The prolonged and enhanced immune response in the non-obese diabetic mouse is dependent on genes in the Idd1/24, Idd12 and Idd18 regions.
In non-obese diabetic (NOD) mice B cells are an absolute requirement for T1D development. NOD mice display various B cell related immune deviations when compared to normal mice such as an enhanced and prolonged immune response towards several antigens, including non-self immunoglobulins. We hypothesized that this trait contributes to diabetes pathogenesis, and investigated the genetic factor(s) governing the altered immune response. A (NODxC57BL/6)F(2) cohort (n = 214) were analyzed for its primary immune response against a BALB/c derived monoclonal antibody, and a genome wide linkage analysis was performed. Significant linkage to the Idd1/Idd24, Idd12 and Idd18.1 regions as well as to a proximal region (marker D2Mit367, 33.5 Mb) on chromosome 2 was detected. We verified the observed linkage by analyzing a set of H2 congenic NOD and C57BL/6 mice and narrowed down the region to 8 Mb. Interaction between Idd1/24 and Idd12, as well as the novel locus on chromosome 2 was observed. However, the action by Idd18.1 was not influenced by any of the other loci. In addition to the known H2 I-Aβ(g7) allelic variant of Idd1 in NOD, candidate gene analysis revealed a significant difference in the transcription of the H2-O/DO molecule. We hypothesize that multiple mechanisms contribute to the loss of immune response control, including that peptide loading on MHC class II in B cells of NOD is altered.
Sundström
Mia
M
Umeå University, Department of Clinical Microbiology, Division of Immunology, SE-901 85 Umeå, Sweden. mia.sundstrom@climi.umu.se
Lejon
Kristina
K
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003920:Diabetes Mellitus / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D007111:Immunity, Cellular / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD
C416186:H-2O antigen; D000949:Histocompatibility Antigens Class II