Abstract

Rheumatoid Arthritis (RA) is an autoimmune disease caused by an interaction between genetic and environmental factors, including microbial dysbiosis. Recent findings evidence that Prevotella (P.) copri, member of the gut microbiota, might be implicated in the immunopathogenesis of RA. P. copri is overrepresented in patients with pre-clinical/new-onset RA, promotes arthritis in susceptible mice and induces specific lymphocyte responses in RA patients. To gain further insight into the role of P. copri in RA and the origin of immunodominant P. copri antigens, we analyzed lymphocyte responses towards distinct subcellular fractions and outer membrane vesicles (OMVs) of P. copri in relation to genetic predisposition and abundance of P. copri in the gut. Peripheral blood mononuclear cells of RA, osteoarthritis and healthy subjects were stimulated with P. copri fractions of membrane, periplasm, cytoplasm and OMVs and the percentage of activated memory CD4+ T cells producing IFN-g or TNF-α was determined by flow cytometry. Specific antibodies to P. copri fractions were analyzed in serum by ELISA. The abundance of P. copri in stool samples was determined by qRT-PCR. The presence of HLA-DR risk alleles was confirmed by NGS high throughput HLA genotyping (DKMS Life Science Lab). While control subjects showed T helper cell responses to P. copri antigens of the cytosolic fraction, P. copri membrane fraction stimulated Th1 cell responses particularly in RA patients. 35% of RA patients presented IgA antibodies to P. copri membrane fraction and OMVs, which were specific to RA. The lymphocyte responses to P. copri were elevated in subjects with P. copri overabundance but not associated to the presence of HLA risk alleles. The results suggest that a differential lymphocyte response to P. copri antigens might, independently of the genetic predisposition, contribute to autoimmune inflammation in RA patients, e.g., through molecular mimicry. The authors thank ANID-Chile for financial support (FONDECYT11220882).