The role of T(H)1 cytokines in the formation of plasmacytes and memory B cells

Abstract

In the humoral response, cytokines directly affect B cells or indirectly through the effector functions of dendritic and T cells. We investigated two models of cytokine action on B cells: the first examined the effect of IL-12 on plasma cell differentiation, the second examined the role of IFNgamma in an autoreactive humoral response.;Because Fcgamma receptors bind to immunoglobulin and activate innate immune cells, these receptors can greatly affect autoimmune diseases involving immune complexes and immunoglobulin deposition. Although we began our studies by examining the role of Fcgamma receptors in a peptide-induced model of systemic lupus erythematosus (SLE), we identified a general mechanism in which dendritic cells influence B cell fate. BALB/c mice immunized with a peptide mimetope of dsDNA generate cross-reactive anti-peptide and anti-dsDNA antibodies. Peptide-immunized Fcgamma-/- mice produce higher serum titers of antibodies and class-switching to additional isotypes. Examination of B cells in Fcgamma-/- mice revealed a bias toward a short-lived plasma cell phenotype. IL-12 has been shown to cause spontaneous IgG secretion in B cells and differentiation to plasma cells. Examination of Fcgamma-/- dendritic cells revealed elevated IL-12 secretion compared to BALB/c dendritic cells. Fcgamma -/- dendritic cells induced proliferation in naive B cells, and this mechanism was dependent on IL-12. Finally, BALB/c mice treated with recombinant IL-12 mimicked the plasma cell phenotype observed in Fcgamma -/- mice. Thus the activated B cells in Fcgamma -/- mice are shifted to a short-lived plasma cell fate, and this bias is mediated by the elevated secretion of IL-12 by dendritic cells.;Because our peptide-induced model of SLE induces TH1 cytokines, we shifted the response to a TH2 profile and examined the effect on the pathogenesis of autoimmune disease. BALB/c IFNgamma-/- mice immunized with the peptide mimetope had decreased serum titers of anti-peptide and anti-dsDNA antibodies as compared to BALB/c mice. Despite similar T cell proliferation in response to the peptide, significantly fewer peptide-specific plasma cells were present in IFNgamma-/- mice. Glomerular deposition of IgG was markedly reduced or completely absent in IFNgamma-/- mice. By shifting the T cell cytokine profile in the peptide-induced SLE model, the anti-self antibody response was nearly eliminated.