1887

Chapter 113 : Molecular Methods for Human Leukocyte Antigen Typing: Current Practices and Future Directions

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $30.00

Preview this chapter:
Zoom in
Zoomout

Molecular Methods for Human Leukocyte Antigen Typing: Current Practices and Future Directions, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555818722/9781555818715_CH113-1.gif /docserver/preview/fulltext/10.1128/9781555818722/9781555818715_CH113-2.gif

Abstract:

The characterization and clinical assessment of the human leukocyte antigen (HLA) genes has undergone significant advances over the last 50 years. As serological methods have given way to more-advanced molecular methods, our understanding of the complexity and polymorphic nature of the HLA genes has been substantially improved. From its basis in serological and cellular testing in the 1960s (antibody and mixed lymphocyte culture) (1–5), through two-dimensional electrophoresis and restriction fragment length polymorphism analysis in the 1970s and '80s (5, 6), the development of PCR in the mid-1980s revolutionized our molecular understanding of the HLA genes. From PCR, methods utilizing sequence-specific oligonucleotide probes (SSOs) and sequence-specific primers (SSPs) provided the means for more directly evaluating the highly variable sequence motifs within the HLA genes (7–10). Subsequently, in the 1990s, Sanger sequence-based typing (SBT) significantly advanced tissue typing and transplantation genetics (11–14) by providing an unprecedented molecular view of HLA polymorphism in the context of exonic variation. Most recently, next-generation sequencing (NGS) appears to definitively address HLA typing complexity, as it provides entire HLA gene characterization and haploid sequence determination.

Citation: Kunkel M, Duke J, Ferriola D, Lind C, Monos D. 2016. Molecular Methods for Human Leukocyte Antigen Typing: Current Practices and Future Directions, p 1069-1090. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch113
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of FIGURE 1
FIGURE 1

Structure of HLA class I and class II genes.

Citation: Kunkel M, Duke J, Ferriola D, Lind C, Monos D. 2016. Molecular Methods for Human Leukocyte Antigen Typing: Current Practices and Future Directions, p 1069-1090. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch113
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2
FIGURE 2

HLA nomenclature. Courtesy of Steven G. E. Marsh, Anthony Nolan Research Institute, London, United Kingdom.

Citation: Kunkel M, Duke J, Ferriola D, Lind C, Monos D. 2016. Molecular Methods for Human Leukocyte Antigen Typing: Current Practices and Future Directions, p 1069-1090. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch113
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3
FIGURE 3

Examples of molecular HLA typing techniques and their methods of interrogating the HLA genes. For any given HLA gene (dark blue rectangles), SSOs of ~20 bp (light blue lines) can provide single-nucleotide resolution of haplotype differences (polymorphic differences, red lines in exon 2), but this results in a complex panel of oligonucleotide probes to discern differences between HLA alleles. This probe set is static and therefore cannot adjust to novel alleles. SSPs (orange arrows) can provide haplotype- or allele-specific resolution of nucleotide differences and additionally provide some level of phasing between polymorphic sites. As with SSOs, these oligonucleotide sets are complex and static, limiting their flexibility. SBT provides whole-exon information on the polymorphic content of the HLA allele (amplification primers [dark green] and sequencing primers [light green arrows]) but cannot discern phasing, as this method generally does not rely on allele-specific primers for amplification as a first step. NGS provides whole-gene amplification (amplification primers, purple arrows) and detection of polymorphic content for any HLA allele (known or unknown) and provides significant phasing between polymorphic sites that are within the read lengths of the system being used (usually between 200 and 1,000 bp). This is accomplished through the alignment of thousands of short overlapping reads that are combined to form a single consensus sequence (blue lines).

Citation: Kunkel M, Duke J, Ferriola D, Lind C, Monos D. 2016. Molecular Methods for Human Leukocyte Antigen Typing: Current Practices and Future Directions, p 1069-1090. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch113
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4
FIGURE 4

(A) Detection of fluorescent terminating nucleotides in a capillary sequencer. (B) Determination of sequence from terminal dideoxy labeling.

Citation: Kunkel M, Duke J, Ferriola D, Lind C, Monos D. 2016. Molecular Methods for Human Leukocyte Antigen Typing: Current Practices and Future Directions, p 1069-1090. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch113
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 5
FIGURE 5

NGS read and FASTQ representation.

Citation: Kunkel M, Duke J, Ferriola D, Lind C, Monos D. 2016. Molecular Methods for Human Leukocyte Antigen Typing: Current Practices and Future Directions, p 1069-1090. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch113
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 6
FIGURE 6

Depth of coverage as derived from NGS reads. NGS reads (whether single or paired-end) are aligned to a consensus reference sequence (Ref.Seq.) to form an overlapping, stacked view of the coverage at any given nucleotide position. The number of reads at any given position represents the depth of coverage and is derived by the number of overlapping reads at that nucleotide position. Read depth at polymorphic positions is split between the reference sequence and the alternative allele (blue and orange bars) and indicates allelic representation.

Citation: Kunkel M, Duke J, Ferriola D, Lind C, Monos D. 2016. Molecular Methods for Human Leukocyte Antigen Typing: Current Practices and Future Directions, p 1069-1090. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch113
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555818722.ch113
1. Terasaki PI, McClelland JD. 1964. Microdroplet assay of human serum cytotoxins. Nature 204:9981000.[CrossRef]
2. Mittal KK, Mickey MR, Singal DP, Terasaki PI. 1968. Serotyping for homotransplantation. 18. Refinement of microdroplet lymphocyte cytotoxicity test. Transplantation 6:913927.[PubMed].[CrossRef]
3. Biddison WE, Kostyu DD, Strominger JL, Krangel MS. 1982. Delineation of immunologically and biochemically distinct HLA-A2 antigens. J Immunol 129:730734.[PubMed]
4. Mölders HH, Breuning MH, Ivanyi P, Ploegh HL. 1983. Biochemical analysis of variant HLA-B27 antigens. Hum Immunol 6:111117.[PubMed].[CrossRef]
5. Monos DS, Tekolf WA, Shaw S, Cooper HL. 1984. Comparison of structural and functional variation in class I HLA molecules: the role of charged amino acid substitutions. J Immunol 132:13791385.[PubMed]
6. Kim SJ, Holbeck SL, Nisperos B, Hansen JA, Maeda H, Nepom GT. 1985. Identification of a polymorphic variant associated with HLA-DQw3 and characterized by specific restriction sites within the DQ β-chain gene. Proc Natl Acad Sci USA 82:81398143.[PubMed].[CrossRef]
7. Olerup O, Zetterquist H. 1992. HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens 39:225235.[PubMed].[CrossRef]
8. Bunce M, Taylor CJ, Welsh KI. 1993. Rapid HLA-DQB typing by eight polymerase chain reaction amplifications with sequence-specific primers (PCR-SSP). Hum Immunol 37:201206.[PubMed].[CrossRef]
9. Wordsworth BP, Allsopp CE, Young RP, Bell JI. 1990. HLA-DR typing using DNA amplification by the polymerase chain reaction and sequential hybridization to sequence-specific oligonucleotide probes. Immunogenetics 32:413418.[PubMed]
10. Scharf SJ, Griffith RL, Erlich HA. 1991. Rapid typing of DNA sequence polymorphism at the HLA-DRB1 locus using the polymerase chain reaction and nonradioactive oligonucleotide probes. Hum Immunol 30:190201.[PubMed].[CrossRef]
