Allelic Variation in Key Peptide-Binding Pockets Discriminates between Closely Related Diabetes-Protective and Diabetes-Susceptible<i>HLA-DQB1*06</i>Alleles

Ettinger, Ruth A.; Papadopoulos, George K.; Moustakas, Antonis K.; Nepom, Gerald T.; Kwok, William W.

doi:10.4049/jimmunol.176.3.1988

Cited by 52 publications

(61 citation statements)

References 58 publications

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“…Replacement of anchor residues with this basic amino acid has been previously shown to disrupt peptide binding (14). As shown in Figure 2, arginine substitution at residues 117, 120, and 125 reversed peptide binding, suggesting that these are primary anchor residues for binding to DR1401.…”

Section: Binding Register Of the Study Peptidementioning

confidence: 88%

Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

James

Moustakas

Berger

et al. 2008

Molecular Immunology

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This study identified the peptide-binding motif of HLA-DRB1*1401 (DR1401). First, peptides containing DR1401 restricted epitopes were identified using tetramer guided epitope mapping. Among these, an influenza B peptide was selected for the motif study. After confirming the binding register for this peptide using a set of arginine substitutions, binding affinities were determined for 33 peptides derived from this influenza B sequence with single amino acid substitutions. The DR1401 peptide binding motif was deduced from the relative binding affinities of these peptides and confirmed by structural modeling. Pocket 1 demonstrated a preference for aliphatic anchor residues and methionine. Pocket 4 accommodated methionine and aliphatic residues, but also allowed some polar and charged amino acids. Pocket 6 preferred basic residues but also allowed some polar and aliphatic amino acids. Pocket 9 preferred aliphatic and aromatic amino acids and tolerated some polar residues but excluded all charged residues. Together these preferences define a distinct set of peptides that can be presented by DR1401. The resulting motif was used to verify T cell epitopes within the novel antigenic peptides identified by tetramer guided epitope mapping and within peptides from published reports that contain putative DR1401 epitopes.

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Section: Binding Register Of the Study Peptidementioning

confidence: 88%

Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

James

Moustakas

Berger

et al. 2008

Molecular Immunology

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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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“…38,39 Allelic variation in DQ6 alleles has been shown to result in change in T-cell receptor recognition and disease association. 4,40,41 Hence, DQA1*0102 may not contribute to disease susceptibility as DQA1*0102/ DQB1*0604 has not been associated with RA in humans whereas mice expressing DQA1*0103/DQB1*0604 are susceptible to developing arthritis. 17 Indeed, an increased occurrence of DQA1*0103 was observed in juvenile idiopathic seropositive arthritis.…”

Section: Discussionmentioning

confidence: 99%

CD74/DQA1 dimers predispose to the development of arthritis in humanized mice

et al. 2015

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SummaryRheumatoid arthritis (RA) is associated with the presence of certain HLA class II genes. However, why some individuals carrying RA non-associated alleles develop arthritis is still unexplained. The trans-heterodimer between two RA non-associated HLA genes can render susceptibility to develop arthritis in humanized mice, DQA1*0103/DQB1*0604, suggesting a role for DQ a chains in pathogenesis. In this study we determined the role of DQA1 in arthritis by using mice expressing DQA1*0103 and lacking endogenous class II molecules. Proximity ligation assay showed that DQA1*0103 is expressed on the cell surface as a dimer with CD74. Upon immunization with type II collagen, DQA1*0103 mice generated an antigen-specific cellular and humoral response and developed severe arthritis. Structural modelling suggests that DQA1*0103/CD74 form a pocket with similarity to the antigen binding pocket. DQA1*0103 mice present type II collagen-derived peptides that are not presented by an arthritis-resistant DQA1*0103/DQB1*0601 allele, suggesting that the DQA1*0103/CD74 dimer may result in presentation of unique antigens and susceptibility to develop arthritis. The present data provide a possible explanation by which the DQA1 molecule contributes to susceptibility to develop arthritis.

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

Cited by 52 publications

References 58 publications

Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

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

CD74/DQA1 dimers predispose to the development of arthritis in humanized mice

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