Identification of self peptides bound to purified HLA-B27

Jardetzky, Theodore S.; Lane, William S.; Robinson, Ruth A.; Madden, Dean R.; Wiley, Don C.

doi:10.1038/353326a0

Cited by 806 publications

(439 citation statements)

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“…Since peptide-elution studies have shown the HLA-B*2705 B-pocket binds almost exclusively arginine [12,28], variable viruses may thus readily escape immune recognition by any alteration of P2. Interestingly two subtly different mechanisms of binding the P2R have been observed in different crystal structures.…”

Section: Discussionmentioning

confidence: 99%

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Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

et al. 2005

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We have solved the crystal structures of three HLA‐B*2705–peptide complexes with the immunodominant viral peptides: EBV EBNA3C 258–266 (RRIYDLIEL), influenza (flu) nucleoprotein NP383–391 (SRYWAIRTR), and HIV gag 264–273 (KRWIILGLNK). Long‐term non‐progression during HIV infection has been associated with presentation by HLA‐B*2705, and T cell recognition, of the highly immunodominant KRWIILGLNK peptide. The tight hydrogen‐bonding network observed between the HLA‐B*2705 B‐pocket and the peptide P2 arginine guanadinium anchor explains why mutation of this residue during HIV infection results in loss of peptide binding, immune escape and progression to AIDS. Prominent, solvent‐exposed structures within these peptides may participate in generating T cell responses to these immunodominant epitopes. In the HLA‐B*2705 complex with flu NP383–391, the amino acid side chains of residues 4, 7 and 8 are solvent‐exposed whilst in the HIV decamer, the main‐chain bulges into the solvent around P7. Thus, HLA‐B*2705 presents viral peptides in a range of conformations. Tetrameric complexes of HLA‐B*2705 with the HIV and flu but not EBV peptides bound strongly to the killer‐Ig‐like receptor (KIR)3DL1. Substitution of EBV P8 glutamate to threonine allowed recognition by KIR3DL1. In the HLA‐B*2705–EBV structure the P8 glutamate side chain is solvent‐exposed and may inhibit KIR3DL1 binding through electrostatic forces.See accompanying Commentary: http://dx.doi.org/10.1002/eji.200425875

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Section: Discussionmentioning

confidence: 99%

“…Previous crystallographic and peptide-elution studies of HLA-B*2705 derived from tissue culture have demonstrated that HLA-B*2705 almost invariably binds self peptides with an arginine at peptide position 2, this side chain being accommodated in the B-pocket [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

et al. 2005

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“…We first looked for evidence of extended versions of peptides identified in either ERAP1-silenced cells or ERAP1-competent cells. As shown in Table 1 (28,(32)(33)(34).…”

Section: Erap1 In Hla-b27 Peptide Presentation 287mentioning

confidence: 99%

Critical Role of Endoplasmic Reticulum Aminopeptidase 1 in Determining the Length and Sequence of Peptides Bound and Presented by HLA–B27

Chen

Fischer

Peng

et al. 2014

Arthritis & Rheumatology

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Objective. HLA-B27 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are the two strongest genetic factors predisposing to ankylosing spondylitis (AS). A key aminopeptidase in class I major histocompatibility complex presentation, ERAP1 potentially contributes to the pathogenesis of AS by altering HLA-B27 peptide presentation. The aim of this study was to analyze the effects of ERAP1 on the HLA-B27 peptide repertoire and peptide presentation to cytotoxic T lymphocytes (CTLs).Methods. ERAP1-silenced and -competent HeLa.B27 and C1R.B27 cells were isotope-labeled, mixed, lysed, and then immunoprecipitated using W6/32 or ME1 antibodies. Peptides bound to HLA-B27 were eluted and analyzed by tandem mass spectrometry. Selected peptides were synthesized and tested for HLA-B27 binding ability. The effect of ERAP1 silencing/ mutation on presentation of an immunodominant viral HLA-B27 epitope, KK10, to CTLs was also studied.Results. In both HeLa.B27 and C1R.B27 cells, the proportion of 9-mer HLA-B27-bound peptides was decreased by ERAP1 silencing, whereas the percentages of longer peptides (11-13 mer) were increased. Surprisingly, following ERAP1 silencing, C-terminally extended peptides were readily identified. These were better able to bind to HLA-B27 than were N-terminally extended peptides lacking an arginine at position 2. In both HeLa.B27 cells and mouse fibroblasts expressing HLA-B27, the absence of ERAP1 reduced peptide recognition by HLA-B27-restricted KK10-specific CTLs following infection with recombinant vaccinia virus or transfection with minigenes expressing KK10 precursors. Presence of an AS-protective variant of ERAP1, K528R, as compared to wild-type ERAP1, reduced the peptide recognition by KK10 CTLs following transfection with extended KK10 minigenes.Conclusion. These results show that ERAP1 directly alters peptide binding and presentation by HLA-B27, thus demonstrating a potential pathogenic mechanism in AS. Inhibition of ERAP1 could potentially be used for treatment of AS and other ERAP1-associated diseases.The human leukocyte antigen HLA-B27 is very strongly associated with development of the common inflammatory rheumatic disease ankylosing spondylitis (AS). However, the pathogenic mechanism remains unclear. Recent genome-wide association studies have identified additional AS-associated genes, of which the strongest association is with endoplasmic reticulum aminopeptidase 1 (ERAP1) (1). The strong genetic association of AS with ERAP1 single-nucleotide polymorphisms has been confirmed in different populations (2-7).

