Polymorphic structural features of modelled HLA-DQ molecules segregate according to susceptibility or resistance to IDDM

Routsias, J.; Papadopoulos, George K.

doi:10.1007/s001250050421

Cited by 17 publications

(27 citation statements)

References 43 publications

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“…We speculate that a difference in hydrophobicity of the peptide binding groove between the protective DQA1*06 alleles compared with the risk factor alleles may result in the binding of antigens of higher hydrophobicity to the protective alleles. Although in some immune-mediated diseases HLA risk factors have been shown to have higher affinity for inciting antigens, in other cases autoantigens may have higher affinity for protective factor alleles (27,28). Therefore, under some conditions, a tight peptide-MHC binding may result in elimination of autoreactive T cell clones from the thymus.…”

Section: Discussionmentioning

confidence: 99%

Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians

Mamyrova

O’Hanlon

Monroe

et al. 2006

Arthritis & Rheumatism

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Objective. To define the relative importance (RI) of class II major histocompatibility complex (MHC) alleles and peptide binding motifs as risk or protective factors for juvenile dermatomyositis (DM), and to compare these with HLA associations in adult DM.Methods. DRB1 and DQA1 typing was performed in 142 Caucasian patients with juvenile DM, and the results were compared with HLA typing data from 193 patients with adult DM and 797 race-matched controls. Random Forests classification and multiple logistic regression were used to assess the RI of the HLA associations.Results. The HLA-DRB1*0301 allele was a primary risk factor (odds ratio [OR] 3.9), while DQA1*0301 (OR 2.8), DQA1*0501 (OR 2.1), and homozygosity for DQA1*0501 (OR 3.2) were additional risk factors for juvenile DM. These risk factors were not present in patients with adult DM without defined autoantibodies. DQA1 alleles *0201 (OR 0.37), *0101 (OR 0.38), and *0102 (OR 0.51) were identified as novel protective factors for juvenile DM, the latter 2 also being protective factors in adult DM. The peptide binding motif DRB1 9 EYSTS 13 was a risk factor, and DQA1 motifs F 25 , S 26 , and 45 (V/A)W(R/K) 47 were protective. Random Forests classification analysis revealed that among the identified risk factors for juvenile DM, DRB1*0301 had a higher RI (100%) than DQA1*0301 (RI 57%), DQA1*0501 (RI 42%), or the peptide binding motifs. In a logistic regression model, DRB1*0301 and DQA1*0201 were the strongest risk and protective factors, respectively, for juvenile DM.Conclusion. DRB1*0301 is ranked higher in RI than DQA1*0501 as a risk factor for juvenile DM. DQA1*0301 is a newly identified HLA risk factor for juvenile DM, while 3 of the DQA1 alleles studied are newly identified protective factors for juvenile DM.

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Section: Discussionmentioning

confidence: 99%

Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians

Mamyrova

O’Hanlon

Monroe

et al. 2006

Arthritis & Rheumatism

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“…In the first homology models of HLA-DQ alleles, it was hypothesized that pocket 4 is prominent and widely accommodating (45,46). The large size has been verified since in the different DQ allele crystal structures (18,20,47).…”

Section: Discussionmentioning

confidence: 99%

Allelic Variation in Key Peptide-Binding Pockets Discriminates between Closely Related Diabetes-Protective and Diabetes-SusceptibleHLA-DQB1*06Alleles

Ettinger

Papadopoulos

Moustakas

et al. 2006

The Journal of Immunology

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HLA-DQA1*0102-DQB1*0602 is associated with protection against type 1 diabetes (T1D). A similar allele, HLA-DQA1*0102-DQB1*0604, contributes to T1D susceptibility in certain populations but differs only at seven amino acids from HLA-DQA1*0102-DQB1*0602. Five of these polymorphisms are found within the peptide-binding groove, suggesting that differences in peptide binding contribute to the mechanism of their association with T1D. In this study, we determine the peptide-binding motif for HLA-DQA1*0102-DQB1*0604 allelic protein (DQ0604) in comparison to the established HLA-DQA1*0102-DQB1*0602 (DQ0602) motif using binding assays with model peptides from T1D autoantigens and homology modeling using the coordinates of the DQ0602-hypocretin 1–13 crystal structure. The peptide binding preferences were deduced with a peptide from insulin that bound both with a 2- to 3-fold difference in avidity using the same amino acids in the peptide as anchors. Peptide binding differences directly influenced by the polymorphisms in or nearby pockets 1, 6, and 9 were observed. In pocket 1, DQ0604 was better able to accommodate aromatic residues due to the β86 and β87 polymorphisms. A negatively charged amino acid was preferred by DQ0604 in pocket 6 due to the positively charged β30His. In pocket 9, DQ0604 preferred aromatic amino acids due to the β9 and β30 polymorphisms and had low tolerance of acidic residues. β57Val in DQ0604 functions differently than β57Ala, in that it pushes α76Arg outside of the pocket, preventing the formation of a salt bridge with an acidic amino acid in the peptide. This study furthers our understanding of the structure-function relationships of MHC class II polymorphisms.

