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Immunol."],"abstract":"<jats:p>\n                    Feedback mechanisms regulate immune activation and prevent excessive tissue damage. TNFAIP3, also known as A20, serves as a crucial brake on inflammation, and mutations or haploinsufficiency of this gene are linked to diseases characterized by inappropriate inflammation. In this study, we document highly conserved patterns of cell type-specific gene expression, regulation, and induction of\n                    <jats:italic>TNFAIP3<\/jats:italic>\n                    , and employ transgenic and gnotobiotic mouse models to investigate how adaptive immunity and the gut microbiome contribute to pathology arising from impaired A20 function. Contrary to our expectations, systemic inflammation resulting from\n                    <jats:italic>Tnfaip3<\/jats:italic>\n                    deficiency in CD11c (\n                    <jats:italic>Itgax<\/jats:italic>\n                    )-expressing cells developed independently of autoreactive antibodies, B cells, and T cells. The microbiome also proved dispensable for disease manifestations in these models. These findings suggest that in diseases caused by insufficient TNFAIP3\/A20 activity, autoantibodies may reflect a downstream consequence of disease rather than a causative driver, suggesting autoinflammatory rather than autoimmune pathology. These insights carry therapeutic implications for the treatment of\n                    <jats:italic>TNFAIP3<\/jats:italic>\n                    -associated diseases.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1856810","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:42:47Z","timestamp":1784266967000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["TNFAIP3\/A20 dysfunction drives innate and sterile hyperinflammation"],"prefix":"10.3389","volume":"17","author":[{"given":"Karel F. 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