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“…Several theories have been proposed, including molecular mimicry and involvement of genes closely linked to the HLA-B locus (1). However, none of these, nor the identification of self peptides bound to purified HLA-B27 molecules, has shed any decisive light on the question (2). If HLA-B27 functions as an immune response gene in the pathogenesis of spondylatihropathies, the effect should be apparent in the immune response.…”

Section: Bacterial Antibodies In Hla-b27+ Healthy Individualsmentioning

confidence: 99%

Bacterial antibodies in HLA‐B27+ healthy individuals

Toivanen

Koskimies

Granfors

et al. 1993

Arthritis & Rheumatism

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1633various vehicles or given vehicle alone, all preparations except physiologic saline caused changes in the tissues at the injection site: necrotic muscle tissue, foreign-body reaction, and eventual scar tissue (5). Studies in rabbits demonstrated that the volume of the injection was the major factor in muscle damage (6,7). Damage caused by all aqueous preparations was ameliorated to various degrees by different oil vehicles.From the results of these animal studies, more frequent problems than are seen in practice might be expected. The 2 patients described herein had received large cumulative volumes of ATG in a small area of muscle. Varying the site of injection in large muscle groups results in a low risk of developing oily abscess. Although magnetic resonance imaging would be a sensitive tool for demonstrating an oily abscess, it is much more expensive than a good ultrasound study. Moreover, in the absence of clinical indications, screening seems unnecessary. James M. Sowa, MD, FACR St. Joseph Hospital Towson, MD 1. 2.3. 4. 5. 6.7. Bacterial antibodies in HLA-B27+ healthy individualsThe mechanisms that cause susceptibility to ankylosing spondylitis and reactive arthritis in HLA-B27 + individuals remain unknown. Several theories have been proposed, including molecular mimicry and involvement of genes closely linked to the HLA-B locus (1). However, none of these, nor the identification of self peptides bound to purified HLA-B27 molecules, has shed any decisive light on the question (2). If HLA-B27 functions as an immune response gene in the pathogenesis of spondylatihropathies, the effect should be apparent in the immune response. Thus far, no clear evidence for this has been found (3). The most obvious targets for such an immune response are the microbes identified as etiologic agents for reactive arthritis. These microbes can be readily investigated by available methods. Therefore, we studied HLA-B27+ healthy blood donors for the occurrence of antibodies against various serotypes of Yersinia enterocolitica and Yersinia pseudotuberculosis as well as against Salmonella and Campylobacter jejuni, all known to cause reactive arthritis (4). Klebsiella pneumoniae was also included, due to its potential association in the pathogenesis of ankylosing spondylitis (5). Proteus mirabilis and Escherichia coli, which have no known connection to HLA-BU-associated diseases, were used as control antigens.The occurrence of the serum antibodies was studied in 927 healthy blood donors typed for the HLA class I antigens Al, 2, 3, 9, 10, 11, 19, and 28; B5, 7, 8, 12, 13, 14, 15, 16, 17, 18, 21, 22, 27, 35, 37, 40, 41, and 47; and Cwl-Cw8. Enzyme immunoassay for IgM-, IgG-, and IgAclass antibodies specific for the various microbes was carried out as described earlier (6). Bacterial strains used for antigen preparation, and the sources from which they were obtained, were as follows: Y enterocolitica 0:3 (strain MY 0; S. Winblad , and E coli (strain 8330; a clinical isolate, Turku). For yersiniae, K pneumoniae, P mirabilis, and E...

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Identification of self peptides bound to purified HLA-B27

Cited by 806 publications

References 44 publications

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

Critical Role of Endoplasmic Reticulum Aminopeptidase 1 in Determining the Length and Sequence of Peptides Bound and Presented by HLA–B27

Bacterial antibodies in HLA‐B27+ healthy individuals

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