11. Cereb N, Maye P, Lee S, Kong Y, Yang SY. 1995. Locus-specific amplification of HLA class I genes from genomic DNA: locus-specific sequences in the first and third introns of HLA-A, -B, and -C alleles. Tissue Antigens 45:111.[PubMed].[CrossRef]
12. Petersdorf EW, Hansen JA. 1995. A comprehensive approach for typing the alleles of the HLA-B locus by automated sequencing. Tissue Antigens 46:7385.[PubMed].[CrossRef]
13. van der Vlies SA, Voorter CE, van den Berg-Loonen EM. 1998. A reliable and efficient high resolution typing method for HLA-C using sequence-based typing. Tissue Antigens 52:558568.[PubMed].[CrossRef]
14. Kurz B, Steiert I, Heuchert G, Müller CA. 1999. New high resolution typing strategy for HLA-A locus alleles based on dye terminator sequencing of haplotypic group-specific PCR-amplicons of exon 2 and exon 3. Tissue Antigens 53:8196.[PubMed].[CrossRef]
15. Dausset J. 1958. Iso-leuco-antibodies. Acta Haematol 20:156166. (In French.)[PubMed].[CrossRef]
16. Park I, Terasaki P. 2000. Origins of the first HLA specificities. Hum Immunol 61:185189.[PubMed].[CrossRef]
17. International Histocompatibility Working Group. 2016. History. International Histocompatibility Working Group, Seattle, WA. http://www.ihwg.org/about/history.html.
18. Sengar DP, Mickey MR, Myhre BA, Chen HH, Terasaki PI. 1971. Mixed leukocyte culture response in HL-A. “Identical individuals”. Transfusion 11:251257.[PubMed].[CrossRef]
19. Hämmerling GJ. 1997. The 1996 Nobel Prize to Rolf Zinkernagel and Peter Doherty. Cell Tissue Res 287:12.[PubMed]
20. Zinkernagel RM, Doherty PC. 1997. The discovery of MHC restriction. Immunol Today 18:1417.[PubMed].[CrossRef]
21. Bjorkman PJ, Strominger JL, Wiley DC. 1985. Crystallization and X-ray diffraction studies on the histocompatibility antigens HLA-A2 and HLA-A28 from human cell membranes. J Mol Biol 186:205210.[PubMed].[CrossRef]
22. Garrett TP, Saper MA, Bjorkman PJ, Strominger JL, Wiley DC. 1989. Specificity pockets for the side chains of peptide antigens in HLA-Aw68. Nature 342:692696.[CrossRef].[PubMed]
23. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. 1987. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 329:512518.[CrossRef].[PubMed]
24. Trowsdale J, Knight JC. 2013. Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet 14:301323.[CrossRef].[PubMed]
25. Avidan N, Le Panse R, Berrih-Aknin S, Miller A. 2014. Genetic basis of myasthenia gravis—a comprehensive review. J Autoimmun 52:146153.[CrossRef].[PubMed]
26. Raychaudhuri S, Sandor C, Stahl EA, Freudenberg J, Lee HS, Jia X, Alfredsson L, Padyukov L, Klareskog L, Worthington J, Siminovitch KA, Bae SC, Plenge RM, Gregersen PK, de Bakker PI. 2012. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet 44:291296.[CrossRef].[PubMed]
27. Traherne JA. 2008. Human MHC architecture and evolution: implications for disease association studies. Int J Immunogenet 35:179192.[CrossRef].[PubMed]
28. Karlin E, Phillips E. 2014. Genotyping for severe drug hypersensitivity. Curr Allergy Asthma Rep 14:418. doi:10.1007/s11882-013-0418-0.[CrossRef].[PubMed] http://dx.doi.org/doi:10.1007/s11882-013-0418-0
29. Yip VL, Alfirevic A, Pirmohamed M. 2015. Genetics of immune-mediated adverse drug reactions: a comprehensive and clinical review. Clin Rev Allergy Immunol 48:165175.[CrossRef].[PubMed]
30. Horton R, Wilming L, Rand V, Lovering RC, Bruford EA, Khodiyar VK, Lush MJ, Povey S, Talbot CC Jr, Wright MW, Wain HM, Trowsdale J, Ziegler A, Beck S. 2004. Gene map of the extended human MHC. Nat Rev Genet 5:889899.[CrossRef].[PubMed]