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“…In extrapolating our results to human Type I diabetes, it should be kept in mind that in humans the role of the b57 residue along with other subtle points in the structure of susceptible and resistant HLA-DQ alleles is paramount [2,8,57,73], as the b9His-b56His-b57Ser combination is unique to I-A g7 .…”

Section: Discussionmentioning

confidence: 99%

Modelling of the MHC II allele I-A g7 of NOD mouse: pH-dependent changes in specificity at pockets 9 and 6 explain several of the unique properties of this molecule

2000

Self Cite

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The non-obese diabetic (NOD) mouse is an animal model of Type I (insulin-dependent) diabetes mellitus [1,2]. Extensive work on this model has shown that the chief genetic determinant of diabetes is the unique MHC class II allele of this mouse, termed I-A g7 [2,3]. The MHC class II molecules exist on professional antigen-presenting cells (APCs, i. e. dendritic cells, B lymphocytes and macrophages). They capture processed antigen fragments, forming complexes that are presented to CD4 + helper T-cells. Because of a deletion in their H-2/I-Ea gene, NOD mice do not express an I-E molecule [4]. Sequencing of the I-A g7 molecule showed a number of remarkable features in its beta chain; a histidine in position 56 and a serine in position 57 [5]. The histidine is unique to I-A g7 of all known mouse, rat, porcine, bovine and human MHC class II alleles [6,7]. The b57Ser is unique to the I-A g7 of all mouse MHC class II alleles but is Diabetologia (2000) 43: 609±624Modelling of the MHC II allele I-A g7 of NOD mouse: pH-dependent changes in specificity at pockets 9 and 6 explain several of the unique properties of this molecule Abstract Aims/hypothesis. We modelled the three-dimensional structure of I-A g7 , the chief genetic component of diabetes in non-obese diabetic mice, to understand the unusual properties of this molecule. Methods. Modelling was done, in complex with established antigenic peptides, based on the structure of I-A k .Results. The selectivity of the I-A g7 molecule changes greatly at pockets 9 and 6 but hardly at all at pockets 1, 4 and 7, between endosomal pH (5.0) and extracellular pH (7.0), in agreement with previous results. This selectivity is attributed to the unique combination of b9His, b56His and b57Ser. The positive charges in and around pocket 9 at pH 5, favour binding by negatively charged residues. At pH 7 however, the uncharged a68, b9 and b56 histidines favour the accommodation of the bulky residues lysine, arginine, phenylalanine and tyrosine at pocket 9. The combination of b9His and a66Glu is responsible for the pHdependent selectivity at pocket 6. Furthermore, the lack of repulsion between b56His and a76Arg at pH 7 leads to a more stable ternary complex. Conclusion/interpretation. These results reconcile previous conflicts over the peptide binding ability of I-A g7 and its motif. They furthermore provide possible explanations for the short lifetime of cell-surface I-A g7 complexes in vivo, the higher threshold of thymic negative selection and inherent self-reactivity shown by immunocytes in these mice and the protection from diabetes afforded to them by several transgenically expressed mouse class II alleles. This contributes to an understanding of the pathogenesis of Type I (insulin-dependent) diabetes mellitus in this animal. [Diabetologia (2000) 43: 609±624] Keywords Autoimmunity, I-A g7 molecule, MHC class II structure, protein modelling, NOD mice, Type I diabetes mellitus.Received: 9 August 1999 and in revised form: 27 January 2000Corresponding author: G. K. Papadopoulos, PhD, Labo...

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Polymorphic structural features of modelled HLA-DQ molecules segregate according to susceptibility or resistance to IDDM

Cited by 17 publications

References 43 publications

Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians

Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians

Allelic Variation in Key Peptide-Binding Pockets Discriminates between Closely Related Diabetes-Protective and Diabetes-SusceptibleHLA-DQB1*06Alleles

Modelling of the MHC II allele I-A g7 of NOD mouse: pH-dependent changes in specificity at pockets 9 and 6 explain several of the unique properties of this molecule

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