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Immunologic Research
Published in: Immunologic Research 1-3/2012

01-09-2012 | Singapore Immunology Network

Structural and functional distinctiveness of HLA-A2 allelic variants

Authors: Kenneth Yuanxiang Chen, Jingxian Liu, Ee Chee Ren

Published in: Immunologic Research | Issue 1-3/2012

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Abstract

Human leukocyte antigen (HLA) class I molecules are involved in the presentation of antigenic peptides to CD8+ cytotoxic T lymphocytes (CTLs), which is important for the development of cellular immunity during viral infections and in cancers. HLA-A2 is one of the most frequent HLA class I specificities and thus is extensively studied structurally and functionally. Since its discovery, more than 300 allelic variants of this HLA specificity have been recorded. Among the HLA-A2 allelic variants, HLA-A*02:01 is the most prevalent, hence commonly used as a model to study HLA-A2-restricted CTL responses. However, HLA-A2 alleles are unevenly distributed globally such that HLA-A2 allelic variants besides A*02:01 are expressed at considerably high frequencies in Asian and African populations. Furthermore, increasing evidence of variations in the peptide-binding repertoire and CTL responses among HLA-A2 allelic variants suggests the need to understand these differences among various frequently expressed HLA-A2 molecules. In this review, the structural and functional distinctiveness of HLA-A2 allelic variants will be discussed.
Literature
1.
2.
Purcell AW, McCluskey J, Rossjohn J. More than one reason to rethink the use of peptides in vaccine design. Nat Rev Drug Discov. 2007;6(5):404–14.PubMedCrossRef
3.
4.
Thorsby E. A short history of HLA. Tissue Antigens. [Historical Article Review]. 2009;74(2):101–16.
5.
Robinson J, Waller MJ, Parham P, de Groot N, Bontrop R, Kennedy LJ, Stoehr P, Marsh SG. IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res. 2003;31(1):311–4.PubMedCrossRef
6.
Ellis JM, Henson V, Slack R, Ng J, Hartzman RJ, Katovich HC. Frequencies of HLA-A2 alleles in five U.S. population groups. Predominance Of A*02011 and identification of HLA-A*0231. Hum Immunol. 2000;61(3):334–40.PubMedCrossRef
7.
Sidney J, Grey HM, Kubo RT, Sette A. Practical, biochemical and evolutionary implications of the discovery of HLA class I supermotifs. Immunol Today. 1996;17(6):261–6.PubMedCrossRef
8.
Mehra NK, Jaini R, Rajalingam R, Balamurugan A, Kaur G. Molecular diversity of HLA-A*02 in Asian Indians: predominance of A*0211. Tissue Antigens. 2001;57(6):502–7.PubMedCrossRef
9.
Middleton D, Williams F, Meenagh A, Daar AS, Gorodezky C, Hammond M, Nascimento E, Briceno I, Perez MP. Analysis of the distribution of HLA-A alleles in populations from five continents. Hum Immunol. 2000;61(10):1048–52.PubMedCrossRef
10.
Browning M, Krausa P. Genetic diversity of HLA-A2: evolutionary and functional significance. Immunol Today. 1996;17(4):165–70.PubMedCrossRef
11.
Macdonald WA, Purcell AW, Mifsud NA, Ely LK, Williams DS, Chang L, Gorman JJ, Clements CS, Kjer-Nielsen L, Koelle DM, Burrows SR, Tait BD, Holdsworth R, Brooks AG, Lovrecz GO, Lu L, Rossjohn J, McCluskey J. A naturally selected dimorphism within the HLA-B44 supertype alters class I structure, peptide repertoire, and T cell recognition. J Exp Med. 2003;198(5):679–91.PubMedCrossRef
12.
Barouch D, Friede T, Stevanovic S, Tussey L, Smith K, Rowland-Jones S, Braud V, McMichael A, Rammensee HG. HLA-A2 subtypes are functionally distinct in peptide binding and presentation. J Exp Med. 1995;182(6):1847–56.PubMedCrossRef
13.
