Hypogammaglobulinaemia occurs in Fas‐deficient MRL‐ lpr mice following deletion of MHC class II molecules

Fas (CD95)‐mediated apoptosis in B and T cells is deficient in both human autoimmune lymphoproliferative syndrome and in MRL‐ lpr mice, a model for systemic lupus erythematosis (SLE). Autoimmune disease in these mice is associated with polyclonal B cell activation, increased serum immunoglobulin and autoantibodies. In non‐autoimmune mice MHC class II is not required for normal serum immunoglobulin expression, and previously we have shown using MHC class II‐deficient MRL‐ lpr mice (MRL‐ lpr Ab−/− ) that generation of specific antibodies to DNA requires MHC class II‐directed T cell help. In contrast, in the present study we demonstrate that MRL‐ lpr Ab−/− mice also have a profound reduction of total serum immunoglobulin levels, suggesting abnormal polyclonal regulation of B cells by MHC class II‐directed T cells occurs in the autoimmune MRL‐ lpr strain. This abrogation of immunoglobulin production does not occur in MHC class II‐deficient non‐obese diabetic (NOD) mice, nor in MHC class I‐deficient NOD or MRL‐ lpr mice. Reduced immunoglobulin levels in MRL‐ lpr Ab−/− mice were not due to a lack of B cells or to an increased loss of circulating immunoglobulin, but were associated with reduced numbers of surface IgG‐positive B cells. These results define a general abnormal regulation of B cells in MRL‐ lpr mice through a process requiring MHC class II, and suggest that Fas deficiency may allow expansion of totally T‐dependent B cells.