Contribution of HLA DRB1, PTPN22, and CTLA4, to RA dysbiosis

This narrative review gathers current evidence for a contribution of rheumatoid arthritis (RA) HLA-DRB1, PTPN22 and CTLA4 polymorphisms to the gut dysbiosis observed in RA, especially at its onset (transient excess of Prevotella). The gut microbiome contains elements which are 30% heritable, including genera like Bacteroides and Veillonella, and to a lesser extent Prevotella. The first months/year seems a critical period for the selection of a core of microbiota, that should be considered as a second self by the immune system, and tolerized by regulatory T and B cells. Imperfect tolerization may increase the risk of RA following further repeated silent translocations of various gut microorganisms, including Prevotella copri, from gut to joints (fostered by a concurrent loss in gut mucosa of protective bacteria like Faecalibacterium prausnitzii). Genetics studies confirmed that Prevotella copri was partly heritable, and strong associations were observed between the overall microbial composition of stools and the HLA-DRB1 RA risk allele, either in a US cohort (P=0.00001), or the Twins UK cohort (P=0.033). This finding also stands for persons still free from RA, and was replicated in the Swiss SCREEN-RA cohort. Gene variants of PTPN22 also modify intestinal microbiota composition, compromise granulocyte-mediated antibacterial defence in gut, and reduce the suppressive effect of gut regulatory B cells. CTLA4 variants may similarly contribute to RA dysbiosis, since immunotherapy by CTLA-4 blockade depends on microbiota, and CTLA4 activates T follicular regulatory cells to reduce immune responses to segmented filamentous bacteria. Suggestions for future works are made.