{"gene":"PILRA","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2000,"finding":"FDF03 (PILRA) is a monomeric 44-kDa transmembrane glycoprotein with a single extracellular V-set Ig-like domain and two cytoplasmic ITIM-like sequences. When overexpressed in pervanadate-treated U937 cells, FDF03 was tyrosine-phosphorylated and recruited SHP-2 and, to a lesser extent, SHP-1 via SH2 domain interactions.","method":"Overexpression in U937 cells, pervanadate treatment, SHP-1/SHP-2 recruitment assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct co-immunoprecipitation/recruitment assay in cells with pervanadate stimulation, single lab, two orthogonal readouts (phosphorylation + phosphatase recruitment)","pmids":["10903717"],"is_preprint":false},{"year":2000,"finding":"Cross-linking of FDF03 (PILRA) inhibited calcium mobilization in response to CD32/FcγRII aggregation in transfected U937 cells, demonstrating that PILRA functions as an inhibitory receptor that suppresses downstream signaling.","method":"Cross-linking experiment, calcium mobilization assay in transfected U937 cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional inhibitory assay with direct cellular readout, single lab, clear mechanistic outcome","pmids":["10903717"],"is_preprint":false},{"year":2000,"finding":"Unlike LAIR-1/p40 engagement, cross-linking of FDF03 (PILRA) did not inhibit GM-CSF-induced monocyte differentiation into dendritic cells, indicating substrate/context specificity of PILRA inhibitory signaling.","method":"Cross-linking experiment, monocyte-to-DC differentiation assay with GM-CSF","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — negative result establishing functional specificity, single lab, single method","pmids":["10903717"],"is_preprint":false},{"year":2025,"finding":"PILRA knockout in human iPSC-derived microglia (iMG) rescued ApoE4-mediated immunometabolic deficits, prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity, and enhanced microglial chemotaxis while attenuating inflammation. These effects were mediated via PPAR and STAT1/3 signaling, as shown by pharmacological inhibitor studies.","method":"CRISPR knockout in iPSC-derived microglia, chimeric AD mouse transplantation, pharmacological inhibitor studies (PPAR inhibitors, STAT1/3 inhibitors), functional assays (lipid storage, mitochondrial bioenergetics, chemotaxis, inflammation)","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO, pharmacological inhibitors, metabolic assays, in vivo chimeric mouse model), single lab with extensive mechanistic follow-up","pmids":["41337541"],"is_preprint":false},{"year":2025,"finding":"AD mice transplanted with human PILRA KO microglia exhibited reduced amyloid pathology and rescued synaptic markers, and a high-affinity ligand-blocking PILRA antibody phenocopied PILRA KO iMG effects, demonstrating PILRA is pharmacologically tractable.","method":"Chimeric AD mouse model transplanted with human PILRA KO iPSC-derived microglia; antibody-blocking experiments in iMG","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo rescue experiment with KO microglia plus antibody phenocopy, multiple orthogonal readouts in single rigorous study","pmids":["41337541"],"is_preprint":false},{"year":2025,"finding":"The synonymous variant rs2405442:T>C in PILRA destroys a ramp of slowly translated codons at the 5' end of the transcript, directly reducing both PILRA mRNA and protein levels in CHO cells.","method":"qPCR and ELISA in CHO cells expressing wildtype vs. mutant PILRA constructs","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — two orthogonal readouts (mRNA and protein) in cell-based assay, single lab, no independent replication","pmids":["40149715"],"is_preprint":false}],"current_model":"PILRA (FDF03) is a myeloid-expressed ITIM-bearing inhibitory receptor that, upon activation, becomes tyrosine-phosphorylated and recruits SHP-2/SHP-1 phosphatases to suppress downstream calcium signaling; in microglia, PILRA loss-of-function rescues ApoE4-driven immunometabolic deficits, reduces amyloid pathology, and enhances chemotaxis via PPAR and STAT1/3 pathways, while a synonymous coding variant (rs2405442:T>C) reduces PILRA expression by disrupting a 5' ribosomal ramp sequence."},"narrative":{"mechanistic_narrative":"PILRA (FDF03) is a myeloid inhibitory immunoreceptor that dampens activating signaling and, in microglia, gates the immunometabolic response to ApoE4 [PMID:10903717, PMID:41337541]. It carries cytoplasmic ITIM-like sequences that become tyrosine-phosphorylated upon receptor engagement and recruit the SH2-domain phosphatases SHP-2 and, to a lesser extent, SHP-1 [PMID:10903717]; through this inhibitory module, PILRA cross-linking suppresses calcium mobilization downstream of CD32/FcγRII aggregation, while leaving GM-CSF-driven monocyte-to-dendritic-cell differentiation intact, marking a context-specific inhibitory output [PMID:10903717]. In human iPSC-derived microglia, loss of PILRA reverses ApoE4-driven deficits—restoring lipid storage and protecting