| 11. |
- Sanjeevi, C. B., et al.
(författare)
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Association between autoantibody markers and subtypes of DR4 and DR4-DQ in Swedish children with insulin-dependent diabetes reveals closer association of tyrosine pyrophosphatase autoimmunity with DR4 than DQ8
- 1998
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Ingår i: Tissue Antigens. - : Wiley. - 0001-2815 .- 1399-0039. ; 51:3, s. 281-286
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Tidskriftsartikel (refereegranskat)abstract
- HLA DQA1(*)0301-DQB1(*)0302 (DQ8) and DQA1(*)0501-DQB1(*)0201 (DQ2) are positively and DQA1(*)0102-DQB1(*)0602 (DQ6) negatively associated with IDDM. In DQA1(*)0301-DQB1(*)0302 (DQ8)-positive patients, susceptibility is also mediated by DRB1(*)0401. The aim of the study was to determine the association between HLA-DR4 and DQ and the presence of GAD65, ICA512, and insulin autoantibodies as well as ICA in 425 Swedish children with IDDM and 367 controls in the age group of 0-15 years. We found that ICA512 autoantibodies were associated primarily with DRB1(*)0401 and not with DQA1(*)0301-DQB1(*)0302 (DQ8). No such hierarchy could be demonstrated for insulin autoantibodies, which were associated with both DQA1(*)0301-DQB1(*)0302 (DQ8) and DRB1(*)0401. GAD65 autoantibodies, known to be closely associated with DQA1(*)0501-DQB1(*)0201 (DQ2)-DRB1(*)0301 haplotype, also showed no preferential association with DQA1(*)0301-DQB1(*)0302 (DQ8) versus DRB1(*)04. These results suggest that the immune response to different β-cell autoantigens may be mediated via HLA class II molecules from different loci. Design of the antigen-specific immuno-intervention trials should take into account these HLA-DR and DQ subtype associations.
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| 12. |
- Sanjeevi, C. B., et al.
(författare)
-
Polymorphic amino acid variations in HLA-DQ are associated with systematic physical property changes and occurrence of IDDM
- 1995
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 44:1, s. 125-131
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Tidskriftsartikel (refereegranskat)abstract
- The association between human leukocyte antigen (HLA) insulin-dependent diabetes was studied in a large population-based investigation using genotyping of 425 new-onset patients, 0-14 years of age, and 367 matched control subjects. As many as 97% of patients compared with 75% of control subjects were positive for one or several of DQA1*0301, DQA1*0501, DQB1*0302, or DQB1*0201. Asp-57 DQB was present among 28% of patients, indicating that this residue alone does not confer protection. Combining Asp- 57 DQB1 with either Arg-52 DQA1 or Leu-69 DQA1 did not explain susceptibility or protection either. DQA1*0301-DQB1*0302 (DQS) and DQA1*0301-DQB1*0301 (DQ7) are identical except for four amino acid substitutions in the β- chain, but DQ8 was positively (odds ratio 8.07; P < 0.001) and DQ7 negatively (odds ratio 0.38; P < 0.001) associated with the disease. Molecular modeling was used to determine whether physicochemical properties such as steric factors and surface electrostatic potentials also differ in a systematic way for various DQ molecules. Amino acids were substituted systematically at the four polymorphic sites, and the solvent-accessible surfaces and electrostatic potentials were computed for each molecule. Dramatic alterations in electrostatic potential were seen for double substitutions at position 45 (G45E) and 57 (A57D) of DQB1. The variation of physicochemical properties due to polymorphic substitutions may be significant to the mechanism of HLA-DQ association with insulin-dependent diabetes, via the effect these property variations have on peptide antigen binding selectivity and subsequent interactions with specific T-cell receptors.
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