Sudo T, Kamikawaji N, Kimura A, Date Y, Savoie CJ, Nakashima H, Furuichi E, Kuhara S, Sasazuki T. Differences in MHC class I self peptide repertoires among HLA-A2 subtypes. J Immunol. 1995;155(10):4749–56.PubMed
14.
Sidney J, Southwood S, Mann DL, Fernandez-Vina MA, Newman MJ, Sette A. Majority of peptides binding HLA-A*0201 with high affinity crossreact with other A2-supertype molecules. Hum Immunol. 2001;62(11):1200–16.PubMedCrossRef
15.
Krausa P, Brywka M 3rd, Savage D, Hui KM, Bunce M, Ngai JL, Teo DL, Ong YW, Barouch D, Allsop CE, et al. Genetic polymorphism within HLA-A*02: significant allelic variation revealed in different populations. Tissue Antigens. 1995;45(4):223–31.PubMedCrossRef
16.
Shankarkumar U, Prasanavar D, Ghosh K, Mohanty D. HLA A*02 allele frequencies and B haplotype associations in Western Indians. Hum Immunol. 2003;64(5):562–6.PubMedCrossRef
17.
Malavige GN, Rostron T, Seneviratne SL, Fernando S, Sivayogan S, Wijewickrama A, Ogg GS. HLA analysis of Sri Lankan Sinhalese predicts North Indian origin. Int J Immunogenet. 2007;34(5):313–5.PubMedCrossRef
18.
Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. Structure of the human class I histocompatibility antigen, HLA-A2. Nature. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. 1987;329(6139):506–12.
19.
Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. 1987;329(6139):512–8.
20.
Madden DR, Garboczi DN, Wiley DC. The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2. Cell. [In Vitro Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. 1993;75(4):693–708.
21.
Kjer-Nielsen L, Clements CS, Brooks AG, Purcell AW, Fontes MR, McCluskey J, Rossjohn J. The structure of HLA-B8 complexed to an immunodominant viral determinant: peptide-induced conformational changes and a mode of MHC class I dimerization. J Immunol. [Research Support, Non-U.S. Gov’t]. 2002;169(9):5153–60.
22.
Tynan FE, Burrows SR, Buckle AM, Clements CS, Borg NA, Miles JJ, Beddoe T, Whisstock JC, Wilce MC, Silins SL, Burrows JM, Kjer-Nielsen L, Kostenko L, Purcell AW, McCluskey J, Rossjohn J. T cell receptor recognition of a ‘super-bulged’ major histocompatibility complex class I-bound peptide. Nat Immunol. [Research Support, Non-U.S. Gov’t]. 2005;6(11):1114–22.
23.
Blicher T, Kastrup JS, Pedersen LO, Buus S, Gajhede M. Structure of HLA-A*1101 in complex with a hepatitis B peptide homologue. Acta Crystallogr Sect F Struct Biol Cryst Commun. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. 2006;62(Pt 12):1179–84.
24.
Saper MA, Bjorkman PJ, Wiley DC. Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 A resolution. J Mol Biol. [Comparative Study Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. 1991;219(2):277–319.
25.
Matsui M, Moots RJ, McMichael AJ, Frelinger JA. Significance of the six peptide-binding pockets of HLA-A2.1 in influenza A matrix peptide-specific cytotoxic T-lymphocyte reactivity. Human immunology. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. 1994;41(2):160–6.
26.
Rotzschke O, Falk K. Naturally-occurring peptide antigens derived from the MHC class-I-restricted processing pathway. Immunology today. [Research Support, Non-U.S. Gov’t Review]. 1991;12(12):447–55.
27.
Ruppert J, Sidney J, Celis E, Kubo RT, Grey HM, Sette A. Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules. Cell. [Comparative Study]. 1993;74(5):929–37.
28.