against lipotoxicity, improving mitochondrial bioenergetics and antioxidant capacity, enhancing chemotaxis, and lowering inflammation—through PPAR and STAT1/3 signaling [PMID:41337541]; transplantation of PILRA-knockout human microglia into AD mice reduces amyloid pathology and rescues synaptic markers, and a ligand-blocking antibody phenocopies the knockout, establishing PILRA as pharmacologically tractable [PMID:41337541]. A synonymous PILRA variant (rs2405442:T>C) disrupts a 5' ramp of slowly translated codons and lowers both mRNA and protein levels [PMID:40149715].","teleology":[{"year":2000,"claim":"Established the molecular basis for PILRA inhibitory signaling by showing it is an ITIM-bearing receptor that recruits tyrosine phosphatases, defining its signaling module.","evidence":"Overexpression in pervanadate-treated U937 cells with phosphorylation and SHP-1/SHP-2 recruitment assays","pmids":["10903717"],"confidence":"Medium","gaps":["Physiological ligand and activating stimulus not identified in this assay","Relative contribution of SHP-1 vs SHP-2 to downstream effects not resolved","Pervanadate is a non-physiological phosphatase inhibitor, not a receptor-engagement context"]},{"year":2000,"claim":"Demonstrated that PILRA functions as a bona fide inhibitory receptor by suppressing activating-receptor calcium signaling, and defined the specificity of that inhibition.","evidence":"Receptor cross-linking with calcium mobilization assay against CD32/FcγRII aggregation, plus a negative GM-CSF differentiation assay, in transfected U937 cells","pmids":["10903717"],"confidence":"Medium","gaps":["Which endogenous activating pathways PILRA naturally counter-regulates is unknown","Mechanism distinguishing inhibited (calcium) from non-inhibited (differentiation) outputs not defined","Single cell line, artificial cross-linking rather than ligand engagement"]},{"year":2025,"claim":"Connected PILRA inhibitory function to disease-relevant microglial biology by showing knockout rescues ApoE4-driven immunometabolic deficits through defined downstream pathways.","evidence":"CRISPR knockout in iPSC-derived microglia with pharmacological PPAR and STAT1/3 inhibitor studies and lipid, mitochondrial, chemotaxis, and inflammation assays","pmids":["41337541"],"confidence":"High","gaps":["How ITIM/SHP signaling mechanistically links to PPAR and STAT1/3 outputs is not delineated","Whether PILRA acts cell-autonomously via its known phosphatase module or through a distinct route is unresolved","The ApoE4 ligand or stimulus engaging PILRA in microglia is not defined"]},{"year":2025,"claim":"Validated PILRA as a therapeutic target in vivo and showed it is druggable by antibody blockade.","evidence":"Chimeric AD mouse transplanted with human PILRA KO iPSC-microglia, plus ligand-blocking antibody phenocopy in iMG","pmids":["41337541"],"confidence":"High","gaps":["Long-term and dose effects of antibody blockade not assessed","Identity of the blocked ligand not specified","Single-study in vivo evidence"]},{"year":2025,"claim":"Provided a mechanistic explanation for how a synonymous PILRA variant alters expression, linking genetic variation to receptor dosage.","evidence":"qPCR and ELISA of wildtype vs mutant PILRA constructs in CHO cells","pmids":["40149715"],"confidence":"Medium","gaps":["Single-lab cell-based assay without independent replication","Effect on endogenous human myeloid/microglial PILRA expression not tested","Link between variant and the microglial/AD phenotypes not directly demonstrated"]},{"year":null,"claim":"The endogenous PILRA ligand engaged in microglia and the mechanistic bridge from its ITIM/SHP signaling to PPAR and STAT1/3 metabolic reprogramming remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified physiological ligand in the microglial context","No mechanistic chain connecting SHP recruitment to transcriptional/metabolic outputs","No structural model of PILRA-ligand engagement in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["PTPN11","PTPN6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKJ1","full_name":"Paired immunoglobulin-like type 2 receptor alpha","aliases":["Cell surface receptor FDF03","Inhibitory receptor PILR-alpha"],"length_aa":303,"mass_kda":34.0,"function":"Paired receptors consist of highly related activating and inhibitory receptors and are widely involved in the regulation of the immune system. PILRA is thought to act as a cellular signaling inhibitory receptor by recruiting cytoplasmic phosphatases like PTPN6/SHP-1 and PTPN11/SHP-2 via their SH2 domains that block signal transduction through dephosphorylation of signaling molecules. Receptor for PIANP (Microbial infection) Acts as an entry co-receptor for herpes simplex virus 1","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9UKJ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PILRA","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PILRA","total_profiled":1310},"omim":[{"mim_id":"616065","title":"PILR-ALPHA-ASSOCIATED NEURAL