Identification of

Objective: The "mucosal origins hypothesis" posits that mucosal sites, such as the gut, are initial sites where immune responses first develop that may, months to years later, result in clinical rheumatoid arthritis (RA). Our goal here was to conduct a discovery-based, hypothesis-generating study using samples from a relatively small number of patients to implicate previously unrecognized highly IgA-coated commensal flora that may have a role in RA pathogenesis (primary outcome). The secondary supporting outcomes were to determine whether HLA-DR-presented microbial peptides from such flora could be identified in synovial tissue and to determine T and B cell responses to these peptides and citrullinated proteins. Methods: Highly IgA-coated bacteria taxa were identified in RA patients' stool samples by 16s rRNA sequencing; HLA-DR-presented peptides derived from the most common, highly IgA-coated microbes were identified from synovial tissue by liquid chromatography-tandem mass spectrometry; T cell responses to the identified microbial and human mimic epitopes were determined by IFNγ ELISpot assays, and citrullinated IgG and IgA antibodies to implicated microbial and human proteins were measured by ELISA. Results: Of 32 RA patients, 28 (88%) had highly IgA-coated Conclusions: These data implicate