Dissection of the effects of tumor necrosis factor-alpha and class II gene polymorphisms within the MHC on murine systemic lupus erythematosus (SLE).

Abstract

Gene(s) in the MHC of the NZW strain (H-2z) up-regulate(s) systemic lupus erythematosus (SLE) in (NZB x NZW) F1 mice. So far, two plausible mechanisms have been implicated: (i) unique mixed haplotype class II molecules formed in the F1 mice act as a restriction element for self-reactive T cells and (ii) a unique polymorphism in the H-2-linked NZW tumor necrosis factor (TNF)-alpha allele which down-regulates TNF-alpha is contributory. Because of the difficulty in dissecting these alleles within the H-2 complex, it has not been determined which is indeed the case. We addressed this issue by establishing three different H-2-congenic (NZB x NZW) F1 mice bearing distinct haplotypes at class II and TNF-alpha regions, i.e. (NZB x NZW) F1 (H-2d/z:A(d/u)E(d/u)TNF(d/z)), (NZB x NZW.PL) F1 (H-2(d/u):A(d/u)E(d/u)TNF(d/d)) and (NZB x NZW.H-2d) F1 (H-2(d/d):A(d/d)E(d/d)TNF(d/d)). Among these, only (NZB x NZW) F1 produced a markedly lower level of TNF-alpha, due to the unique NZW TNF-alpha allele (TNF(z)). Studies of anti-DNA antibodies and lupus nephritis revealed that, compared to (NZB x NZW) F1, the disease of (NZB x NZW.H-2d) F1 was markedly reduced. In (NZB x NZW.PL) F1, the onset of renal disease was significantly delayed, while the extent of proteinuria and renal histopathology in individuals that had developed the disease was comparable to that seen in (NZB x NZW) F1. It seems likely that both class II and TNF-alpha gene polymorphisms are functioning as H-2-linked predisposing genetic elements, and that the TNF-alpha polymorphism acts to modulate an initial process of the renal disease.

• Authors: T Fujimura, S Hirose, Y Jiang, S Kodera, H Ohmuro, D Zhang, Y Hamano, H Ishida, S Furukawa, T Shirai
• Journal: International immunology (Int Immunol) Vol. 10 Issue 10 Pg. 1467-72 (Oct 1998) ISSN: 0953-8178 [Print] England
• PMID: 9796913 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Necrosis Factor-alpha

Topics

• Animals
• Female
• Genes, MHC Class II (genetics)
• Lupus Erythematosus, Systemic (genetics, physiopathology)
• Macrophages, Peritoneal (metabolism)
• Mice
• Mice, Congenic
• Mice, Inbred BALB C
• Mice, Inbred NZB
• Polymorphism, Genetic (physiology)
• Promoter Regions, Genetic (genetics)
• Tumor Necrosis Factor-alpha (biosynthesis, genetics)