PROTEIN; PIANP","url":"https://www.omim.org/entry/616065"},{"mim_id":"605342","title":"PAIRED IMMUNOGLOBULIN-LIKE TYPE 2 RECEPTOR, BETA; PILRB","url":"https://www.omim.org/entry/605342"},{"mim_id":"605341","title":"PAIRED IMMUNOGLOBULIN-LIKE TYPE 2 RECEPTOR, ALPHA; PILRA","url":"https://www.omim.org/entry/605341"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PILRA"},"hgnc":{"alias_symbol":["FDF03"],"prev_symbol":[]},"alphafold":{"accession":"Q9UKJ1","domains":[{"cath_id":"2.60.40.10","chopping":"41-151","consensus_level":"medium","plddt":95.5938,"start":41,"end":151}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKJ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKJ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKJ1-F1-predicted_aligned_error_v6.png","plddt_mean":69.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PILRA","jax_strain_url":"https://www.jax.org/strain/search?query=PILRA"},"sequence":{"accession":"Q9UKJ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKJ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKJ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKJ1"}},"corpus_meta":[{"pmid":"10903717","id":"PMC_10903717","title":"FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10903717","citation_count":88,"is_preprint":false},{"pmid":"29181857","id":"PMC_29181857","title":"Whole-exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer's disease.","date":"2018","source":"Neuropathology and applied neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29181857","citation_count":36,"is_preprint":false},{"pmid":"35918447","id":"PMC_35918447","title":"PILRA polymorphism modifies the effect of APOE4 and GM17 on Alzheimer's disease risk.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35918447","citation_count":18,"is_preprint":false},{"pmid":"37396579","id":"PMC_37396579","title":"PILRA is associated with immune cells infiltration in atrial fibrillation based on bioinformatics and experiment validation.","date":"2023","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37396579","citation_count":15,"is_preprint":false},{"pmid":"31297637","id":"PMC_31297637","title":"The PILRA G78R Variant Correlates with Higher HSV-1-Specific IgG Titers in Alzheimer's Disease.","date":"2019","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/31297637","citation_count":15,"is_preprint":false},{"pmid":"34206597","id":"PMC_34206597","title":"A Possible Role for HSV-1-Specific Humoral Response and PILRA rs1859788 Polymorphism in the Pathogenesis of Parkinson's Disease.","date":"2021","source":"Vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/34206597","citation_count":12,"is_preprint":false},{"pmid":"40149715","id":"PMC_40149715","title":"Ramp Sequence May Explain Synonymous Variant Association with Alzheimer's Disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA).","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/40149715","citation_count":4,"is_preprint":false},{"pmid":"41337541","id":"PMC_41337541","title":"Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer's disease.","date":"2025","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41337541","citation_count":3,"is_preprint":false},{"pmid":"39149451","id":"PMC_39149451","title":"The paired immunoglobulin-like type 2 receptor alpha (PILRA) gene polymorphism rs1859788 reduces risk of Alzheimer's Disease in men homozygous for the ApoE ε4 allele.","date":"2024","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/39149451","citation_count":1,"is_preprint":false},{"pmid":"26399532","id":"PMC_26399532","title":"Cloning and identification of splice variants of the porcine PILRA gene.","date":"2015","source":"Yi chuan = Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/26399532","citation_count":1,"is_preprint":false},{"pmid":"39829933","id":"PMC_39829933","title":"Ramp sequence may explain synonymous variant association with Alzheimer's disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA).","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39829933","citation_count":1,"is_preprint":false},{"pmid":"38408113","id":"PMC_38408113","title":"New candidate SNPs for genetic association with Alzheimer's disease: a linkage disequilibrium analysis for the FCGRIIB and PILRA genes.","date":"2024","source":"Medwave","url":"https://pubmed.ncbi.nlm.nih.gov/38408113","citation_count":0,"is_preprint":false},{"pmid":"41546015","id":"PMC_41546015","title":"Decoding the diabetes-pancreatic adenocarcinoma connection: the critical role of PILRA in intermediate monocyte activity.","date":"2026","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/41546015","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.06.631528","title":"Ramp sequence may explain synonymous variant association with Alzheimer’s disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (  <i>PILRA</i>  )","date":"2025-01-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.06.631528","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.07.25321860","title":"Proteome-wide Mendelian randomization analyses to identify potential