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High-Throughput Immunogenetics for Clinical and Research Applications in Immunohematology: Potential and Challenges

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High-Throughput Immunogenetics for Clinical and Research Applications in Immunohematology: Potential and Challenges High-Throughput Immunogenetics for Clinical and Research Applications in Immunohematology: Potential and Challenges This information is current as of September 29, 2021. Anton W. Langerak, Monika Brüggemann, Frédéric Davi, Nikos Darzentas, Jacques J. M. van Dongen, David Gonzalez, Gianni Cazzaniga, Véronique Giudicelli, Marie-Paule Lefranc, Mathieu Giraud, Elizabeth A. Macintyre, Michael Hummel, Christiane Pott, Patricia J. T. A. Groenen, Kostas Stamatopoulos and the Downloaded from EuroClonality-NGS Consortium J Immunol published online 17 April 2017 http://www.jimmunol.org/content/early/2017/04/16/jimmun ol.1602050 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 29, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published April 17, 2017, doi:10.4049/jimmunol.1602050 High-Throughput Immunogenetics for Clinical and Research Applications in Immunohematology: Potential and Challenges € † ´ ´ ‡ x Anton W. Langerak,* Monika Bruggemann,{ Frederic Davi, Nikos‖ Darzentas, JacquesJ.M.vanDongen,*DavidGonzalez, Gianni Cazzaniga, Ve´ronique Giudicelli,# # †† ‡‡ Marie-Paule Lefranc, Mathieu Giraud,** Elizabethxx A. Macintyre, Michael{{ Hummel, Christiane Pott,† Patricia J. T. A. Groenen, Kostas Stamatopoulos, and the EuroClonality-NGS Consortium1 Analysis and interpretation of Ig and TCR gene rear- (IG/TR) diversity is the combined effect of molecular [mainly rangements in the conventional, low-throughput way V(D)J recombination] and cellular diversification processes Downloaded from have their limitations in terms of resolution, coverage, during maturation of B and T lymphocytes (1–5). and biases. With the advent of high-throughput, next- The result of Ag-independent B and T lymphocyte differ- generation sequencing (NGS) technologies, a deeper anal- entiation and diversification that occurs in bone marrow and ysis of Ig and/or TCR (IG/TR) gene rearrangements is thymus is a broadly diverse, polyclonal repertoire of Ag-specific receptors (naive or primary repertoire), whereas Ag-dependent now within reach, which impacts on all main applications http://www.jimmunol.org/ of IG/TR immunogenetic analysis. To bridge the gener- maturation in the periphery further shapes the IG/TR repertoire ation gap from low- to high-throughput analysis, the through selection processes (immunocompetent or antigen- EuroClonality-NGS Consortium has been formed, with experienced repertoire) (6, 7). IG/TR polyclonality is one end the main objectives to develop, standardize, and validate of a continuum of immune profiles (Fig. 1A). Upon Ag-specific triggering and during inflammation certain IG/TR specificities the entire workflow of IG/TR NGS assays for 1) clon- canpredominateandleadtooneormoresmallclones(i.e.,the ality assessment, 2) minimal residual disease detection, offspring of particular B or T lymphocytes) on top of the poly- and 3) repertoire analysis. This concerns the preanalytical clonal repertoire, thus reflecting a more oligoclonal immune (sample preparation, target choice), analytical (amplifica- profile. At the other end of the continuum, significant outgrowth by guest on September 29, 2021 tion, NGS), and postanalytical (immunoinformatics) phases. of a single lymphocyte clone with particular Ag specificity would Here we critically discuss pitfalls and challenges of IG/TR lead to a monoclonal immune profile, the hallmark of lymphoid NGS methodology and its applications in hemato-oncology malignancies (Fig. 1A). and immunology. The Journal of Immunology, 2017, In view of the extensive diversification mechanisms, the 198: 000–000. probability that two independent B or T cell clones carry exactly the same IG/TR gene rearrangement by chance alone is virtually pecific Ag recognition of the adaptive immune system negligible. IG/TR gene rearrangements thus form unique ge- is mediated by a remarkably diverse repertoire of Ag netic markers that can be justifiably viewed as molecular sig- S receptors—Igs on B lymphocytes (plus Abs secreted natures (DNA fingerprints), which have been instrumental for by plasma cells) and TCRs on T lymphocytes—showing high understanding both normal and pathologic immune responses affinity for a particular Ag. Fundamental to Ig and/or TCR (8–22). In addition, the spectrum of IG/TR repertoire diversity *Department of Immunology, Laboratory for Medical Immunology, Erasmus MC, ORCIDs: 0000-0002-2078-3220 (A.W.L.); 0000-0003-0580-5636 (D.G.); 0000-0003- University Medical Center, 3015 CN Rotterdam, the Netherlands; †Second Medical 2955-4528 (G.C.); 0000-0003-2741-8047 (M.G.); 0000-0003-0520-0493 (E.A.M.). Department,UniversityHospitalSchleswig-Holstein,24105Kiel,Germany; Received for publication December 15, 2016. Accepted for publication January 9, 2017. ‡De´partement d’He´matologie, Assistance Publique – Hoˆpitaux de Paris Hopital Pitie´- Salpeˆtrie`re and Universite´ Pierre et Marie Curie – Universite´ Paris IV, 75005 Paris, See related articles in this issue: IJspeert et al. (J. Immunol. 198, 4156; DOI: https://doi. x France; Molecular Medicine Program, Central European Institute of Technology, org/10.4049/jimmunol.1601921) and Boyer et al. (J. Immunol. 198, 4148; DOI: { Masaryk University, 625 00 Brno, Czech Republic; Centre for Cancer Research and https://doi.org/10.4049/jimmunol.1601924). ‖ Cell Biology, Queen’s University Belfast, Belfast BT9 7AE, United Kingdom; Centro This work was supported by EuroClonality. Ricerca Tettamanti, Clinica Pediatrica Universita` Milano-Bicocca, 20900 Monza, Italy; #UMR 9002 CNRS – Universite´ de Montpellier, 34396 Montpellier, France; **Centre Address correspondence and reprint requests to Dr. Anton W. Langerak, Laboratory for de Recherche en Informatique Signal et Automatique de Lille, CNRS, Universite´ de Medical Immunology, Department of Immunology, Erasmus MC, University Medical Lille, 59000 Lille, France; ††De´partement d’He´matologie, Assistance Publique – Hoˆpitaux Center, Nb-1248a, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands. E-mail de Paris Necker-Enfants Malades and Paris Descartes, 75015 Paris, France; ‡‡Institut fur€ address: [email protected] xx Pathologie, Charite´ – Universita¨tsmedizin Berlin, D-10117 Berlin, Germany; Department Abbreviations used in this article: ALL, acute lymphoblastic leukemia; CLL, chronic of Pathology, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, {{ lymphocytic leukemia; FL, follicular lymphoma; IG/TR, Ig and/or TCR; MRD, min- the Netherlands; and Institute of Applied Biosciences, Center for Research and imal residual disease; NGS, next-generation sequencing; RepSeq, Repertoire Sequencing; Technology Hellas, GR-57001 Thessaloniki, Greece RQ-PCR, real-time quantitative PCR; SHM, somatic hypermutation. 1All listed authors are members of the EuroClonality-NGS Consortium and have written this article on behalf of the entire consortium. Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1602050 2 HIGH-THROUGHPUT IMMUNOGENETICS IN IMMUNOHEMATOLOGY nological conditions, although the true diversity of the IG/TR repertoire is mostly only partly disclosed using low-throughput Sanger-based sequencing. Nevertheless, clonal repertoire analysis has proven clinically relevant, as exemplified by chronic lym- phocytic leukemia (CLL) where identifying IGHV gene muta- tional status is established as one of the most robust prognostic markers in CLL (standardized by the European Research Ini- tiative on CLL [termed ERIC]; ericll.org) (41, 42). Even though many of the low-throughput IG/TR assays have thus been optimized and standardized to a high level, inherently they may occasionally provide suboptimal and even misleading results. Depending on the diagnostic application, the causes of concern as well as the issues at stake are different. However, fundamental to all is the enormous potential di- versity of IG/TR gene rearrangements necessitating the use of multiplex PCR assays with multiple primers that—even in the most optimal situation—are always a compromise. Indeed, PCR biases due to differential performance or misannealing Downloaded from of primers can lead to artificial asymmetries with regard to gene frequencies, resulting in a false impression of repertoire FIGURE 1. IG/TR repertoire diversity translating into clinical applications skewing or even clonality status. The use of consensus primers in low-throughput methodology and high-throughput immunogenetics. (A) in the amplification protocols, though practical, implies a less Continuum of IG/TR repertoire diversity ranging from true polyclonality (far than complete coverage and thus a less comprehensive view of left end) through oligoclonality and low level clonality (middle) to clear repertoire diversity. Moreover, consensus
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