Moreover, in distinct mouse models of inflammatory arthritis, dysregulated cytokine production and autoantibody production have each been shown to drive disease pathology (4C8), and whether these differences in disease pathogenesis are caused by variations in the autoreactive CD4+ T cell response is currently not known

Moreover, in distinct mouse models of inflammatory arthritis, dysregulated cytokine production and autoantibody production have each been shown to drive disease pathology (4C8), and whether these differences in disease pathogenesis are caused by variations in the autoreactive CD4+ T cell response is currently not known. effector T cells (including Th17 cells), and IL-17 is required for arthritis development. These studies show that the degree of CD4+ T cell reactivity for a self-peptide can play a prominent role in determining whether distinct cellular pathways can be targeted to prevent the development of inflammatory arthritis. Introduction Inflammatory arthritis is a debilitating manifestation of a variety of autoimmune disorders (including rheumatoid arthritis (RA)) which are often grouped together because disease develops in the context of systemic immune activation (1, 2). A common feature of these diseases is usually that susceptibility is usually strongly linked to certain MHC class II alleles, implying an important role for CD4+ T cells in disease pathogenesis (1C3). However, the extent to which CD4+ T cells participate in arthritis development through the promotion of pro-inflammatory cytokine production (either derived from T cells or from additional populations such as macrophages), and/or through the support of autoantibody production (such as rheumatoid factor or antibodies to citrullinated proteins), remains unclear (1, 2). Moreover, in distinct mouse models of inflammatory arthritis, dysregulated cytokine production and autoantibody production have each Sulfachloropyridazine been shown to drive disease pathology (4C8), and whether these differences in disease pathogenesis are caused by variations in the autoreactive CD4+ T cell response is currently not known. Mutations in CD4+ TCR signaling molecules have been found to alter the spectrum of disease manifestations that can arise in mouse models of autoimmunity (9, 10). However, the extent to which differences in TCR recognition of self-peptides by autoreactive CD4+ T cells might affect the cellular pathways that are required for arthritis development is not comprehended. Extensive studies in human patients support the conclusion that CD4+ T cells can promote arthritis development via both cytokine- and B cell-dependent effector mechanisms. For example, anti-TNF reagents, which were the first biologic therapies developed for RA, have high response rates in RA patients (11, 12), and antagonists targeting other pro-inflammatory cytokines (including IL-1, IL-6 and IL-17) are also being evaluated for therapeutic efficacy (13C15). More recently, studies evaluating anti-B cell brokers (such as rituximab) have demonstrated efficacy in some patients (16C18). Anti-B cell therapy might affect arthritis development by reducing the levels of arthritogenic autoantibodies (16C19), but B cells can also act as an APC population for effector CD4+ T cells (20C25). Whether B cells can play an important role in supporting CD4+ T cell differentiation in inflammatory arthritis is not well understood (23C25). It is also Sulfachloropyridazine unclear why therapies targeting particular pathways (e.g. cytokines versus B cells) might exhibit different efficacies in arthritis patients. A simple explanation could be Sulfachloropyridazine that distinct autoantigens are targeted by the immune system in patients that respond to different therapeutic strategies. However, an alternative explanation is that qualitative and/or quantitative differences in the autoreactive CD4+ T cell response that drives the disease process can determine which cellular pathways are required for disease pathogenesis. This latter possibility is Sulfachloropyridazine difficult to assess in human patients because the self-antigens that are recognized by autoreactive CD4+ T cells remain poorly characterized (26, 27). We have addressed these questions using a transgenic mouse model in which autoreactive CD4+ T cells with defined specificity for a surrogate self-peptide drive the spontaneous development of inflammatory arthritis (28C30). By varying the reactivity of the CD4+ T cell response to a single self-peptide, we show that B cells are not required for arthritis to develop in the context of a strongly autoreactive CD4+ T cell response (although pro-inflammatory cytokines such as TNF are required). By contrast, Mouse monoclonal to ESR1 eliminating B cells significantly suppresses disease development in the context of a weakly autoreactive CD4+ T cell response, and the requirement for B cells appears to reflect a role for these cells in supporting autoreactive effector CD4+ T cell formation. Additional pathways appear to also be required to support arthritis development in the context of lower CD4+ T cell autoreactivity, because the disease displays a pronounced female gender bias in this setting. These studies demonstrate that the degree of CD4+ T cell reactivity for self-peptide(s) can play a prominent role in determining the cellular pathways that participate in the development of inflammatory arthritis. Materials and Methods Mice TS1, TS1(SW), HACII, TS1xHACII and TS1xHACII.JH?/? mice were previously described (28C36) and have been backcrossed.