Susceptibility to diabetes is widely distributed in normal class IIu haplotype rats.
OBJECTIVE
We did experiments to explore the pathways putatively leading to Type I (insulin-dependent) diabetes mellitus, and their association with the MHC locus, the major genetic determinant of disease susceptibility.


METHODS
Normal MHC congenic rat strains that do not spontaneously develop diabetes or any other autoimmune syndrome were injected with the interferon-alpha inducer polyinosinic-polycytidylic acid (Poly IC).


RESULTS
Insulitis and diabetes developed only in strains expressing Class II(u) genes and was independent of the Class I haplotype. Poly IC induced islet cell Class I hyperexpression, up regulation of pancreatic endothelial intercellular adhesion molecule-1 and vascular adhesion molecule-1 and a T-cell and macrophage infiltration of the pancreatic interstitium in all rat strains studied, including diabetes-resistant strains. Poly IC also induced the generation of diabetes-transferring spleen cells in most Class II(u) haplotype rats, including the diabetes-resistant WF rat.


CONCLUSIONS
The minimum requirements for autoimmune diabetes development in the rat include: RT1 Class II(u) genes, a T-cell repertoire containing beta-cell autoreactive T cells and a triggering event which breaks tolerance by the local up regulation of pancreatic endothelial adhesion receptors. Even when all of the minimum requirements have, however, been met, most Class II(u) rats do not develop diabetes in response to autoimmune stimuli. It is clear, nonetheless, that susceptibility to diabetes is widely distributed in the RT1(u) rat.
Ellerman
K E
KE
Department of Pathology, University of Massachusetts Medical School, Worcester, USA.
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D019264:Adoptive Transfer; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D007515:Islets of Langerhans / Q000473:pathology; D008285:Major Histocompatibility Complex; D051381:Rats; D011913:Rats, Inbred BB; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D011923:Rats, Nude; D013045:Species Specificity
D000949:Histocompatibility Antigens Class II