Interleukin-1 receptor deficiency in the hippocampal formation of (NZB x NZW)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 D1Nds4 (near the IL1r1 gene) polymorphism. IL-1R density was quantified in the brain, spleen and pancreas, using in vitro quantitative autoradiography with recombinant human [125I]-IL-1alpha 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 D1Nds4 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 D1Nds4 polymorphism with the level of IL-1R density suggests that it could be a predisposing gene to disease or a marker for other closely linked predisposing genes.
Jafarian-Tehrani
M
M
Unité de Pharmacologie Neuro-Immuno-Endocrinienne, Institut Pasteur, Paris, France.
Gabellec
M M
MM
Adyel
F Z
FZ
Simon
D
D
Griffais
R
R
Ternynck
T
T
Haour
F
F
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000401:mortality; D015551:Autoimmunity / Q000276:immunology*; D001921:Brain / Q000166:cytology / Q000276:immunology; D018891:Dentate Gyrus / Q000276:immunology / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008814:Mice, Inbred NZB; D018895:Microsatellite Repeats / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D000974:Antibodies, Antinuclear; D017472:Receptors, Interleukin-1