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

Antibodies against type II collagen(CII)are essential for development of collagen-induced arthritis(CIA),but how and where the B-cell response to CII is initiated is not fully known.We show here that naive DBA/1 mice display naturally reactive IgM and IgG anti-CII producing B cells prior to immunization.The CII-reactive B cells were observed in the spleen and recognized as marginal zone(MZ)B cells.After CII immunization,CII-specific B cells expanded rapidly in the spleen,in contrast to the lymph nodes,with the initial response derived from MZ B cells and later by follicular(FO)B cells.This was evident despite that the MZ B cells were subject to stringent tolerance mechanisms by having a greater Fc gamma receptor IIb expression than the FO B cells.Further,the MZ B cells migrated to the FO areas upon immunization,possibly providing antigen and activating FO T cells and subsequently FO B cells.Thus,around CIA onset increased numbers of IgG anti-CII producing FO B cells was seen in the spleen,which was dominated by IgG2a-and IgG2b-positive cells.These data demonstrate that CII-reactive MZ B cells are present before and expand after CII immunization,suggesting an initiating role of MZ B cells in the development of CIA.