Molecular properties of HLA-DQ alleles conferring susceptibility to or protection from insulin-dependent diabetes mellitus: keys to the fate of islet beta-cells.
The major histocompatibility complex Class II alleles, HLA-DQ, and the related HLA-DR, are the chief genetic elements of human type 1 diabetes. These genes code for polymorphic heterodimeric proteins, whose chief function is to trap peptide antigens in the endosome and present them on the surface of antigen-presenting cells (dendritic cells, B lymphocytes, monocytes/macrophages) to CD4(+) T helper cells. A systematic investigation of the molecular properties of HLA-DQ alleles linked to susceptibility or resistance to type 1 diabetes has shown that these properties segregate along lines of susceptibility or resistance. A correlation of these features with the function of each particular segment of the HLA-DQ molecule yields interesting insights into the possible pathways leading to type 1 diabetes. There remain, however, areas to be clarified, including mechanisms by which dominant protection is conferred by certain alleles, the interplay between HLA-DQ and the related locus HLA-DR, that also shows autoantigen-specific reactivity, and the cross-Class help delivered to CD8(+) T cells, the final effectors in pancreatic beta-cell destruction. Clarification of these issues may lead to ways to prevent diabetes in predisposed individuals already exhibiting the genetic and immunological characteristics, and perhaps a cure in those with the disease, by means of transplantation, and measures for prevention of disease recurrence.
University of Ioannina, Greece.
Antonis K
AK
Moustakas
George K
GK
Papadopoulos
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D006684:HLA-DR Antigens / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology; D017434:Protein Structure, Tertiary
D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens