Macrophage scavenger receptor 1 (Msr1) promotes autoantibody-mediated arthritis by impairing B cell tolerance (171.18)

Abstract

Abstract Peripheral tolerance is achieved through several mechanisms, including induction of the hyporesponsive state of anergy in potentially autoreactive lymphocytes. The class A macrophage scavenger receptor, Msr1, is reported to participate in the maintenance of immunological tolerance by performing functions such as the clearance of apoptotic debris and the tonic sampling of self-antigens. We evaluated the role of Msr1 in a mouse model of autoantibody-dependent arthritis. Genetic deficiency of Msr1 in the K/BxN TCR transgenic model (Msr1-/- K/BxN) decreased the incidence and severity of arthritis. However, arthritis induced by transfer of arthritogenic autoantibodies was unimpaired in naïve mice lacking Msr1, suggesting that Msr1 deficiency in K/BxN mice affected the pathogenic events preceding autoantibody synthesis. Indeed, antibodies against the key autoantigen in this model, glucose 6-phosphate isomerase (GPI), were undetectable in Msr1-/- K/BxN mice, despite the presence of an expanded population of GPI-specific B cells. We did not observe any defect in T cell numbers or function. We hypothesized that Msr1 might control the availability of autoantigen and found that Msr1-/- macrophages displayed impaired uptake of GPI. Taken together, these data suggest a model in which deficiency of Msr1 can lead to a higher concentration of soluble autoantigens, resulting in B cell anergy and protection from autoimmune disease.