1The immune system recognizes and attack foreign pathogens while sparing the host’s own proteins and tissues, a phenomenon called immune tolerance. Tolerance mechanisms are though not complete and lymphocytes reacting to self-structures do occur. Innate-type of B lymphocytes account for many B cells expressing self-reactivity in the periphery. It is tempting to speculate that this large reservoir of dormant self-reactive B cells may contribute to autoimmune disease, not only by producing autoantibodies, but also by secreting immune modulating cytokines and presenting self-antigen to T lymphocytes.

2A subtype of B cells that has shown to be enriched for self-reactivity is the innate-like marginal zone (MZ) B cell. In mice MZ B cells are considered to be confined to the spleen, while in humans they are circulating and also found in lymph nodes. An expansion of the MZ B cell compartment has been associated with murine models of autoimmunity, including collagen-induced arthritis (CIA), a model for rheumatoid arthritis (RA). We have found that MZ B cells in naïve mice show naturally IgM reactivity to collagen II (CII), a target protein of the inflammatory attack in RA. Upon immunization with CII in complete Freund’s adjuvant the CII-reactive MZ B cells expand rapidly, suggesting that a dual engagement of the B-cell receptor and toll like receptor may promote the response to self-antigen in the MZ B cells. CII-primed MZ B cells showed significant antigen-presenting capacity as reflected by cognate T-cell proliferation in vitro, and induction of IgG anti-CII antibodies in vivo. Furthermore, the MZ B cells were regulated by complement receptors 1 and 2, and Fc gamma receptor IIb, as lack of these receptors in activated MZ B cells induced increased proliferation, cytokine production and antigen presentation. By examining murine lymph nodes we discovered that cells with a MZ B cell phenotype also exist in mice. The nodal MZ B cells show similarities with splenic MZ B cells as they are naturally self-reactive to CII and expand in an autoimmune setting. The frequency of nodal MZ B cells is low, but increases in aged mice and particularly in females.

3In summary, activation of self-reactive MZ B cells in spleen and lymph nodes may contribute to autoimmunity by antibody-dependent and antibody-independent actions. Complement- and Fc receptors are relevant in controlling the self-reactivity in the cells.