Rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) are chronic inflammatory systemic autoimmune diseases that affect the synovium of small and large joints and have a significant genetic risk component [1,2]. Haplotypes of the Human Leukocyte Antigen (HLA) including HLA-DQ8 and most importantly DR-B1 alleles carrying the shared epitope (SE) are key risk factors for RA and rheumatoid factor (RF)-positive JIA, however a multitude of non-HLA risk loci have been identified [3]. Among these, loss of function haplotypes of the PTPN2 gene – encoding protein tyrosine phosphatase non-receptor 2 (PTPN2) - are highly associated not only with RA and JIA but also with inflammatory bowel disease [4]. Homozygote carriers of risk haplotype-tagging PTPN2 single nucleotide polymorphism (SNP) rs1893217 display around 50 % reduction in the expression of PTPN2 in their CD4+ T cells [5,6].

The arthritis-promoting effect of autoimmunity-associated PTPN2 SNPs can be modeled in PTPN2 haploinsufficient SKG mice [6]. SKG mice carry a mutation of ZAP-70 that impairs thymic selection and develop spontaneous Th17-driven symmetric arthritis which recapitulates aspects of spondylarthropathies (SpA) and RA. Notably, they display seropositivity for RF and anti-citrullinated peptide antibodies and development of lung disease which are typical of RA [[7], [8], [9], [10]]. SKG arthritis can be accelerated by injection of fungal products, such as curdlan, zymosan and mannan [7,11,12]. PTPN2 haploinsufficient SKG mice have enhanced spontaneous and mannan-induced arthritis severity caused by instability of CD4+FoxP3+ regulatory T cells (Tregs) with higher numbers of RORγt+ Tregs and conversion of Tregs into FoxP3−RORγt+ Th17-like exTregs in the joints and joint-draining lymph nodes [6].

Dysbiosis of the colonic microbiome, i.e. an over- or under-representation of bacterial species, has been reported in subsets of RA and JIA patients [13,14]. Dysbiosis can occur with or without subclinical gut inflammation and a key question in the RA field is whether and how colonic dysbiosis can trigger or fuel joint inflammation (so called gut-joint axis) [13,14]. The pathobiont Prevotella copri has been a species of interest since a seminal report by Scher et al. found it overrepresented in the fecal microbiome of a proportion of patients with new onset RA [15]. Other reports have subsequently supported a potential role of P. copri and other Prevotellaceae in RA [16]. Germ-free SKG mice do not develop spontaneous arthritis, however monocolonization of germ-free SKG mice with P. copri or with fecal microbiota from RA patients with over-representation of P. copri caused arthritis with expansion of Th17 cells in the colonic mucosa [17] suggesting that one mechanism of action for P. copri could be through immune stimulation at the gut mucosal level. RA patients display antibodies and T cell responses against autoantigens that cross-react with Prevotella peptides and are preferentially presented by SE HLA variants, pointing to HLA-dependent molecular mimicry as another potential mechanism of action for P. copri in RA [18,19].

An interplay between microbiome and host genetic factors has been hypothesized to occur in the pathogenesis of RA [20]. Potential interactions between dysbiosis and RA-associated HLA variants have been suggested by observations in DR-B1 transgenic mice [21] and experiments in HLA-DQ8 transgenic mice gavaged with P. histicola or Eggerthella lenta [22,23]. However, whether colonic dysbiosis interacts with non-HLA genetic risk alleles to trigger autoimmune arthritis has not been experimentally addressed yet. Here, to assess whether RA/JIA-associated PTPN2 loss of function could interact with RA dysbiotic microbiomes to promote SKG arthritis, we assessed mannan-induced arthritis in PTPN2+/+ vs PTPN2 haploinsufficient (PTPN2+/−) mice kept in germ-free conditions and after colonization with gut microbiota from six RA patients.