLR-specific knockdown with defined signaling readouts in primary human cells, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31662487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"B cell autophagy is required for TLR7-dependent autoimmunity; B cell-specific deletion of Atg5 (autophagy gene) in TLR7-transgenic mice abolished antinuclear antibodies and inflammation, establishing that autophagy delivers RNA ligands to endosomal TLR7 in B cells.\",\n      \"method\": \"Cd19-Cre Atg5f/f × Tlr7 transgenic mice, ANA quantification, inflammatory cytokine measurement, survival analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — B cell-specific genetic ablation of autophagy in TLR7 transgenic model with clear mechanistic pathway placement\",\n      \"pmids\": [\"26120731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Chronic TLR7 signaling drives differentiation of inflammatory hemophagocytes (iHPCs) from Ly6Chi monocytes via IRF5; iHPCs are responsible for anemia and thrombocytopenia in TLR7-overexpressing mice. TLR7 signaling specifies monocyte fate through endosomal TLR/MyD88 signaling.\",\n      \"method\": \"TLR7-overexpressing mice, cell lineage tracing, IRF5-deficient mice, endosomal TLR/MyD88 genetic ablation, experimental malaria model\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic models with cell fate tracing and defined downstream transcription factor, replicated in two disease models\",\n      \"pmids\": [\"30630901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Purine nucleoside phosphorylase (PNP) regulates TLR7 signaling in B lymphocytes and macrophages by controlling intracellular levels of (deoxy)guanosine nucleoside ligands for TLR7; PNP inactivation leads to accumulation of guanosine ligands, promoting germinal center formation and accelerating autoimmunity.\",\n      \"method\": \"PNP inhibitor/genetic inactivation, TLR7-dependent cytokine assays, mouse autoimmunity model, germinal center formation assays\",\n      \"journal\": \"Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological PNP inactivation with TLR7-specific mechanistic link, single lab\",\n      \"pmids\": [\"35653193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNase T2-dependent RNA degradation in endosomes/lysosomes positively regulates TLR7 responses in macrophages (and negatively regulates TLR3 responses); RNase T2 mutants (H122A, C188R) that impair RNA degradation also impair TLR7 responses, showing a direct mechanistic link between endosomal RNA processing and TLR7 activation.\",\n      \"method\": \"RNase T2-deficient macrophages, catalytic mutant rescue experiments, in vitro RNA degradation assays, endosomal colocalization studies\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO macrophages with mutagenesis rescue and in vitro enzymatic assays, single lab\",\n      \"pmids\": [\"34161582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TLR7 escapes X chromosome inactivation in B lymphocytes, monocytes, and plasmacytoid DCs from women and Klinefelter syndrome males; biallelic B cells show higher TLR7 protein expression and greater than twofold increase in TLR7-driven IgG class switching and CD27+ plasma cell proliferation compared to monoallelic cells.\",\n      \"method\": \"Single-cell allelic expression analysis (SNP-based), TLR7 protein quantification by flow cytometry, B cell functional assays (class switching, plasma cell differentiation)\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single-cell allelic resolution with matched functional B cell readouts, multiple primary cell types analyzed\",\n      \"pmids\": [\"29374079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Structure-guided mutagenesis of human TLR7 identified specific ectodomain residues governing GS-9620 (TLR7 agonist) binding; TLR7 exists in a ligand-independent oligomeric state, and GS-9620 activation is associated with compound-induced conformational changes. Downstream, GS-9620 activates NF-κB and Akt pathways as immediate responses in pDCs.\",\n      \"method\": \"Structure-guided mutational analysis, subcellular distribution assays, NF-κB/Akt pathway activation in primary pDCs, oligomerization assay\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-guided mutagenesis with signaling readouts, single lab\",\n      \"pmids\": [\"26784926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TLR7 activates B cell-intrinsic signaling to drive accelerated lupus in TLR9-deficient mice; B cell-specific TLR7 deletion (CD19-Cre) in TLR9-deficient MRL/lpr mice greatly improved disease, while TLR7 deficiency in CD11c+ cells had no impact, revealing a cis regulatory interaction between TLR7 and TLR9 within the B cell compartment.