Organization of the lymphoid organs and B-cell responses. Top: Schematic view of a Peyer patch (left) and lymphoid follicles in the spleen (right) surrounded by the arteriolar marginal sinus. MZ indicates marginal zone; GC, germinal center; DC, dendritic cell; and FDC, follicular dendritic cell. The marginal zone is less conspicuous in the lymph nodes. Bottom left: Antigens having access to B-cell follicles are presented to B cells by FDCs. Antigen-specific B cells are activated by their BCR (signal 1) and proliferate, leading to the formation of the GC. Costimulation (signal 2) is provided by T-cell–derived cytokines and CD40L-CD40 interactions. GC T cells also express FasL, and autoreactive B cells (expressing Fas) are deleted by FasL-Fas interactions. Bottom right: Antigens captured in the blood by dendritic cells or directly accessing the MZ are presented to MZ B cells. MZ B cells are activated by BCR signal (signal 1). Costimulation (signal 2) is provided by DC-derived cytokines and the tumor necrosis factor superfamily member BAFF/BLyS or APRIL. Activated MZ B cells rapidly differentiate into plasma cells that secrete large amounts of IgM. In MZ B cells, mutations in immunoglobulin genes are acquired either during ontogeny in an antigen-independent fashion²⁶  or during T-cell–dependent responses occurring in the GC.²⁷