Independent genetic regulation of T-cell and antigen-presenting cell participation in autoimmune islet inflammation.
Genetic susceptibility to type 1 diabetes in the nonobese diabetic (NOD) mouse involves at least 17 Idd loci. Idd1 has been mapped to a class II gene in the major histocompatibility complex (MHC), whereas the products and functions of the remaining Idd loci are unresolved. To investigate how non-MHC Idd genes regulate islet inflammation and IDDM progression, NOD mice were compared with the nonobese diabetes-resistant (NOR) mouse, a related MHC-identical strain that possesses a subset of the NOD-derived alleles at the Idd loci. Using quantitative reverse transcriptase-polymerase chain reaction amplification and immunohistochemistry, we observed that disease resistance in NOR mice is reflected by a protracted block at the earliest stage of insulitis. In NOD islets, early antigen-presenting cell (APC) recruitment to islet lesions was temporally coincident with progressive T-cell infiltration. In striking contrast, islet infiltrates in NOR mice were composed of APCs with minimal contribution from T-cells and T-cell-derived inflammatory cytokines, conferring apparent resistance to invasive insulitis and beta-cell destruction. This is the first evidence that a subset of Idd susceptibility loci independently regulate T-cell and APC participation in insulitis progression. As progress is made toward identification of the Idd gene products, it will be crucial to determine how they regulate diabetogenesis. Our data define distinct cellular stages of IDDM pathogenesis in which the impact of Idd genes can be readily analyzed.
Fox
C J
CJ
Hospital for Sick Children Research Institute, Department of Immunology, University of Toronto, Ontario, Canada.
Danska
J S
JS
D000375:Aging / Q000235:genetics; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015331:Cohort Studies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005802:Genes, MHC Class II / Q000235:genetics*; D007075:Immunoglobulin M / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D007075:Immunoglobulin M