An Ig mu-heavy chain transgene inhibits systemic lupus erythematosus immunopathology in autoimmune (NZB x NZW)F1 mice.

Intrinsic defects in the B lymphoid lineage are involved in predisposition for systemic lupus erythematosus in (NZB x NZW)F(1) (NZB/W) mice. In addition, a contribution of CD4(+) T cells has been shown to be crucial for the development of fatal glomerulonephritis. To further dissect the role of B and T cells in lupus immunopathology we used Ig mu-heavy chain (muHC) transgenic (Tg) NZB/W mice that we recently established to study mechanisms of B cell tolerance. The Tg NZB/W mice have a very restricted B cell repertoire and only a very minor population of B cells having endogenously rearranged muHC Ig loci are able to undergo isotype switch. Here we analyzed the influence of the restricted B cell repertoire on the development of IgG anti-DNA antibodies and glomerulonephritis as well as the hyperactivation of T(h) cells. IgG anti-DNA antibodies developed delayed but consistently in the Tg NZB/W mice, suggesting that a strong selective mechanism for the development of these autoantibodies is operative. Despite significant autoantibody titers in Tg NZB/W mice, very little immune deposits in the glomeruli and no evidence for renal inflammation were found. The Tg mice have a significantly prolonged survival time and most of the Tg mice lived much longer than 1 year. Interestingly, the generalized T cell activation that normally correlates and coincides with the progression of the disease in NZB/W mice is strongly reduced in older Tg animals. The absence of IgG3 anti-DNA antibodies and the strong reduction of IgG2a anti-DNA antibodies in the Tg mice suggests that particularly the activation of T(h)1 cells is inhibited. This result shows that a significant restriction in the B cell repertoire prevents hyperactivation of T(h) cells and supports the model that T cell hyperactivation in NZB/W mice is secondary to specific interactions with a subpopulation of presumably autoreactive B lymphocytes.

Altered selection processes of B lymphocytes in autoimmune NZB/W mice, despite intact central tolerance against DNA.

Anti-DNA autoantibodies are the hallmark of systemic lupus erythematosus and the (NZBxNZW)F1 (NZB/W) murine model. To investigate potential defects in B cell tolerance, we followed the development of anti-DNA-specific B cells in 2-5-month-old mice transgenic for an unmutated muH chain in the normal C57BL/6 and in the NZB/W background. When the transgenic H chain was combined with a random kappa L chain repertoire about 60% of the antibodies bound to DNA. The analysis of the B cell repertoire in the spleen showed extensive receptor editing and a deletion of DNA reactivity in the C57BL/6 as well as in the autoimmune NZB/W background. NZB/W compared to C57BL/6 transgenic mice had a higher frequency of anti-DNA B cells among follicular B cells that were not censored by central tolerance mechanisms. Furthermore, positive selection of B cells with a recurrent rearrangement into the marginal zone compartment was more pronounced in NZB/W mice. Serum levels of transgenic IgM and of anti-DNA autoantibodies indicate a polyclonal activation of hyperactive B cells in the transgenic NZB/W mice. We propose different B cell receptor signaling thresholds for the NZB/W compared to C57BL/6 B cells. This could explain the quantitative differences in the B cell repertoire as well as the hyperactivity of B cells from NZB/W mice.