| First Author | Fujimura T | Year | 1998 |
| Journal | Int Immunol | Volume | 10 |
| Issue | 10 | Pages | 1467-72 |
| PubMed ID | 9796913 | Mgi Jnum | J:50687 |
| Mgi Id | MGI:1309585 | Doi | 10.1093/intimm/10.10.1467 |
| Citation | Fujimura T, et al. (1998) Dissection of the effects of tumor necrosis factor-alpha and class II gene polymorphisms within the MHC on murine systemic lupus erythematosus (SLE). Int Immunol 10(10):1467-72 |
| abstractText | Gene(s) in the MHC of the NZW strain (H-2(Z)) up- regulate(s) systemic lupus erythematosus (SLE) in (NZB x NZW) F-1 mice. So far, two plausible mechanisms have been implicated: (i) unique mixed haplotype class II molecules formed in the F-1 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) F-1 mice bearing distinct haplotypes at class II and TNF-alpha regions, i.e. (NZB x NZW) F-1 (H-2(d/z): A(d/u) E-d/u TNFd/z), (NZB x NZW.PL) F-1 (H-2d/u: A(d/u) E-d/u TNFd/d) and (NZB x NZW.H-2(d)) F-1 (H-2(d/l)d: A(d/d) E-d/d TNFd/d). Among these, only (NZB x NZW) F-1 produced a markedly lower level of TNF-a, due to the unique NZW TNF- alpha allele (TNFz). Studies of anti-DNA antibodies and lupus nephritis revealed that, compared to (NZB x NZW) F- 1, the disease of (NZB x NZW.H-2(d)) F-1 was markedly reduced. In (NZB x NZW.PL) F-1, 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) F- 1. 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. |
