Background/Purpose:

Specific microorganisms in the gut microbiome may have a pathogenic role in rheumatoid arthritis (RA). Recently, Scher et al. showed that Prevotella copri, an intestinal microbe, was over-expanded in stool samples from patients with new-onset RA (NORA). This organism has a sequence for a peptidylarginine deiminase-like (PAD-like) enzyme, which may lead to citrullinated neoepitopes and anti-citrullinated protein antibodies (ACPA). However, little is known about immune responses to P. copri, and its role in RA pathogenesis is not yet clear.

Methods:

To address these issues, we used an innovative approach that combines discovery-based proteomics and translational research. Accordingly, we identified microbial and self HLA-DR-presented peptides (T cell epitopes) in patients’ synovial tissue, joint fluid or peripheral blood (PB), using tandem mass spectrometry. The identified peptides were synthesized and tested for T cell reactivity with the matching patient’s PBMC by IFN-g ELISpot assay. Immunoreactive peptides or source proteins were then tested for T and B cell responses using cells and sera from our cohort of DMARD-naive NORA patients and controls. All RA patients met the 2010 ACR/EULAR criteria for RA.

Results:

From the HLA-DR-presented peptides isolated from the PB of one RA patient (HLA-DRB1*0401/0101), we identified an immunogenic T cell epitope derived from bacterial signal sequence of a 27-kDa protein of P. copri (Pc-p27), implying that this organism or components of it were present in this patient’s circulating phagocytic cells. When testing was done in additional patients, 17 of 40 (42%) NORA patients had T cell reactivity with this single epitope of Pc-p27. In addition, 10 of 78 NORA patients (13%) had IgG antibodies to Pc-p27; 8 of 78 patients (10%) had IgA antibodies to this protein, but only 1 patient had both IgG and IgA antibody responses. In contrast, no patients with other forms of arthritis or healthy control subjects had T or B cell responses to this protein. IgA antibody responses to Pc-p27 correlated with higher serum IL-23 levels (suggestive of Th17 responses) and more frequent ACPA, whereas IgG antibody responses to the protein correlated with lower IL-23 levels and less frequent ACPA, suggesting that patients may have advantageous (IgG) or disadvantageous (IgA) responses to this P. copri protein. Moreover, Th1 responses to the identified epitope of Pc-p27, as determined by IFN-g secretion, were usually concordant with IgG antibody responses to the protein, but no patients with IgA antibody responses to Pc-p27 had this Th1 response.

Conclusion:

The identification of a single T cell epitope in an individual patient provided a bridge to the discovery of a broadly immunogenic P. copri protein. There appears to be dichotomous immune responses to this protein. We postulate that Th1 responses and IgG antibodies to Pc-p27 more effectively control the expansion or systemic spread of the organism. In contrast, IgA antibodies to Pc-p27, which are associated with higher IL-23 levels (suggestive of Th17 responses) and greater frequency of ACPA, may be less effective in controlling the organism and may enhance the development of autoimmune responses.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-a-broadly-immunogenic-prevotella-copri-t-cell-epitope-in-patients-with-rheumatoid-arthritis/