therapeutic targets for lung function and respiratory disease","date":"2025-02-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.07.25321860","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10526,"output_tokens":1498,"usd":0.027024,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8277,"output_tokens":2436,"usd":0.051143,"stage2_stop_reason":"end_turn"},"total_usd":0.078167,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"FDF03 (PILRA) is a monomeric 44-kDa transmembrane glycoprotein with a single extracellular V-set Ig-like domain and two cytoplasmic ITIM-like sequences. When overexpressed in pervanadate-treated U937 cells, FDF03 was tyrosine-phosphorylated and recruited SHP-2 and, to a lesser extent, SHP-1 via SH2 domain interactions.\",\n      \"method\": \"Overexpression in U937 cells, pervanadate treatment, SHP-1/SHP-2 recruitment assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct co-immunoprecipitation/recruitment assay in cells with pervanadate stimulation, single lab, two orthogonal readouts (phosphorylation + phosphatase recruitment)\",\n      \"pmids\": [\"10903717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Cross-linking of FDF03 (PILRA) inhibited calcium mobilization in response to CD32/FcγRII aggregation in transfected U937 cells, demonstrating that PILRA functions as an inhibitory receptor that suppresses downstream signaling.\",\n      \"method\": \"Cross-linking experiment, calcium mobilization assay in transfected U937 cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional inhibitory assay with direct cellular readout, single lab, clear mechanistic outcome\",\n      \"pmids\": [\"10903717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Unlike LAIR-1/p40 engagement, cross-linking of FDF03 (PILRA) did not inhibit GM-CSF-induced monocyte differentiation into dendritic cells, indicating substrate/context specificity of PILRA inhibitory signaling.\",\n      \"method\": \"Cross-linking experiment, monocyte-to-DC differentiation assay with GM-CSF\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — negative result establishing functional specificity, single lab, single method\",\n      \"pmids\": [\"10903717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PILRA knockout in human iPSC-derived microglia (iMG) rescued ApoE4-mediated immunometabolic deficits, prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity, and enhanced microglial chemotaxis while attenuating inflammation. These effects were mediated via PPAR and STAT1/3 signaling, as shown by pharmacological inhibitor studies.\",\n      \"method\": \"CRISPR knockout in iPSC-derived microglia, chimeric AD mouse transplantation, pharmacological inhibitor studies (PPAR inhibitors, STAT1/3 inhibitors), functional assays (lipid storage, mitochondrial bioenergetics, chemotaxis, inflammation)\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO, pharmacological inhibitors, metabolic assays, in vivo chimeric mouse model), single lab with extensive mechanistic follow-up\",\n      \"pmids\": [\"41337541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AD mice transplanted with human PILRA KO microglia exhibited reduced amyloid pathology and rescued synaptic markers, and a high-affinity ligand-blocking PILRA antibody phenocopied PILRA KO iMG effects, demonstrating PILRA is pharmacologically tractable.\",\n      \"method\": \"Chimeric AD mouse model transplanted with human PILRA KO iPSC-derived microglia; antibody-blocking experiments in iMG\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo rescue experiment with KO microglia plus antibody phenocopy, multiple orthogonal readouts in single rigorous study\",\n      \"pmids\": [\"41337541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The synonymous variant rs2405442:T>C in PILRA destroys a ramp of slowly translated codons at the 5' end of the transcript, directly reducing both PILRA mRNA and protein levels in CHO cells.\",\n      \"method\": \"qPCR and ELISA in CHO cells expressing wildtype vs. mutant PILRA constructs\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — two orthogonal readouts (mRNA and protein) in cell-based assay, single lab, no independent replication\",\n      \"pmids\": [\"40149715\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PILRA (FDF03) is a myeloid-expressed ITIM-bearing inhibitory receptor that, upon activation, becomes tyrosine-phosphorylated and recruits SHP-2/SHP-1 phosphatases to suppress downstream calcium signaling; in microglia, PILRA loss-of-function rescues ApoE4-driven immunometabolic deficits, reduces amyloid pathology, and enhances chemotaxis via PPAR and STAT1/3 pathways, while a synonymous coding variant (rs2405442:T>C) reduces PILRA expression by disrupting a 5' ribosomal ramp sequence.