Molecular Modelling of HLA‐DQ Suggests a Mechanism of Resistance in Type 1 Diabetes

Abstract

Genetic resistance and susceptibility to insulin-dependent diabetes mellitus (IDDM) have been associated with the HLA class II region on chromosome 6. In many races, the DQB1*0602 allele has been observed at a decreased frequency in IDDM, suggesting a protective role. A DNA sequence analysis of five patients, previously typed as having allele DQB1*0602, revealed sequence variation: one is DQB1*0603 and four possess unique sequences related to DQB1*0602 (one patient) or DQB1*0603 (three patients). Samples from four unaffected controls possessed normal DQB1*0602 sequences, and all patients and controls have normal DQA1 sequences. Each of the four unique patient sequences yields predicted amino acid sequences differing from the more common DQB1 alleles by variation at codons 9, 38 (silent), 59, and/or 62. Molecular modelling of the predicted protein sequence of these permissive variants reveals an HLA-DQ structure from diabetic patients that differs in the surface contour of the peptide-binding groove from normal DQB1*0602 sequence. In all the models of permissive molecules, the surface area corresponding to the HLA-DR pockets 6, 7 and 9 are modified. These pockets accommodate side chains of the bound peptide; thus modification of this region could alter peptide specificity. This 'pocket change' suggests that the normal allele could confer dominant protection against the development of IDDM by affecting peptide and/or T cell receptor (TCR) binding. This could regulate the deletion or suppression of T cell clones inappropriately recognizing the beta cells of the pancreas.

Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians

“…We speculate that a difference in hydrophobicity of the peptide binding groove between the protective DQA1*06 alleles compared with the risk factor alleles may result in the binding of antigens of higher hydrophobicity to the protective alleles. Although in some immune-mediated diseases HLA risk factors have been shown to have higher affinity for inciting antigens, in other cases autoantigens may have higher affinity for protective factor alleles (27,28). Therefore, under some conditions, a tight peptide-MHC binding may result in elimination of autoreactive T cell clones from the thymus.…”

The genetics of HLA-associated disease

“…Furthermore, if inheritance of T1D MHC susceptibility genes is recessive, why are some protective alleles, such as HLA-DRB1*1501 and/or -DQB1*0602 [16][17][18], occasionally found in T1D patients? One possibility is that an ancient crossover produced a HLA-DRB1*1501-susceptibility DQB1 gene haplotype [16].…”

Genetics of Type 1A Diabetes

“…It was reported that four patients with type 1A diabetes who were initially found to have the conventional DQB1*0602 with standard sequence-specific oligonucleotide (SSO) typing techniques actually had novel variants of this allele with sequencing (Hoover and Marta, 1997). This finding would suggest that the conventional DQA 1 *0 102-DQB I*0602 haplotype is never found in patients with type IA diabetes and that this haplotype confers absolute protection from the disease.…”