Subtle differences in HLA DQ haplotype-associated presentation of AChR alpha-chain peptides may suffice to mediate myasthenia gravis.
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 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 alpha34-49 were associated with A1*0102:B1*0602/0604, A1*0301:B1*0302 and A1*0401/0303:B1*0301. Peptide alpha146-162 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.
Deitiker
Philip R
PR
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Oshima
Minako
M
Smith
R Glenn
RG
Mosier
Dennis R
DR
Atassi
M Zouhair
MZ
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D005260:Female; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics* / Q000276:immunology; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006239:Haplotypes; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000235:genetics* / Q000276:immunology*; D021122:Protein Subunits / Q000276:immunology; D011950:Receptors, Cholinergic / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D008562:Membrane Glycoproteins; D021122:Protein Subunits; D011950:Receptors, Cholinergic