A new model defines the minimal set of polymorphism in HLA-DQ and -DR that determines susceptibility and resistance to autoimmune diabetes

Abstract

Background: The mechanism underlying autoimmune diabetes has been difficult to define. There is a strong genetic contribution and numerous studies associate the major histocompatibility complex, especially the class II region, with predisposition or resistance. However, how these molecules are implicated remains obscure.

Presentation of the hypothesis: We have supplemented structural analysis with computational biophysical and sequence analyses and propose an heuristic for distinguishing between human leukocyte antigen molecules that predispose to insulin dependent diabetes mellitus and those that are protective. Polar residues at both beta37 and beta9 suffice to distinguish accurately between class II alleles that predispose to type 1 diabetes and those that do not. The electrostatic potential within the peptide binding pocket exerts a strong influence on diabetogenic epitopes with basic residues. Diabetes susceptibility alleles are predicted to bind autoantigens strongly with tight affinity, prolonged association and altered cytokine expression profile. Protective alleles bind moderately, and neutral alleles poorly or not at all. Non-Asp beta57 is a modifier that supplements disease risk but only in the presence of the polymorphic, polar pair at beta9 and beta37. The nature of beta37 determines resistance on one hand, and susceptibility or dominant protection on the other.

Conclusion: The proposed ideas are illustrated with structural, functional and population studies from the literature. The hypothesis, in turn, rationalizes their results. A plausible mechanism of immune mediated diabetes based on binding affinity and peptide kinetics is discussed. The number of the polymorphic markers present correlates with onset of disease and severity. The molecular elucidation of disease susceptibility and resistance paves the way for risk prediction, treatment and prevention of disease based on analogue peptides.

Reviewers: This article was reviewed by Eugene V. Koonin, Michael Lenardo, Hossam Ashour, and Bhagirath Singh. For the full reviews, please go to the Reviewers' comments section.

Figure 1

Electrostatic potential map of the P9 pocket. Electrostatic potential maps have been calculated separately for DR52a and DQ8 without their peptide and mapped to their van der Waals surface. The P9 pockets are shown here with their respective peptide P9 anchor side chain and selected residues in the pocket superimposed. The DR52a pocket is neutral and DQ8 shows a highly positive (blue) potential. The difference reflects the preference for a hydrophobic peptide side chain in DR52a P9 versus the preference for an acidic side chain in DQ8. The electrostatic difference is hypothesized to be a factor in susceptibility to T1D. Details of the calculations are given under supplementary materials (Additional file 1).

Figure 2

Hydrogen bond interactions involving insulin B chain P9 anchor in DQ8. There is a hydrogen bonding network involving the insulin peptide glutamic acid anchor and DQ8 α76 arginine, crystallographic water, β37 tyrosine, and β9 tyrosine. Two of the bonds from α76 are shown with relaxed constraints. This network of bonds hyper-stabilizes the insulin peptide.

Figure 3

Hydrogen bond interactions involving GAD65 P9 Glu in I-Ag7. Hydrogen bonding interactions between the peptide P9 glutamic acid and residues in mouse I-Ag7 are shown. There is notably no hydrogen bond between the peptide P9 Glu and β37 Tyr. There is instead an important hydrogen bond between peptide P9 Glu and β57 Ser. A hydrogen bond is also maintained between α76 Arg and β57 Ser. These interactions vary from the equivalent interactions between insulin B peptide P9 Glu in human DQ8.