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PILRA (FDF03) is a myeloid inhibitory immunoreceptor that dampens activating signaling and, in microglia, gates the immunometabolic response to ApoE4 [#0, #3]. It carries cytoplasmic ITIM-like sequences that become tyrosine-phosphorylated upon receptor engagement and recruit the SH2-domain phosphatases SHP-2 and, to a lesser extent, SHP-1 [#0]; through this inhibitory module, PILRA cross-linking suppresses calcium mobilization downstream of CD32/FcγRII aggregation, while leaving GM-CSF-driven monocyte-to-dendritic-cell differentiation intact, marking a context-specific inhibitory output [#1, #2]. In human iPSC-derived microglia, loss of PILRA reverses ApoE4-driven deficits—restoring lipid storage and protecting against lipotoxicity, improving mitochondrial bioenergetics and antioxidant capacity, enhancing chemotaxis, and lowering inflammation—through PPAR and STAT1/3 signaling [#3]; transplantation of PILRA-knockout human microglia into AD mice reduces amyloid pathology and rescues synaptic markers, and a ligand-blocking antibody phenocopies the knockout, establishing PILRA as pharmacologically tractable [#4]. A synonymous PILRA variant (rs2405442:T>C) disrupts a 5' ramp of slowly translated codons and lowers both mRNA and protein levels [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the molecular basis for PILRA inhibitory signaling by showing it is an ITIM-bearing receptor that recruits tyrosine phosphatases, defining its signaling module.\",\n      \"evidence\": \"Overexpression in pervanadate-treated U937 cells with phosphorylation and SHP-1/SHP-2 recruitment assays\",\n      \"pmids\": [\"10903717\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Physiological ligand and activating stimulus not identified in this assay\",\n        \"Relative contribution of SHP-1 vs SHP-2 to downstream effects not resolved\",\n        \"Pervanadate is a non-physiological phosphatase inhibitor, not a receptor-engagement context\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that PILRA functions as a bona fide inhibitory receptor by suppressing activating-receptor calcium signaling, and defined the specificity of that inhibition.\",\n      \"evidence\": \"Receptor cross-linking with calcium mobilization assay against CD32/FcγRII aggregation, plus a negative GM-CSF differentiation assay, in transfected U937 cells\",\n      \"pmids\": [\"10903717\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Which endogenous activating pathways PILRA naturally counter-regulates is unknown\",\n        \"Mechanism distinguishing inhibited (calcium) from non-inhibited (differentiation) outputs not defined\",\n        \"Single cell line, artificial cross-linking rather than ligand engagement\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected PILRA inhibitory function to disease-relevant microglial biology by showing knockout rescues ApoE4-driven immunometabolic deficits through defined downstream pathways.\",\n      \"evidence\": \"CRISPR knockout in iPSC-derived microglia with pharmacological PPAR and STAT1/3 inhibitor studies and lipid, mitochondrial, chemotaxis, and inflammation assays\",\n      \"pmids\": [\"41337541\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"How ITIM/SHP signaling mechanistically links to PPAR and STAT1/3 outputs is not delineated\",\n        \"Whether PILRA acts cell-autonomously via its known phosphatase module or through a distinct route is unresolved\",\n        \"The ApoE4 ligand or stimulus engaging PILRA in microglia is not defined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Validated PILRA as a therapeutic target in vivo and showed it is druggable by antibody blockade.\",\n      \"evidence\": \"Chimeric AD mouse transplanted with human PILRA KO iPSC-microglia, plus ligand-blocking antibody phenocopy in iMG\",\n      \"pmids\": [\"41337541\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Long-term and dose effects of antibody blockade not assessed\",\n        \"Identity of the blocked ligand not specified\",\n        \"Single-study in vivo evidence\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided a mechanistic explanation for how a synonymous PILRA variant alters expression, linking genetic variation to receptor dosage.\",\n      \"evidence\": \"qPCR and ELISA of wildtype vs mutant PILRA constructs in CHO cells\",\n      \"pmids\": [\"40149715\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single-lab cell-based assay without independent replication\",\n        \"Effect on endogenous human myeloid/microglial PILRA expression not tested\",\n        \"Link between variant and the microglial/AD phenotypes not directly demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous PILRA ligand engaged in microglia and the mechanistic bridge from its ITIM/SHP signaling to PPAR and STAT1/3 metabolic reprogramming remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No identified physiological ligand in the microglial context\",\n        \"No mechanistic chain connecting SHP recruitment to transcriptional/metabolic outputs\",\n        \"No structural model of PILRA-ligand engagement in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PTPN11\", \"PTPN6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}