Zhang C, Anderson A, DeLisi C. Structural principles that govern the peptide-binding motifs of class I MHC molecules. J Mol Biol. [Research Support, U.S. Gov’t, Non-P.H.S.]. 1998;281(5):929–47.
29.
Nielsen M, Lundegaard C, Blicher T, Lamberth K, Harndahl M, Justesen S, Roder G, Peters B, Sette A, Lund O, Buus S. NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence. PLoS One. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. 2007;2(8):e796.
30.
Zhao B, Png AE, Ren EC, Kolatkar PR, Mathura VS, Sakharkar MK, Kangueane P. Compression of functional space in HLA-A sequence diversity. Hum Immunol. 2003;64(7):718–28.PubMedCrossRef
31.
Liu J, Chen KY, Ren EC. Structural insights into the binding of hepatitis B virus core peptide to HLA-A2 alleles: towards designing better vaccines. Eur J Immunol. [Research Support, Non-U.S. Gov’t]. 2011;41(7):2097–106.
32.
Borbulevych OY, Baxter TK, Yu Z, Restifo NP, Baker BM. Increased immunogenicity of an anchor-modified tumor-associated antigen is due to the enhanced stability of the peptide/MHC complex: implications for vaccine design. J Immunol. 2005;174(8):4812–20.PubMed
33.
Chen JL, Stewart-Jones G, Bossi G, Lissin NM, Wooldridge L, Choi EM, Held G, Dunbar PR, Esnouf RM, Sami M, Boulter JM, Rizkallah P, Renner C, Sewell A, van der Merwe PA, Jakobsen BK, Griffiths G, Jones EY, Cerundolo V. Structural and kinetic basis for heightened immunogenicity of T cell vaccines. J Exp Med. 2005;201(8):1243–55.PubMedCrossRef
34.
Provenzano M, Panelli MC, Mocellin S, Bracci L, Sais G, Stroncek DF, Spagnoli GC, Marincola FM. MHC-peptide specificity and T-cell epitope mapping: where immunotherapy starts. Trends Mol Med. 2006;12(10):465–72.PubMedCrossRef
35.
Sidney J, Peters B, Frahm N, Brander C, Sette A. HLA class I supertypes: a revised and updated classification. BMC Immunol. 2008;9:1.PubMedCrossRef
36.
Brusic V, Petrovsky N, Zhang G, Bajic VB. Prediction of promiscuous peptides that bind HLA class I molecules. Immunol Cell Biol. 2002;80(3):280–5.PubMedCrossRef
37.
Zhang GL, Khan AM, Srinivasan KN, August JT, Brusic V. MULTIPRED: a computational system for prediction of promiscuous HLA binding peptides. Nucleic acids research. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S. Research Support, U.S. Gov’t, P.H.S. Validation Studies]. 2005;33(Web Server issue):W172-9.
38.
Zhu S, Udaka K, Sidney J, Sette A, Aoki-Kinoshita KF, Mamitsuka H. Improving MHC binding peptide prediction by incorporating binding data of auxiliary MHC molecules. Bioinformatics. [Research Support, Non-U.S. Gov’t]. 2006;22(13):1648–55.
39.
Tan AT, Loggi E, Boni C, Chia A, Gehring AJ, Sastry KS, Goh V, Fisicaro P, Andreone P, Brander C, Lim SG, Ferrari C, Bihl F, Bertoletti A. Host ethnicity and virus genotype shape the hepatitis B virus-specific T-cell repertoire. J Virol. 2008;82(22):10986–97.PubMedCrossRef
40.
Bertoni R, Sidney J, Fowler P, Chesnut RW, Chisari FV, Sette A. Human histocompatibility leukocyte antigen-binding supermotifs predict broadly cross-reactive cytotoxic T lymphocyte responses in patients with acute hepatitis. J Clin Investig. [Research Support, U.S. Gov’t, P.H.S.]. 1997;100(3):503–13.
41.
