Exceptional stability of the HLA-DQA1* 0102/DQB1* 0602 αβ protein dimer, the class II MHC molecule associated with protection from insulin-dependent diabetes …

RA Ettinger, AW Liu, GT Nepom… - The Journal of …, 1998 - journals.aai.org
RA Ettinger, AW Liu, GT Nepom, WW Kwok
The Journal of immunology, 1998journals.aai.org
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 IA g7 is relatively unstable,
in contrast to other murine IA alleles, suggesting a correlation between unstable MHC class …
Abstract
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 IA g7 is relatively unstable, in contrast to other murine IA 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 αβ dimer in SDS may play a role in IDDM protection.
journals.aai.org