Research Article: Identification of Akkermansia muciniphila as a candidate gut commensal involved in the pathogenesis of rheumatoid arthritis

Abstract:
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. 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 IFN? ELISpot assays, and citrullinated IgG and IgA antibodies to implicated microbial and human proteins were measured by ELISA. Of 32 RA patients, 28 (88%) had highly IgA-coated Akkermansia muciniphila ( Am ) in stool samples. HLA-DR presentation of peptides derived from two Am proteins, including the molecular chaperone DnaK protein ( Am -cDnaK), was identified from RA synovial tissue, suggesting that the microbe or its components may reach the joints. Eight of 21 patients (38%) had T cell responses to the Am -cDnaK peptide and a human heat shock protein-mimic peptide (Hu-HSPA5) and/or IgG antibodies to citrullinated forms of these proteins. Reactivity was found primarily in pre-RA and early RA soon after transition to clinical RA and less commonly during later flares of arthritis. These data implicate Am as a candidate gut commensal involved in RA pathogenesis and may serve as a compass for planning larger studies to test the hypothesis that Am , as well as certain other highly IgA-coated commensal flora or their components, may sometimes reach joints where they initiate or enhance autoimmune T cell responses via epitope mimicry and epitope spreading, leading to antibody responses to citrullinated host proteins in joints.

Introduction:
Rheumatoid arthritis (RA), a chronic inflammatory form of polyarthritis, is propagated by both genetic and environmental factors ( 1 ). Presentation of antigens to Th1 cells by certain HLA-DR molecules with a shared epitope (SE) and the development of anti-citrullinated protein antibodies (ACPA) are key markers of the disease ( 2 , 3 ). Increasing evidence points to the “mucosal origins hypothesis” as initial sites in which these immune responses first develop, particularly in the gut, periodontium, or lung, often…

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