31. Yasukochi Y, Satta Y. 2013. Current perspectives on the intensity of natural selection of MHC loci. Immunogenetics 65:479483.[CrossRef].[PubMed]
32. Cano P, Klitz W, Mack SJ, Maiers M, Marsh SG, Noreen H, Reed EF, Senitzer D, Setterholm M, Smith A, Fernández-Viña M. 2007. Common and well-documented HLA alleles: report of the Ad-Hoc committee of the American Society for Histocompatiblity and Immunogenetics. Hum Immunol 68:392417.[CrossRef].[PubMed]
33. Mack SJ, Cano P, Hollenbach JA, He J, Hurley CK, Middleton D, Moraes ME, Pereira SE, Kempenich JH, Reed EF, Setterholm M, Smith AG, Tilanus MG, Torres M, Varney MD, Voorter CE, Fischer GF, Fleischhauer K, Goodridge D, Klitz W, Little AM, Maiers M, Marsh SG, Müller CR, Noreen H, Rozemuller EH, Sanchez-Mazas A, Senitzer D, Trachtenberg E, Fernandez-Vina M. 2013. Common and well-documented HLA alleles: 2012 update to the CWD catalogue. Tissue Antigens 81:194203.[CrossRef].[PubMed]
34. Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Geraghty DE, Hansen JA, Hurley CK, Mach B, Mayr WR, Parham P, Petersdorf EW, Sasazuki T, Schreuder GM, Strominger JL, Svejgaard A, Terasaki PI, Trowsdale J. 2005. Nomenclature for factors of the HLA system, 2004. Tissue Antigens 65:301369.[CrossRef].[PubMed]
35. Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Fernández-Viña M, Geraghty DE, Holdsworth R, Hurley CK, Lau M, Lee KW, Mach B, Maiers M, Mayr WR, Müller CR, Parham P, Petersdorf EW, Sasazuki T, Strominger JL, Svejgaard A, Terasaki PI, Tiercy JM, Trowsdale J. 2010. Nomenclature for factors of the HLA system, 2010. Tissue Antigens 75:291455.[CrossRef].[PubMed]
36. Nunes E, Heslop H, Fernandez-Vina M, Taves C, Wagenknecht DR, Eisenbrey AB, Fischer G, Poulton K, Wacker K, Hurley CK, Noreen H, Sacchi N Harmonization of Histocompatibility Typing Terms Working Group. 2011. Definitions of histocompatibility typing terms: Harmonization of Histocompatibility Typing Terms Working Group. Hum Immunol 72:12141216.[CrossRef].[PubMed]
37. Holcomb CL, Höglund B, Anderson MW, Blake LA, Böhme I, Egholm M, Ferriola D, Gabriel C, Gelber SE, Goodridge D, Hawbecker S, Klein R, Ladner M, Lind C, Monos D, Pando MJ, Pröll J, Sayer DC, Schmitz-Agheguian G, Simen BB, Thiele B, Trachtenberg EA, Tyan DB, Wassmuth R, White S, Erlich HA. 2011. A multi-site study using high-resolution HLA genotyping by next generation sequencing. Tissue Antigens 77:206217.[CrossRef].[PubMed]
38. Gabriel C, Danzer M, Hackl C, Kopal G, Hufnagl P, Hofer K, Polin H, Stabentheiner S, Pröll J. 2009. Rapid high-throughput human leukocyte antigen typing by massively parallel pyrosequencing for high-resolution allele identification. Hum Immunol 70:960964.[CrossRef].[PubMed]
39. Bentley G, Higuchi R, Hoglund B, Goodridge D, Sayer D, Trachtenberg EA, Erlich HA. 2009. High-resolution, high-throughput HLA genotyping by next-generation sequencing. Tissue Antigens 74:393403.[CrossRef].[PubMed]
40. Lind C, Ferriola D, Mackiewicz K, Heron S, Rogers M, Slavich L, Walker R, Hsiao T, McLaughlin L, D'Arcy M, Gai X, Goodridge D, Sayer D, Monos D. 2010. Next-generation sequencing: the solution for high-resolution, unambiguous human leukocyte antigen typing. Hum Immunol 71:10331042.[CrossRef].[PubMed]
41. De Santis D, Dinauer D, Duke J, Erlich HA, Holcomb CL, Lind C, Mackiewicz K, Monos D, Moudgil A, Norman P, Parham P, Sasson A, Allcock RJ. 2013. 16th IHIW: review of HLA typing by NGS. Int J Immunogenet 40:7276.[CrossRef].[PubMed]
