Critical contribution of beta chain residue 57 in peptide binding ability of both HLA-DR and -DQ molecules.

Abstract

Position 57 in the a3 chain of HLA class II molecules maintains an Asp/non-Asp dimorphism that has been conserved through evolution and is implicated in susceptibility to some autoimmune diseases. The latter effect may be due to the influence of this residue on the ability of class II alleles to bind specific pathogenic peptides. We utilized highly homologous pairs ofboth DR and DQ alleles that varied at residue 57 to investigate the impact of this dimorphism on binding of model peptides. Using a direct binding assay of biotinylated peptides on whole cells expressing the desired alleles, we report several peptides that bind differentially to the allele pairs depending on the presence or absence of Asp at position 57. Peptides with negatively charged residues at anchor position 9 bind well to alleles not containing Asp at position 57 in the f3 chain but cannot bind well to homologous Asp-positive alleles. By changing the peptides at the single residue predicted to interact with this position 57, we demonstrate a drastically altered or reversed pattern of binding.Ala analog peptides confirm these interactions and identify a limited set of interaction sites between the bound peptides and the class II molecules. Clarification of the impact of specific class II polymorphisms on generating unique allele-specific peptide binding "repertoires" will aid in our understanding of the development of specific immune responses and HLAassociated diseases.

T Cell Recognition of Desmoglein 3 Peptides in Patients with Pemphigus Vulgaris and Healthy Individuals

“…A previous study demonstrated that non-PV-associated HLA class II alleles such as DQB1*0301 restricted Dsg3-driven T cell responses (43). DQB1*0301 is homologous to the PV-associated DQB1*0503 which differs from the common DQB1*0501 allele only by a valine to aspartic acid substitution at putative peptide binding position DQB-chain position 57 (44,45). These findings may explain why PV patients and healthy individuals who do not carry the "classical" PV-associated HLA class II alleles develop autoreactive T cell responses against Dsg3 (Table I and II).…”

Type 1 Diabetes-Predisposing MHC Alleles Influence the Selection of Glutamic Acid Decarboxylase (GAD) 65-Specific T Cells in a Transgenic Model

“…Also, the relationship between T cell responsiveness and peptide binding affinity to MHC is extremely complex, with certain weakly binding self-peptides capable of potent T cell stimulation and, sometimes, even induction of autoimmunity (60). Studies on the peptide binding motif of HLA DQ8 have revealed that pockets 4 and 9 on the MHC molecule, which interact with complementary residues on the peptide, are key sites of diseaseassociated polymorphisms (61,62). It has been shown that peptides binding DQ8 with high affinity have large aliphatic side chains in pocket 4 and negatively charged side chains in pocket 9, forming a stable peptide-MHC complex.…”

Differential effects of DRB1*0301 and DQA1*0501-DQB1*0201 on the activation and progression of islet cell autoimmunity

“…7,12,13 A direct involvement of class II molecules in disease pathogenesis has been implicated by their functional role in binding and presenting peptides to T lymphocytes, and studies showing differences in antigen selectivity and binding affinity for the products of high-and low-risk alleles. [14][15][16][17] However, there is limited genetic evidence to support this view because of the strong linkage disequilibrium across the MHC. 16,18,19 DR3-DQ2 is of special interest, in part because of its association with multiple immunopathologies and in part because of the extended conservation of this haplotype.…”