Identification of Akkermansia muciniphila as a candidate gut commensal involved in the pathogenesis of rheumatoid arthritis.

The majority of RA patients had highly IgA-coated Akkermansia muciniphila in their stool samples.

• 28 of 32 RA patients (88%) had highly IgA-coated Akkermansia muciniphila (Am) in stool samples.
• Highly IgA-coated bacterial taxa were identified using 16S rRNA sequencing of RA patients' stool samples.
• This finding was a primary outcome of the discovery-based, hypothesis-generating study.
• The study used samples from a relatively small number of patients by design.

HLA-DR-presented peptides derived from two Akkermansia muciniphila proteins were identified in RA synovial tissue.

• Peptides were identified from RA synovial tissue by liquid chromatography-tandem mass spectrometry.
• One of the identified proteins was the molecular chaperone DnaK protein (Am-cDnaK).
• The presence of these peptides in synovial tissue suggests that the microbe or its components may reach the joints.
• HLA-DR presentation of microbial peptides in synovial tissue was a secondary supporting outcome of the study.

A substantial subset of RA patients showed T cell responses to Akkermansia muciniphila-derived and human mimic epitopes, along with IgG antibodies to citrullinated forms of these proteins.

• 8 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.
• T cell responses were determined by IFN-γ ELISpot assays.
• Citrullinated IgG and IgA antibodies to implicated microbial and human proteins were measured by ELISA.
• The human mimic peptide (Hu-HSPA5) is described as a 'human heat shock protein-mimic peptide,' suggesting molecular mimicry between the bacterial and human proteins.

Immune reactivity to Akkermansia muciniphila-derived and mimic epitopes was found primarily in pre-RA and early RA, and less commonly during later flares of arthritis.

• Reactivity was found primarily in pre-RA and early RA soon after transition to clinical RA.
• Reactivity was less commonly observed during later flares of arthritis.
• This temporal pattern suggests that Am-related immune responses may be more prominent in the earliest phases of RA development.

The authors hypothesize that Akkermansia muciniphila and other highly IgA-coated commensal flora may sometimes reach joints and initiate or enhance autoimmune responses via epitope mimicry and epitope spreading.

• The proposed mechanism involves microbial components reaching joints where they initiate or enhance autoimmune T cell responses via epitope mimicry and epitope spreading.
• This is posited to lead to antibody responses to citrullinated host proteins in joints.
• The findings are framed within the 'mucosal origins hypothesis,' which posits that mucosal sites such as the gut are initial sites where immune responses develop that may, months to years later, result in clinical RA.
• The authors describe these data as a 'compass for planning larger studies to test the hypothesis.'