An Ig mu-heavy chain transgene inhibits systemic lupus erythematosus immunopathology in autoimmune (NZB x NZW)F-1 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 additio n, a contribution of CD4(+) T cells has been shown to be crucial for the de velopment of fatal glomerulonephritis. To further dissect the role of B and T cells in lupus immunopathology we used Ig mu -heavy chain (mu HC) transg enic (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 mu HC Ig loci are able to undergo isotype switch. Here we analyzed the infl uence of the restricted B cell repertoire on the development of IgG anti-DN A antibodies and glomerulonephritis as well as the hyperactivation of T-h c ells. IgG anti-DNA antibodies developed delayed but consistently in the Tg NZB/W mice, suggesting that a strong selective mechanism for the developmen t of these autoantibodies is operative. Despite significant autoantibody ti ters 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 significantl y prolonged survival time and most of the Tg mice lived much longer than 1 year. Interestingly, the generalized T cell activation that normally correl ates and coincides with the progression of the disease in NZB/W mice is str ongly 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 sugges ts that particularly the activation of T(h)1 cells is inhibited. This resul t shows that a significant restriction in the B cell repertoire prevents hy peractivation of T-h cells and supports the model that T cell hyperactivati on in NZB/W mice is secondary to specific interactions with a subpopulation of presumably autoreactive B lymphocytes.