<i>Pocketcheck</i>: updating the <scp>HLA</scp> class I peptide specificity roadmap

Huyton, Trevor; Ladas, Nektarios; Schumacher, Heike; Blasczyk, Rainer; Bade‐Doeding, Christina

doi:10.1111/j.1399-0039.2012.01928.x

Cited by 20 publications

(31 citation statements)

References 23 publications

(31 reference statements)

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Section: Resultsmentioning

confidence: 99%

“…3), where they act to define the sizes and shapes of individual peptide residues accommodated by specific MHC-I molecules (20,21). Collectively these four MHC-I residues physically contact six of nine peptide residues (21), and residues 67 and 116 are critical anchor residues of particular importance in defining the peptide specificity of MHC-I antigen-binding grooves through their interactions with peptide positions P2 and P9, respectively (20,21). Positions 67 and 116 also are critical determinants of the interactions of HLA-B molecules with the killer immunoglobulin-like receptors (KIR) KIR3DL1 and KIR3DS1, which regulate the activation of natural killer (NK) cells and CD8 + cytotoxic T lymphocytes (CTLs) (22).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Ombrello

Kirino

Bakker

et al. 2014

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

122

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The HLA protein, HLA-B*51, encoded by HLA-B in MHC, is the strongest known genetic risk factor for Behçet disease (BD). Associations between BD and other factors within the MHC have been reported also, although strong regional linkage disequilibrium complicates their confident disentanglement from HLA-B*51. In the current study, we examined a combination of directly obtained and imputed MHC-region SNPs, directly obtained HLA-B locus types, and imputed classical HLA types with their corresponding polymorphic amino acid residues for association with BD in 1,190 cases and 1,257 controls. SNP mapping with logistic regression of the MHC identified the HLA-B/MICA region and the region between HLA-F and HLA-A as independently associated with BD (P < 1.7 × 10 −8 ). HLA-B*51, -A*03, -B*15, -B*27, -B*49, -B*57, and -A*26 each contributed independently to BD risk. We directly examined rs116799036, a noncoding SNP upstream of HLA-B that was recently suggested to underlie the association of HLA-B*51 with BD, but we were unable to replicate that finding in our collection. Instead, we mapped the BD association to seven MHC class I (MHC-I) amino acid residues, including anchor residues that critically define the selection and binding of peptides to MHC-I molecules, residues known to influence MHC-Ikiller immunoglobulin-like receptor interactions, and a residue located in the signal peptide of HLA-B. The locations of these variants collectively implicate MHC-I peptide binding in the pathophysiology of BD. Furthermore, several lines of evidence suggest a role for altered regulation of cellular cytotoxicity in BD pathogenesis.HLA imputation | autoinflammation | antigen presentation | killer immunoglobulin-like receptors | natural killer cells

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Ombrello

Kirino

Bakker

et al. 2014

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

122

View full text Add to dashboard Cite

show abstract

“…These four residues contact six of the nine amino acids of the presented peptide antigen and act to define the sizes and shapes of peptides accommodated in the MHC I groove. Additionally, residues 67 and 116 are hypothesized to be critical anchor residues, defining the peptide specificity of MHC I antigen binding via interactions with peptide positions P2 and PX (P9), respectively [23,24]. Moreover, HLA-B residue 67 is one of two amino acids that differ between HLA-B*51 and HLA-B*52, a near-identical HLA-B protein which confers no significant effect on BD risk [13].…”

Section: Pathogenesis Via Altered Peptide Presentationmentioning

confidence: 99%

Is Behçet's disease a ‘class 1-opathy’? The role of HLA-B*51 in the pathogenesis of Behçet's disease

Giza

Koftori

Chen

et al. 2017

Clinical and Experimental Immunology

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Summary The association between carriage of the human leucocyte antigen (HLA)-B*51 allele and development of Behçet's disease (BD) has been known since the early 1970s, but the exact mechanisms responsible for its role in pathogenesis remain much-debated. In an effort to explain the disease process, it has been suggested that BD constitutes one of a newly termed group of diseases, the ‘MHC-I-opathies’. Other MHC-I-opathies include ankylosing spondylitis and HLA-B*27-associated spondyloarthropathies and HLA-C*0602-associated skin psoriasis. Recent work analysing the peptidome of HLA-B*51 suggests that altered peptide presentation by HLA-B*51 is vital to the disease process. In this review, we argue that immune receptor interactions with HLA-B*51 or the HLA-B*51-peptide complex could lead to development of inflammation in BD. The evidence for CD8+ T cell involvement is weak, and based on emerging studies it seems more likely that natural killer (NK) or other cell interactions, perhaps mediated by leucocyte immunoglobulin-like receptor (LILR) or killer immunoglobulin-like receptor (KIR) receptors, are culpable in pathogenesis. HLA misfolding leading directly to inflammation is another hypothesis for BD pathogenesis that deserves greater investigation. Ultimately, greater understanding of HLA-B*51's unique role in BD will probably lead to improved development of therapeutic strategies.

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“…Our previously described bioinformatic tool "Pocketcheck" [8] is a database of contact data for deposited HLA-class I crystal structures and highlights those heavy chain residues that frequently contact particular peptide residue positions [8]. From these data it is clear that position 156 can contact positions 3, 4, 5, 6 and/or 7 of a bound peptide but is unable to directly contact the C-terminal (PΩ) position of a peptide.…”

Section: Molecular Modelling Of the B*44:35 156glu Micropolymorphismmentioning

confidence: 99%

Differential Impact of HLA-B*44 Allelic Mismaches at Position 156 on Peptide Binding Specificities and T-Cell Diversity

Badrinath¹,

Huyton

Kunze‐Schumacher³

et al. 2014

J Stem Cell Res Ther

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The molecular understanding of how we can mismatch patients and donors and still have successful clinical outcomes will help to guide the future of unrelated bone-marrow transplantation.Single amino acid mismatches at position 156 on the alpha 2 helix of B*44 variants have been described to cause immunological episodes. The magnitude of permissivity between B44/156 variants differs from peptide presentation independent of the peptide loading complex (B*44:28) to influencing clinical episodes (B*44:02 vs. B*44:03). We here investigated if the single exchange of an Asp>Glu as occurring in B*44:35 at residue 156 would force an immune response in vitro.We developed an in vitro system by recombinant co-expression of a single membrane-bound allogeneic HLA class I molecule in donor cells and co-incubating these cells with autologous T-cells. This strategy enables the study of single HLA class I mismatches and excludes the influence of minor antigens. We found these T-cells to be able to differentially discriminate between mismatched B*44 subtypes and their micropolymorphism. To understand how certain pHLA landscapes shaping the alloreactive immune response, we sequenced the individual peptides derived from B*44/156 subtypes using LC-ESI-MS/MS technology. Based on the peptide data we modeled the structure of the B*44:35 variant and can describe the unexpected immunological reaction of the mismatched B*44 subtypes through structural manipulation of the heavy chain.The meticulous characterization of peptide-binding profiles for key alleles, as well as the evaluation of T-cell responses and structural analysis in the context of one-allele mismatches will open the door to a new era in bonemarrow transplantation.

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Pocketcheck: updating the HLA class I peptide specificity roadmap

Cited by 20 publications

References 23 publications

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Is Behçet's disease a ‘class 1-opathy’? The role of HLA-B*51 in the pathogenesis of Behçet's disease

Differential Impact of HLA-B*44 Allelic Mismaches at Position 156 on Peptide Binding Specificities and T-Cell Diversity

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