Exceptional stability of the HLA-DQA1*0102/DQB1*0602 alpha beta protein dimer, the class II MHC molecule associated with protection from insulin-dependent diabetes mellitus.
HLA-DQ alleles are closely associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM) but the immunologic mechanisms involved are not understood. Structural studies of the IDDM-susceptible allele, HLA-DQA1*0301/DQB1*0302, have classified it as a relatively unstable dimer, particularly at neutral pH. This is reminiscent of studies in the nonobese diabetic mouse, in which I-A(g7) is relatively unstable, in contrast to other murine I-A alleles, suggesting a correlation between unstable MHC class II molecules and IDDM susceptibility. We have addressed this question by analysis of dimer stability patterns among various HLA-DQ molecules. In EBV-transformed B-lymphoblastoid cell lines and PBL, the protein encoded by the IDDM-protective allele HLA-DQA1*0102/DQB1*0602 was the most SDS stable when compared with other HLA-DQ molecules, including HLA-DQA1*0102/DQB1*0604, a closely related allele that is not associated with protection from IDDM. Expression of six different HLA-DQ allelic proteins and three different HLA-DR allelic proteins in the bare lymphocyte syndrome cell line, BLS-1, revealed that HLA-DQA1*0102/DQB1*0602 is SDS stable even in the absence of HLA-DM, while other HLA class II molecules are not. These results suggest that the molecular property of HLA-DQ measured by resistance to denaturation of the alphabeta dimer in SDS may play a role in IDDM protection.
Ettinger
R A
RA
Virginia Mason Research Center, Department of Immunology, University of Washington School of Medicine, Seattle 98101, USA.
Liu
A W
AW
Nepom
G T
GT
Kwok
W W
WW
D000483:Alleles; D001402:B-Lymphocytes / Q000737:chemistry; D002461:Cell Line, Transformed; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D019281:Dimerization; D020022:Genetic Predisposition to Disease / Q000276:immunology* / Q000378:metabolism; D006683:HLA-DQ Antigens / Q000235:genetics / Q000378:metabolism*; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D011489:Protein Denaturation; D012967:Sodium Dodecyl Sulfate
D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D012967:Sodium Dodecyl Sulfate