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ß Protein Dimer, the Class II MHC Molecule Associated with Protection from Insulin-Dependent Diabetes Mellitus1
*
Virginia Mason Research Center and
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98101
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-Ag7 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 
ß dimer in SDS may play a role in IDDM
protection.
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