Wentworth PA, Sette A, Celis E, Sidney J, Southwood S, Crimi C, Stitely S, Keogh E, Wong NC, Livingston B, Alazard D, Vitiello A, Grey HM, Chisari FV, Chesnut RW, Fikes J. Identification of A2-restricted hepatitis C virus-specific cytotoxic T lymphocyte epitopes from conserved regions of the viral genome. Int Immunol. [Research Support, U.S. Gov’t, P.H.S.]. 1996;8(5):651–9.
42.
Altfeld MA, Livingston B, Reshamwala N, Nguyen PT, Addo MM, Shea A, Newman M, Fikes J, Sidney J, Wentworth P, Chesnut R, Eldridge RL, Rosenberg ES, Robbins GK, Brander C, Sax PE, Boswell S, Flynn T, Buchbinder S, Goulder PJ, Walker BD, Sette A, Kalams SA. Identification of novel HLA-A2-restricted human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte epitopes predicted by the HLA-A2 supertype peptide-binding motif. J Virol. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. 2001;75(3):1301–11.
43.
Khanna R, Burrows SR, Nicholls J, Poulsen LM. Identification of cytotoxic T cell epitopes within Epstein-Barr virus (EBV) oncogene latent membrane protein 1 (LMP1): evidence for HLA A2 supertype-restricted immune recognition of EBV-infected cells by LMP1-specific cytotoxic T lymphocytes. Eur J Immunol. 1998;28(2):451–8.PubMedCrossRef
44.
Ressing ME, de Jong JH, Brandt RM, Drijfhout JW, Benckhuijsen WE, Schreuder GM, Offringa R, Kast WM, Melief CJ. Differential binding of viral peptides to HLA-A2 alleles. Implications for human papillomavirus type 16 E7 peptide-based vaccination against cervical carcinoma. Eur J Immunol. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. 1999;29(4):1292–303.
45.
Sette A, Vitiello A, Reherman B, Fowler P, Nayersina R, Kast WM, Melief CJ, Oseroff C, Yuan L, Ruppert J, Sidney J, del Guercio MF, Southwood S, Kubo RT, Chesnut RW, Grey HM, Chisari FV. The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J Immunol. [Research Support, U.S. Gov’t, P.H.S.]. 1994;153(12):5586–92.
46.
Rehermann B, Fowler P, Sidney J, Person J, Redeker A, Brown M, Moss B, Sette A, Chisari FV. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis. J Exp Med. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. 1995;181(3):1047–58.
47.
Lee HG, Lim JS, Lee KY, Choi YK, Choe IS, Chung TW, Kim K. Peptide-specific CTL induction in HBV-seropositive PBMC by stimulation with peptides in vitro: novel epitopes identified from chronic carriers. Virus Res. 1997;50(2):185–94.PubMedCrossRef
48.
Chung MK, Yoon H, Min SS, Lee HG, Kim YJ, Lee TG, Lim JS, Kim CM, Park SN. Induction of cytotoxic T lymphocytes with peptides in vitro: identification of candidate T-cell epitopes in hepatitis B virus X antigen. J Immunother. [Comparative Study Research Support, Non-U.S. Gov’t]. 1999;22(4):279–87.
49.
Desmond CP, Bartholomeusz A, Gaudieri S, Revill PA, Lewin SR. A systematic review of T-cell epitopes in hepatitis B virus: identification, genotypic variation and relevance to antiviral therapeutics. Antivir Ther. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Review]. 2008;13(2):161–75.
50.
Payami H, Schellenberg GD, Zareparsi S, Kaye J, Sexton GJ, Head MA, Matsuyama SS, Jarvik LF, Miller B, McManus DQ, Bird TD, Katzman R, Heston L, Norman D, Small GW. Evidence for association of HLA-A2 allele with onset age of Alzheimer’s disease. Neurology. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. 1997;49(2):512–8.
51.
Candore G, Balistreri CR, Colonna-Romano G, Lio D, Caruso C. Major histocompatibility complex and sporadic Alzheimer’s disease: a critical reappraisal. Exp Gerontol. [Research Support, Non-U.S. Gov’t Review]. 2004;39(4):645–52.
