Interaction between RA/JIA-associated PTPN2 loss of function and patient microbiome promotes the gut-joint axis in mice

Gut dysbiosis is observed in patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), however, how it promotes disease in interaction with other environmental and genetic risk factors remains unclear. Here we assessed interactions between gut dysbiosis and RA/JIA-associated loss of function haplotypes of the PTPN2 gene by inducing mannan-induced arthritis in germ-free WT and PTPN2 haploinsufficient (PTPN2+/-) SKG mice subjected to fecal microbiota transplantation from 6 RA patients. Mannan-induced arthritis and lymph node T cell immunophenotypes were identical in germ free WT vs PTPN2+/- SKG mice. While no difference in arthritis severity was seen among WT mice recipient of RA gut microbiota, two of the RA microbiomes (RA02 and RA86) enhanced arthritis in PTPN2+/- mice. The microbiome of RA patient microbiota recipient mice exclusively clustered by patient of origin and the RA86 microbiome was found to carry a significant expansion of P. copri, a pathobiont associated with RA dysbiosis. RA68 microbiota-recipient PTPN2+/- mice selectively displayed increased joint CSF2 expression and an expansion of FoxP3+ regulatory T cells and Ror(gamma)t+ Th17 in joint draining lymph nodes, without evidence of increased intestinal inflammation, gut barrier leakage or expansion of P. copri in post-mannan fecal samples. Monocolonization with P. copri caused enhanced Th17-driven arthritis in PTPN2+/- vs WT mice. Our data support current views about P. copri promotion of autoimmune arthritis, and suggests that its pathogenicity can be amplified via interaction with a dysbiotic context and risk factors that enhance gut mucosa immune responses.