Abstract
BACKGROUND: Marginal zone B cells have been implicated in the production of autoantibodies in murine models of lupus. It has been suggested that they contribute to lupus immunopathogenesis through their enhanced effector functions and their repertoire that is biased toward autoreactive specificities. In the B6.NZM2410.Sle.Sle2.Sle3 (B6.TC) model of lupus, the majority of marginal zone B cells are located outside the marginal zone and inside the follicles. Genetic alterations of this strain have shown a correlation between autoimmune pathogenesis and the presence of intrafollicular marginal zone B cells. This study was designed first to strengthen our original observations and to determine how the marginal zone B cells from the lupus-prone mice respond to stimulations and interact with T cells. RESULTS: The intrafollicular location of B6.TC MZB cells starts before disease manifestations and puts MZB cells in direct contact with CD4+ T cells. Two different autoreactive B cell receptor (BCR) transgenic models showed that the expression of the Sle susceptibility loci enhances the presence of MZB cells inside the follicles. In vitro, B6.TC MZB cells were better effectors than B6 MZB cells with enhanced proliferation and antibody (Ab) production, including anti-DNA Ab, in response to stimulation with TLR ligands, immune complexes or anti-CD40. Furthermore, B6.TC MZB and CD4+ T cells showed a reciprocally enhanced activation, which indicated that their contacts inside B6.TC follicles have functional consequences that suggest an amplification loop between these two cell types. CONCLUSIONS: These results showed that the NZM2410 susceptibility loci induce MZB cells to locate into the follicles, and that this breach of follicular exclusion occurs early in the development of the autoimmune pathogenesis. The enhanced responses to stimulation and increased effector functions of MZB cells from lupus-prone mice as compare to non-autoimmune MZB cells provide a mechanism by which the failure of MZB cell follicular exclusion contributes to the autoimmune process.