{"doi":"10.15252/emmm.202012112","title":"Resolving mechanisms of immune‐mediated disease in primary CD4 T cells","abstract":"Deriving mechanisms of immune-mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is most enriched for immune-mediated disease SNPs. This enabled the effects of candidate SNPs to be examined in a relevant cellular context and generated testable hypotheses into disease mechanisms. To illustrate the power of this approach, we investigated a locus that has been linked to six immune-mediated diseases but cannot be fine-mapped. By studying the lead expression-modulating SNP, we uncovered an NF-κB-driven regulatory circuit which constrains T-cell activation through the dynamic formation of a super-enhancer that upregulates TNFAIP3 (A20), a key NF-κB inhibitor. In activated T cells, this feedback circuit is disrupted-and super-enhancer formation prevented-by the risk variant at the lead SNP, leading to unrestrained T-cell activation via a molecular mechanism that appears to broadly predispose to human autoimmunity.","journal":"EMBO Molecular Medicine","year":2020,"id":91368,"datarank":1.411035281353449,"base_score":3.828641396489095,"endowment":3.828641396489095,"self_citation_contribution":0.5742962094733643,"citation_network_contribution":0.8367390718800848,"self_endowment_contribution":0.5742962094733643,"citer_contribution":0.8367390718800848,"corpus_percentile":null,"corpus_rank":null,"citation_count":45,"citer_count":34,"citers_with_citation_signal":29,"citers_with_endowment":29,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE135925","GSE136092"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":79310,"name":"Abigail F. Groff","orcid":"0000-0002-7424-9410","position":1,"is_corresponding":false},{"id":457452,"name":"Oliver S. Burren","orcid":"0000-0002-3388-5760","position":2,"is_corresponding":false},{"id":79311,"name":"Chiara Gerhardinger","orcid":"0000-0002-6113-0381","position":3,"is_corresponding":false},{"id":457453,"name":"Kaia Mattioli","orcid":"0000-0002-4536-9237","position":4,"is_corresponding":false},{"id":457454,"name":"Anna Hutchinson","orcid":"0000-0002-9224-4410","position":5,"is_corresponding":false},{"id":458235,"name":"Theodore Hu","orcid":null,"position":6,"is_corresponding":false},{"id":457455,"name":"Tanmay Anand","orcid":"0000-0002-2071-0312","position":7,"is_corresponding":false},{"id":457456,"name":"Madeline Epping","orcid":"0000-0002-9656-725X","position":8,"is_corresponding":false},{"id":227483,"name":"Chris Wallace","orcid":"0000-0001-9755-1703","position":9,"is_corresponding":false},{"id":65628,"name":"Kenneth G. C. Smith","orcid":"0000-0003-3829-4326","position":10,"is_corresponding":false},{"id":7803,"name":"John L. Rinn","orcid":"0000-0002-7231-7539","position":11,"is_corresponding":false},{"id":251313,"name":"James Lee","orcid":"0000-0001-5711-9385","position":12,"is_corresponding":false},{"id":457451,"name":"Christophe Bourges","orcid":"0000-0001-8122-0475","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-18T22:28:45.409789Z","pmid":"32239644","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}