Marginal zone B cells are naturally reactive to collagen type II and initiate the immune response in collagen-induced arthritis

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, OVAimmunization 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 CIIimmunization. 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.