Marginal Zone B Cells Are Naturally Reactive to Collagen Type Ii and Initiate the Immune Response in Collagen-induced Arthritis Manuscript in Submission

"Marginal zone B cells are naturally reactive to collagen type II and are involved in the initiation of the immune response in collagen-induced arthritis" Access to the published version may require subscription. Abstract B cells are important in collagen-induced arthritis (CIA) and antibodies against type II collagen (CII) are essential for disease development. How and where the autoimmune B cell response is activated in CIA is not fully known. Here we describe where autoreactive B cells are initiated following immunization with CII. Unimmunized mice and mice immunized with ovalbumin (OVA) were used as controls. Surprisingly, we discovered that naïve DBA/1 mice display IgM, but also IgG, positive B cells reactive to CII prior immunization. The self-reactive B cells were observed in the spleen and identified as marginal zone (MZ) B cells. After CII-immunization, CII-specific B cells expanded rapidly in the spleen, while the concurrent response in the lymph nodes was sparse. In contrast, OVA-immunization resulted in an early OVA-specific B cell response in the lymph nodes rather than in the spleen. The early IgG anti-CII response following CII-immunization was derived from MZ B cells. After immunization the MZ B cells migrated into the follicles, possibly depositing immune complexes onto follicular dendritic cells and activating T cells and follicular B cells. Thus, around disease onset increased numbers of IgG anti-CII producing follicular B cells was seen in the spleen and lymph nodes. These data demonstrate that CII-reactive MZ B cells are present before and expanded after CII-immunization. This autoreactive B cell response, present prior to concurrent T cell activation, may contribute to the breakage of T cell tolerance and consequently to the activation of follicular B cells and the generation of pathogenic IgG anti-CII antibodies. 2 Introduction Autoantibody production is a characteristic of autoimmune diseases such as rheumatoid arthritis (RA). In mouse models of autoimmune arthritis it is well established that antibodies (Ab) play an essential role in disease development. Thus, in collagen-induced arthritis (CIA) high titres of IgG against collagen type II (CII) are essential for disease onset and transfer of the Ab to naïve mice induces arthritis [1, 2]. Furthermore, mice deficient in activating Fc gamma receptors (FcγR) are protected from CIA, while absence of the inhibitory FcγRIIb, which normally regulates Ab production, results in increased anti-CII Ab titres and augmented CIA [3]. Protection of CIA in B cell-deficient mice has further demonstrated a pathogenic role of B cells …