52.
Listi F, Candore G, Balistreri CR, Grimaldi MP, Orlando V, Vasto S, Colonna-Romano G, Lio D, Licastro F, Franceschi C, Caruso C. Association between the HLA-A2 allele and Alzheimer disease. Rejuvenation Res. [Research Support, Non-U.S. Gov’t]. 2006;9(1):99–101.
53.
Muto M, Nagai K, Mogami S, Nakano J, Sasazuki T, Asagami C. HLA antigens in Japanese patients with psoriatic arthritis. Tissue Antigens. [Research Support, Non-U.S. Gov’t]. 1995;45(5):362–4.
54.
Muto M, Date Y, Ichimiya M, Moriwaki Y, Mori K, Kamikawaji N, Kimura A, Sasazuki T, Asagami C. Significance of antibodies to streptococcal M protein in psoriatic arthritis and their association with HLA-A*0207. Tissue Antigens. 1996;48(6):645–50.PubMedCrossRef
55.
Liu JB, Li M, Chen H, Zhong SQ, Yang S, Du WD, Hao JH, Zhang TS, Zhang XJ, Zeegers MP. Association of vitiligo with HLA-A2: a meta-analysis. J Eur Acad Dermatol Venereol. [Meta-Analysis]. 2007;21(2):205–13.
56.
Peebles RS, Carpenter CT, Dupont WD, Loyd JE. Mediastinal fibrosis is associated with human leukocyte antigen-A2. Chest. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. 2000;117(2):482–5.
57.
Shiina T, Inoko H, Kulski JK. An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens. [Review]. 2004;64(6):631–49.
58.
Brynedal B, Duvefelt K, Jonasdottir G, Roos IM, Akesson E, Palmgren J, Hillert J. HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS One. [Research Support, Non-U.S. Gov’t]. 2007;2(7):e664.
59.
Link J, Lorentzen AR, Kockum I, Duvefelt K, Lie BA, Celius EG, Harbo HF, Hillert J, Brynedal B. Two HLA class I genes independently associated with multiple sclerosis. J Neuroimmunol. [Research Support, Non-U.S. Gov’t]. 2010;226(1–2):172–6.
60.
Vejbaesya S, Eiermann TH, Suthipinititharm P, Bancha C, Stephens HA, Luangtrakool K, Chandanayingyong D. Serological and molecular analysis of HLA class I and II alleles in Thai patients with psoriasis vulgaris. Tissue Antigens. [Research Support, Non-U.S. Gov’t]. 1998;52(4):389–92.
61.
Yu KJ, Gao X, Chen CJ, Yang XR, Diehl SR, Goldstein A, Hsu WL, Liang XS, Marti D, Liu MY, Chen JY, Carrington M, Hildesheim A. Association of human leukocyte antigens with nasopharyngeal carcinoma in high-risk multiplex families in Taiwan. Human Immunol. [Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural]. 2009;70(11):910–4.
62.
Baumforth KR, Young LS, Flavell KJ, Constandinou C, Murray PG. The Epstein-Barr virus and its association with human cancers. Mol Pathol. [Review]. 1999;52(6):307–22.
63.
Hildesheim A, Apple RJ, Chen CJ, Wang SS, Cheng YJ, Klitz W, Mack SJ, Chen IH, Hsu MM, Yang CS, Brinton LA, Levine PH, Erlich HA. Association of HLA class I and II alleles and extended haplotypes with nasopharyngeal carcinoma in Taiwan. J Natl Cancer Inst. 2002;94(23):1780–9.PubMedCrossRef
64.
Metadata
Title
Structural and functional distinctiveness of HLA-A2 allelic variants
Authors
Kenneth Yuanxiang Chen
Jingxian Liu
Ee Chee Ren
Publication date
01-09-2012
Publisher
Springer-Verlag
Published in
Immunologic Research / Issue 1-3/2012
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI
https://doi.org/10.1007/s12026-012-8295-5

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