Subtle differences in HLA DQ haplotype-associated presentation of AChR alpha-chain peptides may suffice to mediate myasthenia gravis.

ABSTRACT

The HLA DQA1 and DQB1 alleles were determined on a set of 24 myasthenia gravis patients that had previously been examined for their T-cell proliferative responses to the 18 overlapping peptides representing the extracellular domain of hAChR alpha-chain. Patient responses according to assumed cis or trans haplotypes were significantly higher in most cases relative to normal controls. Comparisons of in vitro peptide-stimulated T-cell responses of patient pairs which had DQA1DQB1 in common displayed responses in tighter distribution relative to comparisons in which patient pairs did not share the same DQA1DQB1 haplotype. Similar haplotypes, such as DQA1*0102DQB1*0602 and DQA1*0102DQB1*0604, tended to exhibit similar responses and were grouped according to this similarity. Modified F-test and Student's T-test analyses on DQ isoform bearing groups revealed that high responses to peptide alpha34-49 were associated with A1*0102B1*0602/0604, A1*0301B1*0302 and A1*0401/0303B1*0301. Peptide alpha146-162 showed higher responses in A1*0301B1*0302 group and moderate responses in A1*0401/0303B1*0301 groups. Differences in the age of disease onset relative to DQ haplotypes were also observed. Groups of A1*0301B1*0302, A1*0501B1*0201 and A1*0102B1*0604 showed earlier ages of disease onset relative to those of A1*0102B1*0602 or A1*0505B1*0301.