Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy

Siebold, Christian; Hansen, Bo Moelholm; Wyer, Jessica R.; Harlos, K.; Esnouf, Robert E.; Svejgaard, A.; Bell, John I.; Strominger, Jack L.; Jones, E Y; Fugger, Lars

doi:10.1073/pnas.0308458100

Cited by 140 publications

(106 citation statements)

References 38 publications

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“…The discrepancies between *0602 and *0603 occur at aa 9 and 30, residues that contribute to pocket 6 of the class II molecule, and have been shown to influence the binding of peptides. 43,44 These aa differences might alter the ability to present specific HPV peptides, thereby affecting the efficiency of the immune reaction against HPV. The DQB1*0602 is implicated in other diseases connected to the immune system.…”

Section: Discussionmentioning

confidence: 99%

MHC loci affecting cervical cancer risk: distinguishing the effects of HLA-DQB1 and non-HLA genes TNF, LTA, TAP1 and TAP2

Ivansson

Magnusson

et al. 2008

Genes Immun

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Cervical cancer has been associated with specific human leukocyte antigen (HLA) haplotypes/alleles and with polymorphisms at the nearby non-HLA loci TNF, LTA, TAP1 and TAP2. Distinguishing effects of individual loci in the major histocompatibility complex (MHC) region are difficult due to the complex linkage disequilibrium (LD) pattern characterized by high LD, punctuated by recombination hot spots. We have evaluated the association of polymorphism at HLA class II DQB1 and the TNF, LTA, TAP1 and TAP2 genes with cervical cancer risk, using 1306 familial cases and 288 controls. DQB1 was strongly associated; alleles *0301, *0402 and *0602 increased cancer susceptibility, whereas *0501 and *0603 decreased susceptibility. Among the non-HLA loci, association was only detected for the TAP2 665 polymorphism, and interallelic disequilibrium analysis indicated that this could be due to LD with DQB1. As the TAP2 665 association was seen predominantly in non-carriers of DQB1 susceptibility alleles, we hypothesized that TAP2 665 may have an effect not attributable to LD with DQB1. However, a logistic regression analysis suggested that TAP2 665 was strongly influenced by LD with DQB1. Our results emphasize the importance of large sample sizes and underscore the necessity of examining both HLA and non-HLA loci in the MHC to assign association to the correct locus.

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Section: Discussionmentioning

confidence: 99%

MHC loci affecting cervical cancer risk: distinguishing the effects of HLA-DQB1 and non-HLA genes TNF, LTA, TAP1 and TAP2

Ivansson

Magnusson

et al. 2008

Genes Immun

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“…12,13 Intriguingly, as DQ6/8 trans-dimer formation is not possible, DQ6/8 heterozygous individuals only express the respective cis-dimers. 14,15 Biopsies taken from newly diagnosed patients to obtain autoreactive T cells from the proximal pancreatic lymph nodes are a rarity, and little is known of insulinspecific T cells in human beings. Both proinflammatory and regulatory insulin-reactive T cells have been identified in T1D patients and healthy control subjects who were HLA class II restricted.…”

Section: Introductionmentioning

confidence: 99%

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

et al. 2011

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Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 transmolecules composed of a and b chains from DQ2 and DQ8 express unique b-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis-and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to 'epitope stealing', thereby inducing a regulatory, rather than a pathogenic immune response.

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“…Indeed, MHC alleles mediating dominant protection have been identified . For example, humans carrying the MHC II molecule encoded by HLA-DQA1 Ã 0102/HLA-DQB1 Ã 0602 are almost completely protected against diabetes even in the presence of the predisposing allele HLA-DQB1 Ã 0302 (Siebold et al 2004). Structural studies comparing the predisposing and protecting MHC molecules suggest that differences in the P6 and P9 pockets may lead to the presentation of an expanded peptide repertoire by the protecting MHC molecule.…”

Section: K5mentioning

confidence: 99%

Does intra-individual major histocompatibility complex diversity keep a golden mean?

Woelfing

Traulsen

Milinski

et al. 2008

Phil. Trans. R. Soc. B

144

192

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An adaptive immune response is usually initiated only if a major histocompatibility complex (MHC) molecule presents pathogen-derived peptides to T-cells. Every MHC molecule can present only peptides that match its peptide-binding groove. Thus, it seems advantageous for an individual to express many different MHC molecules to be able to resist many different pathogens. However, although MHC genes are the most polymorphic genes of vertebrates, each individual has only a very small subset of the diversity at the population level. This is an evolutionary paradox. We provide an overview of the current data on infection studies and mate-choice experiments and conclude that overall evidence suggests that intermediate intra-individual MHC diversity is optimal. Selective forces that may set an upper limit to intra-individual MHC diversity are discussed. An updated mathematical model based on recent findings on T-cell selection can predict the natural range of intra-individual MHC diversity. Thus, the aim of our review is to evaluate whether the number of MHC alleles usually present in individuals may be optimal to balance the advantages of presenting an increased range of peptides versus the disadvantages of an increased loss of T-cells.

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Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy

Cited by 140 publications

References 38 publications

MHC loci affecting cervical cancer risk: distinguishing the effects of HLA-DQB1 and non-HLA genes TNF, LTA, TAP1 and TAP2

MHC loci affecting cervical cancer risk: distinguishing the effects of HLA-DQB1 and non-HLA genes TNF, LTA, TAP1 and TAP2

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Does intra-individual major histocompatibility complex diversity keep a golden mean?

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