\",\n      \"method\": \"Conditional TLR7 floxed allele deletion (CD19-Cre and CD11c-Cre), bone marrow chimera strategy, MRL/lpr lupus-prone background\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with epistasis design, multiple genetic controls\",\n      \"pmids\": [\"37606042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TLR7 in B cells promotes production of galactose-deficient IgA1 (Gd-IgA1) via the TLR7-GALNT2 axis in IgA nephropathy; TLR7 overexpression increases GALNT2 protein levels while TLR7 knockdown reduces them, and GALNT2 overexpression augments Gd-IgA1 production.\",\n      \"method\": \"TLR7 overexpression and knockdown in B cells, GALNT2 protein quantification, Gd-IgA1 ELISA, patient B cell functional assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain and loss of function with defined effector molecule, single lab, replicated in patient-derived cells\",\n      \"pmids\": [\"32699192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Neuronal substance P induces death of TACR1high cancer cells, releasing extracellular ssRNAs that activate TLR7 in neighboring tumor cells to non-canonically activate a prometastatic gene expression program, driving breast cancer metastasis.\",\n      \"method\": \"3D co-cultures, in vivo mouse mammary tumor models, TLR7-deficient cancer cells, TACR1 antagonist treatment, gene expression profiling\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific TLR7 loss-of-function with defined ligand (extracellular ssRNA) and downstream gene expression program, multiple in vivo models\",\n      \"pmids\": [\"39112700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TLR7 gain-of-function interface mutations at the dimerization interface (F507S and L528I) cause systemic and neuroinflammatory disease; the mutations are predicted to enhance TLR7 homodimerization, which enhances TLR7 signaling.\",\n      \"method\": \"Human patient variant identification, structural modeling of dimerization interface, functional signaling assays in patient-derived cells\",\n      \"journal\": \"Journal of clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — human variants with structural modeling and functional validation, single lab; dimerization mechanism is partly computational\",\n      \"pmids\": [\"38324161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TLR7 and TLR8 activation in human CD34-derived DCs induces DC maturation via JNK and NF-κB; TLR7 (but not TLR8) activation additionally engages the Jak/STAT signaling pathway to drive CD40 expression and cytokine production, while p38MAPK plays a positive role downstream of TLR7 but inhibitory role downstream of TLR8.\",\n      \"method\": \"Selective TLR7 (imiquimod) and TLR8 (3M002) agonists, kinase inhibitor panel, primary human CD34-DCs, cytokine ELISA\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection in primary human cells with two orthogonal agonists, single lab\",\n      \"pmids\": [\"19164127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TLR7 in dendritic cells promotes neutrophil activation and migration in pustular psoriasis via a TLR7-MyD88-DC-CXCL16 axis; TLR7 induces DC secretion of CXCL16, which activates neutrophils expressing its receptor CXCR6, and this was confirmed in Cd11c-Cre Myd88f/f conditional knockout mice.\",\n      \"method\": \"Conditional MyD88 KO (Cd11c-Cre), Mrp8-Cre Cxcr6f/f KO mice, imiquimod psoriasis model, DC-neutrophil co-culture with TLR7 inhibitor/agonist\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mice with defined pathway, single lab\",\n      \"pmids\": [\"37160878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TLR7 signaling in B cells promotes germinal center formation, affinity maturation, IgG2b/2c isotype switching, and BCR repertoire diversity upon VLP immunization in a B cell-intrinsic manner; chimeric mice lacking TLR7 exclusively in B cells failed to show these enhanced IgG responses.\",\n      \"method\": \"TLR7-deficient chimeric mice with B cell-specific TLR7 deletion, VLP immunization, deep BCR repertoire sequencing, germinal center analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — B cell-intrinsic KO with BCR deep sequencing and GC analysis, single lab\",\n      \"pmids\": [\"35126381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TLR7/8 sensing of lysosomal nucleosides drives histiocytosis in SLC29A3-deficient mice; TLR7 increases phagocyte numbers by driving Ly6Chi monocyte proliferation and maturation, requiring downstream FcRγ and DAP10 for monocyte proliferation.\",\n      \"method\": \"Slc29a3-/- × Tlr7-/- mice, monocyte lineage analysis, FcRγ and DAP10-deficient mice, patient-derived monocyte assays\",\n      \"journal\": \"Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple KO combinations, defined downstream signaling molecules, replicated in patient-derived cells\",\n      \"pmids\": [\"37462944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TLR7 promotes smoke-induced emphysema and COPD through mast cell activity; TLR7 deficiency reduces emphysema severity, TLR7 agonist inhalation alone induces emphysema that is prevented by mast cell stabilizer or mast cell protease-6 (Mcpt6) deficiency, establishing a TLR7→mast cell tryptase pathway in lung damage.