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.
Wellmann
U
U
Department of Genetics, Hematopoiesis Unit, Nikolaus Fiebiger Center for Molecular Medicine and Institute for Pathology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany.
Letz
M
M
Schneider
A
A
Amann
K
K
Winkler
T H
TH
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000097:blood; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003433:Crosses, Genetic; D004247:DNA / Q000276:immunology; D005260:Female; D005803:Genes, Immunoglobulin / Q000502:physiology; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007143:Immunoglobulin Heavy Chains / Q000235:genetics* / Q000502:physiology; D007148:Immunoglobulin mu-Chains / Q000235:genetics* / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB / Q000235:genetics* / Q000276:immunology*; D008822:Mice, Transgenic; D015996:Survival Rate; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D019076:Transgenes / Q000276:immunology*
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007148:Immunoglobulin mu-Chains; D004247:DNA