Susceptibility to diabetes is widely distributed in normal class IIu haplotype rats

Diabetologia. 2000 Jul;43(7):890-8. doi: 10.1007/s001250051466.

Abstract

Aims/hypothesis: 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.

Conclusion/interpretation: 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology
  • Genes, MHC Class II*
  • Genetic Predisposition to Disease*
  • Haplotypes
  • Histocompatibility Antigens Class II / genetics
  • Islets of Langerhans / pathology
  • Major Histocompatibility Complex
  • Rats
  • Rats, Inbred BB
  • Rats, Inbred Lew
  • Rats, Inbred Strains
  • Rats, Inbred WF
  • Rats, Nude
  • Species Specificity

Substances

  • Histocompatibility Antigens Class II