\",\n      \"method\": \"TLR7-deficient mice, Mcpt6-deficient mice, imiquimod inhalation model, cromolyn mast cell stabilizer, anti-TLR7 monoclonal antibody treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KO models plus pharmacological interventions establishing pathway, replicated in human COPD tissue\",\n      \"pmids\": [\"37963864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tlr7 (X-linked) regulates sex-specific type I interferon responses to myelin; Tlr7 deletion dampens sex differences and protects against demyelination in mouse models of aging and Alzheimer's disease-related tau pathology, with XY sex chromosomes heightening IFN response through Tlr7.\",\n      \"method\": \"Single-nuclei transcriptomics, Tlr7-knockout mice, sex chromosome manipulation (Four Core Genotypes approach), demyelination mouse model, TLR7 inhibitor treatment\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with single-cell transcriptomics and pharmacological confirmation, sex-chromosome-specific mechanism demonstrated\",\n      \"pmids\": [\"39607927\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TLR7 is an endosomal (and cell-surface) single-stranded RNA sensor that recognizes two classes of ligands in two binding pockets—guanosine/deoxyguanosine nucleosides (pocket 1, generated by PLD3/PLD4 from RNase T2-processed RNA) and short pyrimidine-rich RNA fragments (pocket 2)—and signals through MyD88 to activate NF-κB, MAPK, and IRF5 (via the TASL–SLC15A4 adaptor complex) to produce inflammatory cytokines and type I interferons; TLR7 trafficking and signaling threshold are controlled by UNC93B1 (which recruits syntenin-1 to sort TLR7 into multivesicular bodies) and by SHP2-mediated dephosphorylation of TLR7-Tyr1024 (which promotes Golgi-to-endosome trafficking), while its endosomal abundance is regulated by the BORC–Arl8b–UNC93B1 axis; gain-of-function variants (TLR7Y264H, F507S, L528I) or X-chromosome escape from inactivation increase TLR7 dosage and drive B cell-intrinsic autoimmunity through MyD88-dependent pathways, whereas TLR9 cross-regulates TLR7-dependent responses within B cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TLR7 is an endosomal single-stranded RNA sensor of innate immunity that signals through MyD88 to drive type I interferon and inflammatory cytokine production [#0]. Rather than recognizing intact RNA, TLR7 detects degradation products generated within the endolysosome: lysosomal RNase T2 cleaves RNA, and the exonucleases PLD3/PLD4 release guanosine-derived 2',3'-cGMP for one binding pocket and pyrimidine-rich fragments for a second pocket, so that both ligand classes are produced cooperatively from RNA processing [#4, #23]. Consistent with this, TLR7 senses free guanosine, deoxyguanosine and oxidized guanosine nucleosides, with oligoribonucleotide co-presentation strengthening nucleoside binding [#2, #3], and the nucleoside salvage enzyme PNP limits ligand availability by clearing (deoxy)guanosine [#22]. Structurally TLR7 cycles between open (inactive) and closed (active) conformations and exists as a ligand-independent oligomer, with antagonists stabilizing the open state [#5, #25]. Downstream of receptor engagement TLR7 recruits MyD88 to activate NF-\\u03baB, MAPK/JNK and Jak/STAT cascades [#14, #30], and engages the SLC15A4-associated adaptor TASL through its pLxIS motif to activate IRF5 specifically along the IRF branch [#9]. TLR7 abundance, localization and signaling threshold are set by trafficking machinery: UNC93B1 recruits syntenin-1 to sort TLR7 into multivesicular bodies and terminate signaling [#7] and interacts with the BORC\\u2013Arl8b axis to control endosomal receptor turnover [#8], while SHP2-mediated dephosphorylation of TLR7-Tyr1024 promotes Golgi-to-endosome trafficking and ubiquitination [#12]. Excess TLR7 dosage or activity drives B cell-intrinsic autoimmunity: gain-of-function variants (Y264H; dimerization-interface F507S/L528I) cause lupus and neuroinflammatory disease in a MyD88-dependent manner [#6, #29], escape from X-chromosome inactivation raises biallelic TLR7 expression and amplifies B cell responses [#24], and UNC93B1 mutations that disrupt TLR7 trafficking cause childhood-onset lupus [#8, #10]. Chronic TLR7 signaling also specifies pathogenic monocyte fates via IRF5 [#21] and contributes to histiocytosis, psoriasis, emphysema, demyelination, and breast cancer metastasis through tissue-specific effector pathways [#28, #33, #34, #35].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the founding identity of TLR7 as an endosomal ssRNA sensor coupled to MyD88, defining both ligand class and signaling adaptor.\",\n      \"evidence\": \"TLR7- and MyD88-deficient mice with viral and synthetic ssRNA in endosomal recognition assays\",\n      \"pmids\": [\"14976261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the precise molecular feature of RNA recognized\", \"Did not resolve how RNA reaches the endosomal receptor\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed TLR7 ectodomain residues distinguish RNA versus imidazoquinoline ligands and that ligand class dictates distinct phosphorylation and transcriptional outputs, hinting at dual recognition modes.