Subtle differences in HLA DQ haplotype-associated presentation of AChR α-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 α-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 DQA1:DQB1 in common displayed responses in tighter distribution relative to comparisons in which patient pairs did not share the same DQA1:DQB1 haplotype. Similar haplotypes, such as DQA1*0102:DQB1*0602 and DQA1*0102:DQB1*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 α34–49 were associated with A1*0102:B1*0602/0604, A1*0301:B1*0302 and A1*0401/0303:B1*0301. Peptide α146–162 showed higher responses in A1*0301:B1*0302 group and moderate responses in A1*0401/0303:B1*0301 groups. Differences in the age of disease onset relative to DQ haplotypes were also observed. Groups of A1*0301:B1*0302, A1*0501:B1*0201 and A1*0102:B1*0604 showed earlier ages of disease onset relative to those of A1*0102:B1*0602 or A1*0505:B1*0301.

• Acetylcholine receptor
• autoimmunity
• HLA
• myasthenia gravis
• T-cell

• Ab
• antibody
• AChR
• acetylcholine receptor
• hAChR
• human AChR
• DQIBG
• DQ isoform bearing group
• MG
• myasthenia gravis
• PBL
• peripheral blood lymphocytes
• SD
• standard deviation
• SE
• standard error of the mean
• SI
• stimulation index (cpm of ³H-thymidine incorporated by antigen-stimulated T-cells/cpm incorporated by unstimulated cells)

Acknowledgement

This study was supported by a grant from the Muscular Dystrophy Association. The support of the Welch Foundation, due to the award to M.Z.A. of the Robert A. Welch Chair of Chemistry, is also gratefully acknowledged. The authors thank Mr Gerrit Heetderks for his excellent technical assistance.