Objective Prevotella copri, an intestinal microbe, may over-expand in stool samples of patients with new-onset rheumatoid arthritis (NORA), but it is not yet clear whether the organism has immune relevance in RA pathogenesis. Methods HLA-DR-presented peptides (T cell epitopes) from P. copri were sought directly from patients' synovial tissue or peripheral blood mononuclear cells (PBMC) using tandem mass spectrometry, followed by testing the antigenicity of peptides or their source proteins using samples from RA patients or comparison groups. T cell reactivity was determined by ELISpot assays; antibody responses were measured by ELISA, and cytokine/chemokine determinations were made by Luminex. 16S rDNA of P. copri was sought in serum and synovial fluid samples using nested PCR. Results In PBMC, we identified an HLA-DR-presented peptide from a 27-kD protein of P. copri (Pc-p27), which stimulated Th1 responses in 42% of NORA patients. In both NORA and chronic RA patients, one subgroup had IgA antibody responses to Pc-p27 or the whole organism, which correlated with Th17 cytokine responses and frequent anti-citrullinated protein antibodies (ACPA). The other subgroup had IgG P. copri antibodies, which were associated with Prevotella DNA in synovial fluid, P. copri-specific Th1 responses, and less frequent ACPA. In contrast, P. copri antibody responses were rarely found in patients with other rheumatic diseases or in healthy controls. Conclusion Subgroups of RA patients have differential IgG or IgA immune reactivity with P. copri, which appears to be specific for this disease. These observations provide evidence that P. copri is immune-relevant in RA pathogenesis.

An association has previously been shown between antibiotic-refractory Lyme arthritis, the human histocompatibility leukocyte antigen (HLA)–DR4 molecule, and T cell recognition of an epitope of Borrelia burgdorferi outer-surface protein A (OspA163–175). We studied the frequencies of HLA-DRB1-DQA1-DQB1 haplotypes in 121 patients with antibiotic-refractory or antibiotic-responsive Lyme arthritis and correlated these frequencies with in vitro binding of the OspA163–175 peptide to 14 DRB molecules. Among the 121 patients, the frequencies of HLA-DRB1-DQA1-DQB1 haplotypes were similar to those in control subjects. However, when stratified by antibiotic response, the frequencies of DRB1 alleles in the 71 patients with antibiotic-refractory arthritis differed significantly from those in the 50 antibiotic-responsive patients (log likelihood test, P = 0.006; exact test, P = 0.008; effect size, Wn = 0.38). 7 of the 14 DRB molecules (DRB1*0401, 0101, 0404, 0405, DRB5*0101, DRB1*0402, and 0102) showed strong to weak binding of OspA163–175, whereas the other seven showed negligible or no binding of the peptide. Altogether, 79% of the antibiotic-refractory patients had at least one of the seven known OspA peptide–binding DR molecules compared with 46% of the antibiotic-responsive patients (odds ratio = 4.4; P < 0.001). We conclude that binding of a single spirochetal peptide to certain DRB molecules is a marker for antibiotic-refractory Lyme arthritis and might play a role in the pathogenesis of the disease.

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