\",\n      \"evidence\": \"Ectodomain mutagenesis and proteome/genome-wide analysis in primary human monocyte-derived DCs\",\n      \"pmids\": [\"24813206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding sites inferred from mutagenesis, not direct structure\", \"Mechanistic link between ligand class and downstream output not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified guanosine-family nucleosides as endogenous TLR7 ligands whose binding is enhanced by oligoribonucleotides, reframing TLR7 as a sensor of RNA degradation products rather than intact RNA.\",\n      \"evidence\": \"ITC binding assays plus cytokine readouts in mouse and human cells with Unc93b1 controls\",\n      \"pmids\": [\"26489884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the enzymatic source of nucleoside ligands\", \"Two-pocket structural basis not yet defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated functional cell-surface TLR7 in addition to endolysosomal pools, expanding the receptor's localization and showing surface receptor can be targeted therapeutically.\",\n      \"evidence\": \"Anti-TLR7 antibody internalization, fractionation/immunofluorescence and in vivo treatment of Unc93b1 D34A autoimmune mice\",\n      \"pmids\": [\"25648980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of surface versus endosomal TLR7 to physiologic signaling unclear\", \"Trafficking route between surface and endosome not defined here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that deoxyguanosine activates TLR7 independently of supplied ssRNA but still requires MyD88 and endosomal maturation, confirming nucleosides as bona fide RNA-independent agonists.\",\n      \"evidence\": \"Cytokine assays in TLR7-/- and MyD88-/- macrophages/pDCs with bafilomycin A1 blockade\",\n      \"pmids\": [\"31608988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show which pocket dG occupies\", \"Source of endogenous dG in vivo not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined UNC93B1\\u2013syntenin-1 sorting into multivesicular bodies as the mechanism that selectively terminates TLR7 signaling, linking receptor trafficking to autoimmunity.\",\n      \"evidence\": \"Reciprocal Co-IP, phosphorylation-dependent binding, exosome fractionation and UNC93B1 mutant autoimmune mice\",\n      \"pmids\": [\"31546246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase phosphorylating UNC93B1 not identified\", \"TLR9 selectivity mechanism not fully explained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the structural framework of TLR7 conformational equilibrium and a defined antagonist pocket, enabling rational stabilization of the inactive open state.\",\n      \"evidence\": \"X-ray crystallography, cryo-EM and structure-guided antagonist with in vivo autoimmunity protection\",\n      \"pmids\": [\"33060576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture full active dimer with both physiologic ligands\", \"Conformational dynamics during signaling not resolved in cells\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified TASL as the SLC15A4-bound, pLxIS-motif adaptor that specifically couples endosomal TLRs to IRF5, defining the IRF branch of TLR7 signaling distinct from NF-\\u03baB/MAPK.\",\n      \"evidence\": \"TASL knockout, pLxIS mutagenesis and pathway dissection in human immune cells\",\n      \"pmids\": [\"32433612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TASL\\u2013IRF5 engagement not resolved here\", \"How signal selectivity between TLR7/8/9 is achieved unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked endosomal RNA processing to TLR7 activation by showing RNase T2 catalytic activity is required to generate TLR7-activating ligands, oppositely regulating TLR3.\",\n      \"evidence\": \"RNase T2-deficient macrophages with catalytic mutant rescue and in vitro degradation assays\",\n      \"pmids\": [\"34161582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the exact RNase T2 product engaging TLR7\", \"Single lab; ligand chemistry resolved only later\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined SHP2-mediated dephosphorylation of TLR7-Tyr1024 as a post-translational switch promoting Golgi-to-endosome trafficking and ubiquitination, tuning inflammatory output.\",\n      \"evidence\": \"SHP2 inhibitor, conditional SHP2 KO, TLR7 Tyr1024 point-mutant knock-in mice and fractionation\",\n      \"pmids\": [\"34936223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase adding the Tyr1024 phosphate not identified\", \"Generalizability beyond macrophage skin inflammation untested here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Proved a single human gain-of-function variant (Y264H) increasing nucleoside sensing is sufficient to cause lupus and that pathology is entirely MyD88-dependent and B cell-intrinsic.