Alleviation of insulitis in NOD mice is associated with expression of transgenic MHC E molecules on primary antigen-presenting cells.
Major histocompatibility complex (MHC) class II genes are important in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) both in the mouse and in man. The non-obese diabetic (NOD) mouse, which is a good model for human IDDM, has a particular MHC class II with an A complex consisting of A alpha d and the unique A beta g7 chain, as well as an absent E molecule due to a deletion in the Ea promoter region. Transgenic insertion of a functional Ea gene protects against insulitis and diabetes, but when the transgene expression is restricted to certain compartments of the immune system by deleting parts of the promoter region, the protection against insulitis is disrupted. We have analysed three promoter-mutated lines where one lacks expression on B cells and has a reduced expression on approximately 1/3 of the dendritic cells and macrophages (Sma), one lacks thymic cortical expression and has a slightly reduced B-cell expression (delta X), and one lacks expression in the thymic medulla, on macrophages, dendritic cells and about half of the B cells (delta Y). None of these lines is protected against insulitis, but Sma and delta X display a reduced intensity of insulitis, with an average of 10-15% of the islets infiltrated in each mouse, while delta Y resembles non-transgenic mice with 30-35% infiltrated islets. Bone-marrow chimeras between Sma and delta Y mice demonstrate that peripheral cells of Sma origin reduce insulitis significantly when developed in the delta Y host, while insulitis is enhanced when delta Y bone marrow is given to Sma mice. This shows that E expression on the primary antigen-presenting macrophages and dendritic cells is of crucial importance to the alleviation of insulitis.
Pilström
B
B
Department of Immunology, Stockholm University, Sweden. bjon.pilstrom@imun.su.se
Böhme
J
J
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D016026:Bone Marrow Transplantation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004198:Disease Susceptibility; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D005802:Genes, MHC Class II / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D018183:Transplantation Chimera
D000949:Histocompatibility Antigens Class II