{"doi":"10.1002/art.42008","title":"Host Genetics But Not Commensal Microbiota Determines the Initial Development of Systemic Autoimmune Disease in <scp>BXD2</scp> Mice","abstract":"OBJECTIVE: To determine the extent to which the gut microbiome influences systemic autoimmunity in a mouse model of lupus. METHODS: We generated germ-free (GF) lupus-prone BXD2 mice, which under normal conditions develop spontaneous germinal centers (GCs) and high titers of serum autoantibodies. GF status was confirmed by gut bacterial culture. The autoimmune phenotypes of 6- and 12-month-old gnotobiotic GF BXD2 mice and specific pathogen-free (SPF) BXD2 mice were compared. Serum levels of autoantibodies were measured by enzyme-linked immunosorbent assay. Histologic sections of the mouse kidney and joints were evaluated. Flow cytometry was used to analyze GCs and age-associated B cells. CD4+ T cells were analyzed for PD-1+ICOS+ activated T cells, T follicular regulatory (Tfr) cells (Foxp3+CD25+ PD-1+CXCR5+), and PD-1+ICOS+ T cells expressing interleukin-17A (IL-17A) or interferon-γ (IFNγ) after stimulation with phorbol myristate acetate (PMA)/ionomycin. RESULTS: In 6-month-old mice, GF status did not affect splenomegaly, GC B cells, age-associated B cells, or serum autoantibody levels, except for IgG antihistone. GF BXD2 mice exhibited a significantly higher percentage of Tfr cells compared to their SPF counterparts (P < 0.05). At 12 months of age, however, GF BXD2 mice had significantly diminished IgG autoantibody levels and a lower percentage of GC B cells and age-associated B cells (P < 0.05). Following stimulation with PMA/ionomycin, PD-1+ICOS+ CD4+ T cells expressed significantly lower IL-17A, but not IFNγ, levels in GF BXD2 mice compared to SPF BXD2 mice (P < 0.01). SPF BXD2 mice and GF BXD2 mice developed equivalent renal and joint disease with no significant differences in severity. CONCLUSION: Our results suggest a model in which genetics plays a dominant role in determining the initial development of autoimmunity. In contrast, gut microbiomes may regulate the persistence of certain aspects of systemic autoimmunity.","journal":"Arthritis & Rheumatology","year":2021,"id":193407,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9461,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":761802,"name":"Fatima K. Alduraibi","orcid":"0000-0002-3770-471X","position":1,"is_corresponding":false},{"id":761803,"name":"David Ponder","orcid":"0000-0002-3598-4332","position":2,"is_corresponding":false},{"id":762511,"name":"Wayne Duck","orcid":null,"position":3,"is_corresponding":false},{"id":418348,"name":"Casey D. Morrow","orcid":"0000-0001-8812-2341","position":4,"is_corresponding":false},{"id":382830,"name":"Jeremy B. Foote","orcid":"0000-0002-6621-6096","position":5,"is_corresponding":false},{"id":318087,"name":"Trenton R. Schoeb","orcid":"0000-0001-9137-5462","position":6,"is_corresponding":false},{"id":290233,"name":"Huma Fatima","orcid":null,"position":7,"is_corresponding":false},{"id":62274,"name":"Charles O. Elson","orcid":"0000-0001-8873-1534","position":8,"is_corresponding":false},{"id":375924,"name":"Hui‐Chen Hsu","orcid":"0000-0002-0317-5725","position":9,"is_corresponding":false},{"id":375925,"name":"John D. Mountz","orcid":"0000-0001-9061-3158","position":10,"is_corresponding":false},{"id":375921,"name":"Huixian Hong","orcid":"0000-0001-7283-8775","position":0,"is_corresponding":true}],"reference_count":19,"raw_metadata":null,"created_at":"2026-07-18T23:49:51.300073Z","pmid":"34725967","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":[]}