\",\n      \"evidence\": \"Human de novo variant, knock-in mouse, MyD88-deficient rescue epistasis and B cell assays\",\n      \"pmids\": [\"35477763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the contribution of non-B-cell TLR7\", \"Structural effect of Y264H on the binding pocket not directly visualized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed PNP controls TLR7 by limiting intracellular guanosine ligand levels, identifying nucleoside metabolism as a tunable upstream determinant of TLR7-driven autoimmunity.\",\n      \"evidence\": \"PNP genetic/pharmacologic inactivation with TLR7-dependent cytokine and germinal center assays\",\n      \"pmids\": [\"35653193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Quantitative relationship between PNP activity and TLR7 threshold not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the enzymatic two-step generation of both TLR7 ligand classes, showing RNase T2 then PLD3/PLD4 homodimers produce 2',3'-cGMP for pocket 1 and pyrimidine fragments for pocket 2.\",\n      \"evidence\": \"Reconstitution biochemistry, PLD homodimer crystallography/cryo-EM and cell-based loss-of-function\",\n      \"pmids\": [\"38697119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo stoichiometry of the two pockets during physiologic signaling unclear\", \"How disease PLD mutants alter human TLR7 thresholds quantitatively not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the BORC\\u2013Arl8b\\u2013UNC93B1 axis as a controller of endosomal TLR7 turnover, with a patient UNC93B1 mutation causing TLR7 accumulation and childhood-onset lupus.\",\n      \"evidence\": \"UNC93B1\\u2013Arl8b interaction studies, patient-derived mutant analysis and endosomal TLR7 quantification\",\n      \"pmids\": [\"38207015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full BORC subunit requirements not dissected\", \"How turnover defect translates to specific B cell autoimmunity not detailed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed UNC93B1 missense variants confer selective TLR7 hyperactivation via protein instability and altered TLR7 interaction, demonstrating UNC93B1 controls TLR7 subtype-specific recognition.\",\n      \"evidence\": \"Patient cells and UNC93B1-variant mouse macrophages with TLR7/8/9 agonist and interaction assays\",\n      \"pmids\": [\"38207055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of TLR7-versus-TLR9 selectivity at residue level incomplete\", \"Structural consequence of variants not solved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified dimerization-interface gain-of-function variants (F507S, L528I) that enhance TLR7 homodimerization to cause systemic and neuroinflammatory disease, extending the GOF allelic series beyond ligand sensing.\",\n      \"evidence\": \"Human patient variants, structural modeling and functional signaling in patient cells\",\n      \"pmids\": [\"38324161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dimerization enhancement is partly computational\", \"Direct structural confirmation of altered dimer interface lacking\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a non-canonical TLR7 role in cancer: tumor-cell TLR7 senses extracellular ssRNA released by substance-P-killed cells to drive a prometastatic program, extending TLR7 beyond immune cells.\",\n      \"evidence\": \"3D co-cultures, TLR7-deficient cancer cells, TACR1 antagonism and in vivo mammary tumor models\",\n      \"pmids\": [\"39112700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptor usage for the prometastatic program not defined\", \"Whether canonical MyD88/IRF pathways are involved unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the two ligand pockets, conformational equilibrium, trafficking checkpoints and adaptor choice (MyD88/NF-\\u03baB vs TASL/IRF5) are integrated to set quantitative signaling thresholds across distinct cell types and diseases remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of the active TLR7 dimer bound to both physiologic ligands\", \"Cell-type-specific determinants of NF-\\u03baB versus IRF5 branch selection undefined\", \"Mechanism distinguishing protective immunity from pathogenic autoimmunity at a single threshold unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 4, 17]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 9, 14]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 7, 8, 23]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [3, 23, 33]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 9, 14, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 9, 12, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 8, 28, 34]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MYD88\", \"UNC93B1\", \"TASL\", \"SLC15A4\", \"SHP2\", \"TREML4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}