Mast Cell Promotion of T Cell–Driven Antigen‐Induced Arthritis Despite Being Dispensable for Antibody‐Induced Arthritis in Which T Cells Are Bypassed

Abstract

Objective. The function of mast cells (MCs) in autoimmune disorders has been a subject of controversy recently. MC-deficient Kit W/W-v mice were found to be resistant to K/BxN serum-transfer arthritis, whereas Kit W-sh/W-sh mice and a genetic model of MC deficiency independent of the Kit mutation were found to be fully susceptible. This debate might lead to the assumption that MCs are dispensable in autoimmunity in general. Thus, the purpose of this study was to examine the relevance of MCs to arthritis using a genetic model of inducible MC deficiency without compromised Kit signaling.Methods. We compared MC functions in K/BxN serum-induced arthritis and in collagen-induced arthritis (CIA) in a mouse model of inducible MC deficiency by analyzing joint inflammation, parameters of cartilage degradation and bone erosion, and the autoreactive adaptive immune response.Results. We observed a redundant role of MCs in K/BxN serum-induced arthritis, where joint inflammation is triggered by cartilage-bound immune complexes independently of T cells. In contrast, we found MCs to be critically relevant in CIA, which is provoked by two arms of autoimmune attack: autoreactive antibodies and effector T cells. In addition to diminished joint inflammation in the absence of MCs, we found a dramatic loss of T cell expansion upon immunization, accompanied by reduced T cell cytokine responses.Conclusion. In this analysis of an arthritis model in which the cellular arm of adaptive immunity was not bypassed, we identified MCs as important promoters of T cell-conditioned autoimmune disorders and, consequently, as potential therapeutic targets in rheumatoid arthritis.

Negative regulatory roles of ORMDL3 in the FcεRI-triggered expression of proinflammatory mediators and chemotactic response in murine mast cells

“…Mast cells are potent producers of various cytokines and chemokines involved in both asthma and autoimmune diseases [22,23,42,43]. In further experiments, we therefore quantified the levels of mRNA encoding cytokines (TNF-a, IL-6, and IL-13; Fig.…”

“…cells, macrophages, eosinophils and neutrophils, and enhanced Th2 cytokine levels in the lungs of transgenic mice [19]. Although mast cells are crucial effector cells in IgE-dependent allergic disorders [21,22] and are critical for promoting the severity of collagen-induced arthritis, which is an autoimmune inflammatory disease [23], the involvement of ORMDL3 in FceRI-dependent activation and mast cell-mediated inflammation has not yet been determined.…”

IgE and Mast Cells

“…While Cre-Master mice show no alterations in disease progression in the K/BxN serum transfer model of arthritis (Feyerabend et al, 2011), a gain-of-function mutation directed by Mcpt5 Cre in mast cells exacerbated collagen-induced arthritis (Heger et al, 2014). Perhaps most interestingly, a comparison of results obtained using models of autoimmune arthritis suggests that mast cells may be more critical in priming the autoreactive T cell response but might be dispensable in antibody-mediated pathology, where neutrophils can substitute as effector cells (Schubert et al, 2014). The importance of mast cells in shaping evolving T cell responses, either directly or through effects on dendritic cells, will depend a great deal on the strength of the stimulus used and, in rodent models, whether potent adjuvants are used that circumvent immunological priming requirements.…”

Mast-Cell-Derived TNF Amplifies CD8+ Dendritic Cell Functionality and CD8+ T Cell Priming

“…We and others demonstrated MCs to impact on neutrophil recruitment to sites of inflammation (Dudeck et al, 2011a;De Filippo et al, 2013;Weber et al, 2015;Biedermann et al, 2000;Wezel et al, 2015;Wershil et al, 1991;Zhang et al, 1992). In addition to local responses, MCs have been shown to promote the induction of adaptive T cell responses (Dudeck et al, 2011a;Schubert et al, 2015;Heib et al, 2007;Gregory et al, 2005;McLachlan et al, 2003). The relevance of MCs in T cell expansion has often been linked to their regulation of dendritic cell (DC) migration from site of infection or inflammation to draining lymph nodes (LNs) to present peripherally engulfed antigens and prime antigen-specific T cells.…”