A functional variant in FCRL3 is associated with higher Fc receptor–like 3 expression on T cell subsets and rheumatoid arthritis disease activity†

Rheumatoid arthritis (RA) is a debilitating inflammatory arthritis affecting 1% of the world’s population. The etiology of RA is multifactorial and our knowledge of the specific environmental and genetic factors leading to and sustaining aberrant immune activation in the disease is limited. Regulatory T cells (Treg) are a subset of T cells that are critical in maintaining immune self-tolerance and preventing autoimmune disease1; as such, they may play a key role in RA pathogenesis. Treg mediate an inhibitory effect on immune activity by suppressing the proliferation and function of effector T cells. In mouse models of RA, adoptive transfer of Treg results in resolution of arthritis2. Studies utilizing peripheral blood samples from patients with RA have shown that Treg are functionally deficient and, moreover, anti-tumor necrosis factor (TNF) treatment restores Treg function in these patients3–6. Recent work from our laboratory and from others has identified a transmembrane cell surface receptor, Fc Receptor Like-3 (FcRL3), that is highly expressed on CD4+ Treg but not on conventional CD4+ T cells7,8. FcRL3 is also expressed on other T cell subsets, B cells, and NK cells7,9,10. FcRL3 is part of a genetically-conserved gene family bearing high structural homology to classical Fc receptors, with multiple extracellular Ig domains and with intracellular domains that carry either immunoreceptor tyrosine based activation motifs (ITAMs), immunoreceptor tyrosine based inhibition motifs (ITIMs), or both11. Given these signaling domains and expression on multiple immune cell types, the FcRL family members likely modulate immune cell functions by affecting signaling pathways11–13. No physiologic function has been ascribed to FcRL3 and its ligand is unknown. The presence of both ITAMs and ITIMs in the FcRL3 intracellular domain suggest that engagement of it by cognate ligand might enhance or inhibit cell function. In vitro studies utilizing the FcRL3 intracellular domain have shown that it may serve as a negative regulator of B cell receptor signaling14. Our lab has demonstrated that FcRL3+ Treg are less capable of suppressing effector T cell proliferation in vitro than their FcRL3− Treg counterparts8. Taken together, these data suggest FcRL3 may also function as a negative regulator of Treg function. A single nucleotide polymorphism (SNP) in FCRL3 located in the promoter (-169 T→C, FCRL3_3, rs7528684) leads to enhanced NFκB binding and to increased FCRL3 promoter activity9. The FCRL3 -169C variant is associated with higher expression of FcRL3 on Treg and B cells8,9,15 and has been identified as a potential genetic risk factor in multiple autoimmune diseases, including RA, autoimmune pancreatitis, systemic lupus erythematosus, and autoimmune thyroid disease9,16,17. FcRL3 may therefore lie within a common pathway in autoimmune disease pathogenesis. In this study, we investigated the relevance of FcRL3 to RA disease by examining associations between the FCRL3 -169C variant, FcRL3 expression on FcRL3-expressing T cells subsets and B cells, RA disease activity, and erosive RA disease.