42. Wang C, Krishnakumar S, Wilhelmy J, Babrzadeh F, Stepanyan L, Su LF, Levinson D, Fernandez-Viña MA, Davis RW, Davis MM, Mindrinos M. 2012. High-throughput, high-fidelity HLA genotyping with deep sequencing. Proc Natl Acad Sci USA 109:86768681.[CrossRef].[PubMed]
43. Gabriel C, Fürst D, Faé I, Wenda S, Zollikofer C, Mytilineos J, Fischer GF. 2014. HLA typing by next-generation sequencing—getting closer to reality. Tissue Antigens 83:6575.[CrossRef].[PubMed]
44. Glasel JA. 1995. Validity of nucleic acid purities monitored by 260nm/280nm absorbance ratios. Biotechniques 18:6263.[PubMed]
45. Ginevri F, Nocera A, Comoli P, Innocente A, Cioni M, Parodi A, Fontana I, Magnasco A, Nocco A, Tagliamacco A, Sementa A, Ceriolo P, Ghio L, Zecca M, Cardillo M, Garibotto G, Ghiggeri GM, Poli F. 2012. Posttransplant de novo donor-specific hla antibodies identify pediatric kidney recipients at risk for late antibody-mediated rejection. Am J Transplant 12:33553362.[CrossRef].[PubMed]
46. Katerinis I, Hadaya K, Duquesnoy R, Ferrari-Lacraz S, Meier S, van Delden C, Martin PY, Siegrist CA, Villard J. 2011. De novo anti-HLA antibody after pandemic H1N1 and seasonal influenza immunization in kidney transplant recipients. Am J Transplant 11:17271733.[CrossRef].[PubMed]
47. O'Leary JG, Kaneku H, Susskind BM, Jennings LW, Neri MA, Davis GL, Klintmalm GB, Terasaki PI. 2011. High mean fluorescence intensity donor-specific anti-HLA antibodies associated with chronic rejection postliver transplant. Am J Transplant 11:18681876.[CrossRef].[PubMed]
48. Bunce M, O'Neill CM, Barnardo MC, Krausa P, Browning MJ, Morris PJ, Welsh KI. 1995. Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCR-SSP). Tissue Antigens 46:355367.[PubMed].[CrossRef]
49. Duke JL, Lind C, Mackiewicz K, Ferriola D, Papazoglou A, Derbeneva O, Wallace D, Monos DS. 2015. Towards allele-level human leucocyte antigens genotyping—assessing two next-generation sequencing platforms: Ion Torrent Personal Genome Machine and Illumina MiSeq. Int J Immunogenet 42:346358.[CrossRef].[PubMed]
50. Major E, Rigó K, Hague T, Bérces A, Juhos S. 2013. HLA typing from 1000 Genomes whole genome and whole exome Illumina data. PLoS One 8:e78410. doi:10.1371/journal.pone.0078410.[CrossRef].[PubMed] http://dx.doi.org/doi:10.1371/journal.pone.0078410

Tables

Generic image for table
TABLE 1

HLA genes, gene fragments, and pseudogenes

Citation: Kunkel M, Duke J, Ferriola D, Lind C, Monos D. 2016. Molecular Methods for Human Leukocyte Antigen Typing: Current Practices and Future Directions, p 1069-1090. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch113
Generic image for table
TABLE 2

Advantages and disadvantages of molecular methods for HLA typing and of NGS platforms

Citation: Kunkel M, Duke J, Ferriola D, Lind C, Monos D. 2016. Molecular Methods for Human Leukocyte Antigen Typing: Current Practices and Future Directions, p 1069-1090. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch113
Generic image for table
TABLE 3

Summary of NGS platform capabilities

Citation: Kunkel M, Duke J, Ferriola D, Lind C, Monos D. 2016. Molecular Methods for Human Leukocyte Antigen Typing: Current Practices and Future Directions, p 1069-1090. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch113

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error