Interaction between haploinsufficiency of PTPN2 and patient microbiome promotes autoimmune arthritis in mice.

Sendo S, Vela AJ, Ro M, Thiruppathy D, Wilkinson EL, Zhao Z, Hsieh WC, Yang S, Coras R, Bergot AS, Guma M, Nguyen A, McBride DA, Devkota S, Thomas R, Shah NJ, Svensson MND, Zengler K, Stanford SM, Bottini N

J. Autoimmun. 156 (-) 103452 [2025-09-00; online 2025-08-01]

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 RA/JIA-associated PTPN2 gene by inducing mannan-induced arthritis in germ-free PTPN2+/+ and PTPN2 haploinsufficient (PTPN2+/-) SKG mice reconstituted with fecal microbiota from six patients with seropositive RA. Mannan-induced arthritis and lymph node T cell immunophenotypes were identical in germ free PTPN2+/+ vs PTPN2+/- SKG mice. While no difference in arthritis severity was seen among PTPN2+/+ mice recipient of RA gut microbiota, two microbiomes (RA#02 and RA#86) enhanced arthritis in PTPN2+/- mice. The microbiome of RA patient microbiota recipient mice exclusively clustered by patient of origin and the RA#86 microbiome was found to carry a significant expansion of Prevotella genera, which is associated with RA dysbiosis. RA#86 microbiota-recipient PTPN2+/- mice selectively displayed increased joint GM-CSF expression and an expansion of CD4+RORγt+FoxP3- T cells in the joints, 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 arthritis and CD4+RORγt+FoxP3- T cells expansion in PTPN2+/- vs PTPN2+/+ mice. Our data support current views about P. copri promotion of autoimmune arthritis and suggest that its pathogenicity can be amplified via interaction with a dysbiotic context and risk factors that enhance gut mucosa immune responses.

PubMed 40752380

DOI 10.1016/j.jaut.2025.103452

Crossref 10.1016/j.jaut.2025.103452

mid: NIHMS2145224
pmc: PMC12974606
pii: S0896-8411(25)00097-6