HLA-DQw3.2 allele of the DR4 haplotype is associated with insulin-dependent diabetes; correlation between DQ ? restriction fragments and DQ ? chain variation

Monos, Dimitri; Spielman, Richard S.; Gogolin, Kathryn J.; Radka, Susan F.; Baker, Lester; Zmijewski, Chester M.; Kamoun, Malek

doi:10.1007/bf00346526

Cited by 32 publications

(7 citation statements)

References 25 publications

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“…The HLA-DQ3 .1 gene, which differs from the DQ3 .2 by four amino acid substitutions in the first domain, is associated with HLA-DR4, DR5, and DR8 . On different DR4 haplotypes, which in some cases may carry a DQ3.2 gene and in other cases a DQ3 .1 gene, these DQallelic differences are presumed to account for major functional differences, including a significantly different risk of disease susceptibility for diabetes mellitus (16)(17)(18)(19)(20)(21) .…”

Section: Resultsmentioning

confidence: 99%

Polymorphic DQ alpha and DQ beta interactions dictate HLA class II determinants of allo-recognition.

Kwok

Mickelson

Masewicz

et al. 1990

The Journal of Experimental Medicine

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T cell activation mediated by the TCR is triggered by a complex of an antigenic peptide with a cell surface protein encoded by the MHC. The specific control of the trimolecular interaction between a particular antigen, MHC molecule, and TCR follows a set of genetically programmed parameters . MHC polymorphisms regulate one of these parameters, termed MHC restriction, by which some MHC alleles form "permissive" complexes that permit T cell response, and other MHC alleles do not. Recent studies using murine class II MHC molecules (1-2) have demonstrated that the act of binding a peptide is necessary, but not always sufficient to trigger potentially reactive T cells; presumably, precise structural interactions between amino acids on the peptide and on the class II molecule itself are crucial for recognition. Structural variation among class II molecules can be critically important for this function . In the example of the H-26 "12 mouse, three amino acid substitutions in the class II Ia (3 chain distinguish the bm12 strain from the parental B6 strain, and apparently confer a wide variety of distinct immunologic characteristics, including alloreactivity against the parental B6, differential responsiveness to defined antigenic peptides, and differential susceptibility to experimentally induced myasthenia gravis (3-5).As the bm12 mouse example illustrates, specific substitutions in class 11 0 chains may have dramatic consequences for immune function . Among human class II molecules, both the class II a and the class 11 0 chains in functional class II dimers potentially contribute structural variation affecting function, particularly at the HLA-DQ locus, where both a and a genes are highly polymorphic. Structural models of recognition events involving HLA class II molecules suggest that polymorphic sites on a and /3 chains potentially interact with each other, with peptide, and with TCR (6-7).To evaluate the fine structural requirements ofthis interaction, we analyzed human T cell-MHC interactions in vitro by evaluating the effects of specific molecular substitutions within the class II HLA-DQ a and /3 chain components . We have previously described the use of site-directed mutagenesis on cloned human MHC genes,

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Section: Resultsmentioning

confidence: 99%

Polymorphic DQ alpha and DQ beta interactions dictate HLA class II determinants of allo-recognition.

Kwok

Mickelson

Masewicz

et al. 1990

The Journal of Experimental Medicine

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“…Although class II DQ molecules are heterodimers with a and ,B chains, the 1 chain determines the DQw3 specificity and related alloepitopes (8). The DQ3.2 and DQ3.1,B alleles can also be distinguished by restriction fragment length polymorphisms, two-dimensional protein gel electrophoresig, and oligonucleotide hybridization (4,6,8,9). These methods have been widely used to highlight the strong association of the DQ3.2f3 gene with IDDM susceptibility (1-6, 9, 10 Oligonucleotide HybridizatiQn.…”

mentioning

confidence: 99%

Mutational analysis of the HLA-DQ3.2 insulin-dependent diabetes mellitus susceptibility gene.

Kwok

Lotshaw

Milner

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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“…We are very grateful to Dr John Trowsdale, ICRF London, for invaluable advice and for providing the structure of expressed molecules (25). These polymorphisms can also be recognised by alloreactive T cell clones confirming their functional relevance (26).…”

Section: Aeknowledyenentsmentioning

confidence: 84%

Restriction fragment length polymorphism analysis of HLA haplotypes in families with Type I diabetes mellitus

et al. 1990

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HLA Class II polymorphisms were analysed in 27 families with at least one Type I diabetic proband using Southern blotting technique according to 10th Histocompatibility Workshop Standards. The probes used were DRB, DQA1, DQB1 and DOB. We have studied 108 haplotypes and performed segregation analysis with HLA serology and restriction fragment length polymorphism (RFLP) data and compared "affected" with "non-affected" haplotypes (not inherited by IDDM patients). RFLPs correlated well with DR and DQ serology and detected additional polymorphisms. In particular, DQB polymorphism analysis showed segregation of the DQw3 splits with 88.5% of the DR4 affected haplotypes bearing the DQw3.2 split (now DQw8) and 11.5% the DQw3.1 split (now DQw7) while in the non-affected DR4 haplotypes 33.3% were DQw3.2 and 66.6% were DQw3.1. Haplotype analysis showed that DR4-DQw3.2 was in strong linkage with the U fragment (2.1 kb Taq I) of DQA2 (DX alpha) and with the L fragment (5.4 kb BamH I) of DOB. This study confirms previous observations of DQB polymorphisms in heterozygous IDDM patients, supports the protective effect of DQw3.1 (DQw7) against the development of the disease and demonstrates the importance of DQw3.2 (DQw8) for susceptibility to Type I diabetes.

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HLA-DQw3.2 allele of the DR4 haplotype is associated with insulin-dependent diabetes; correlation between DQ ? restriction fragments and DQ ? chain variation

Cited by 32 publications

References 25 publications

Polymorphic DQ alpha and DQ beta interactions dictate HLA class II determinants of allo-recognition.

Polymorphic DQ alpha and DQ beta interactions dictate HLA class II determinants of allo-recognition.

Mutational analysis of the HLA-DQ3.2 insulin-dependent diabetes mellitus susceptibility gene.

Restriction fragment length polymorphism analysis of HLA haplotypes in families with Type I diabetes mellitus

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