Interleukin-1 receptor deficiency in the hippocampal formation of (NZBxNZW)F2 mice: genetic and molecular studies relating to autoimmunity

Interleukin-1 receptor (IL-1R) deficiency has been previously described in the dentate gyrus of autoimmune NZB and (NZB x NZW) F1 (or BWF1) mice. In this study, the genetic and molecular characterization of this defect were investigated in BWF2 mice in relation to anti-DNA antibody production and microsatellite DlNds4 (near the ILlrl gene) polymorphism. IL-IR density was quantified in the brain, spleen and pancreas, using in vitro quantitative autoradiography with recombinant human [I-125]-IL-1 alpha as the ligand. This study of the dentate gyrus of F2 mice revealed three phenotypes: NZW like, NZB-like and F1-like, which occurred in a ratio of 1:1:2, with IL-1R densities of 100%, 17% and 59%, respectively as compared to control NZW mice (100%). In contrast, IL-1R densities observed in the choroid plexus and peripheral organs were similar. Moreover a high production of IgG2a anti-DNA antibodies was observed in F2 mice, as in their parents, particularly those with the NZB-like phenotype. Microsatellite mapping of DlNds4 revealed polymorphism in both parents and BWF2 mice in relation to the level of IL-1R density in the dentate gyrus. In spite of the acute defect in IL-1 binding in the dentate gyrus of NZB mice, molecular analysis of IL-1R mRNA (type I, II and accessory protein) showed similar amounts of mRNA, measured following RT-PCR amplification, in the hippocampal formation of both NZB and control C3H/He mice. In conclusion, the transmission of the IL-1R defect in the dentate gyrus of NZB mice is monofactorial and the defect appears to be at the post-transcriptional level of IL-1R synthesis. The lack of IL-1R in the dentate gyrus seems to correlate with some autoimmune characteristics. Correlation of DlNds4 polymorphism with the level of LL-IR density suggests that it could be a predisposing gene to disease or a marker for other closely linked predisposing genes. (C) 1998 Elsevier Science B.V.