Background/Purpose:   Prevotella copri, an intestinal commensal microbe, may be prominent in stool samples of patients with new-onset rheumatoid arthritis (NORA). However, it has been unclear whether the organism is immune-relevant in RA pathogenesis.

Methods:  HLA-DR-presented peptides were identified directly from RA patients’ synovial tissue or peripheral blood mononuclear cells (PBMC) by tandem mass spectrometry. P. copri peptides or source proteins were then tested for T cell reactivity by IFN-γ ELISpot assay and for antibody responses by ELISA using cells and sera from DMARD-naive NORA patients, chronic RA (CRA) patients, and controls. For comparison, humoral responses to P. gingivalis, B. fragilis,and E. coli were also tested. Serum samples were analyzed for innate, Th1, and Th17 mediators by Luminex. Moreover, available serum and synovial fluid (SF) samples were tested for the presence of P. copri 16S rDNA by nested PCR. All RA patients met the 2010 ACR/EULAR criteria for RA. 

Results:   We identified an HLA-DR-presented peptide from a 27-kD protein of P. copri (Pc-p27), which stimulated Th1 responses in 17 of 40 NORA patients (42%), but not in Lyme arthritis patients (P=0.0007) or healthy controls (P<0.0001). We then found that 17 of 78 NORA patients (22%) and 16 of 49 CRA patients (33%) had IgG or IgA antibody responses to Pc-p27, but rarely to both. Similar results were obtained when testing was done with the whole P. copri organism. Three types of comparison groups suggested that P. copri antibody responses are specific for RA. First, P. copri antibodies were rarely found in patients with other rheumatic diseases or in healthy controls. Second, antibody levels to 2 other gut commensals, B. fragilis and E. coli, were similar or less in RA patients than those in patients with other type of arthritis or in healthy controls. Third, although IgG and often IgA antibodies to the oral periodontal pathogen, P. gingivalis, were detected in 25% of the 127 RA patients, there was little overlap between this group and those with P. copri antibodies. In patients with P. copri IgA antibodies, these responses correlated with Th17 cytokines and most had anti-citrullinated protein antibodies (ACPA). In contrast, serum P. copri IgG levels correlated with the Th1 cytokine CXCL10, and with significantly less frequent ACPA (P=0.01). Of 18 patients in whom both serum and SF were available, 3 of 5 patients with IgG P. copri antibodies had 16S DNA for Prevotella detected in SF compared with none of the patients with IgA P. copri antibodies or no P. copriantibodies (P=0.01).

Conclusion:   Subgroups of RA patients have differential immune responses to P. copri. IgA antibody responses to P. copri correlated with Th17 cytokine responses and frequent ACPA, which may signify localized interactions between microbes and host immune cells in the gut mucosa. In contrast, IgG P. copri antibody responses were associated with Prevotella 16S DNA in SF, Th1 immune responses, and infrequent ACPA, which may result from systemic spread of the organism, presumably carried to joints within cells. These observations suggest that P. copri is an immune-relevant bacterium in subgroups of patients with RA, supporting a new paradigm in RA pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evidence-for-prevotella-copri-as-an-immune-relevant-bacterium-in-rheumatoid-arthritis/