Autoimmunity and the pathogenesis of type 1 diabetes

Abstract

Type 1 diabetes mellitus (TID) is an autoimmune genetic disease with unidentified environmental agents affecting its pathogenesis. Susceptibility is determined by the interaction of MHC and non-MHC genes in the thymus, primarily by the IDDM1 locus, which is extremely polymorphic and thus generates multitudes of predisposing and protective haplotypes for binding self-peptides. By presenting these peptide antigens to immature T-cells for activation and selection, most autoreactive cells will be deleted, but inefficient presentation and subsequent deficiencies of non-MHC genes allow some cells to escape to the periphery and to be eliminated by anergy or regulatory T-cells. T-cell dysregulation to a Th1 response with secretion of inflammatory cytokines promotes a self-perpetuating autoimmune cascade leading to overt disease unless blocked by suppressive cytokines from Th2-type cells. Since autoantibodies reflect target-cell destruction, early insulin autoantibodies may be transient due to benign insulitis induced by insulin or proinsulin. Multiple autoantibodies denote epitope spreading to cryptic autoantigens, likely involving posttranslational variants. Thus, the resulting T1D development requires coordinated abnormal variations, and this requirement limits its occurrence to a small minority of susceptible individuals.

Keywords::

• Insulitis
• insulin-dependent diabetes
• proinsulin
• insulin
• abnormal immune response
• autoimmunity

Acknowledgements

We are most grateful for the thoughtful comments of the referee and editor. Their suggestions have considerably raised the quality of our manuscript. Special thanks are also due to Mr M.M. Vaska and Ms Denise Upton, Librarians, Health Sciences Library, University of Calgary, for outstanding assistance.

Declaration of interest

None of the authors have any conflicts of interest (commercial or otherwise) to declare with regard to the writing of this review. No specific funding or other form of support was used in the writing of this article.