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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01913

Repertoire sequencing of B cells elucidates the role of UNG and mismatch repair proteins in somatic hypermutation in humans

  • 1Department of Immunology, Erasmus Medical Center, Netherlands
  • 2Leiden University Medical Center, Netherlands
  • 3Département d'oncologie Médicale, Institut Gustave Roussy, France
  • 4Juliana Children's Hospital, Netherlands
  • 5Olgahospital, Germany
  • 6Center for Human and Clinical Genetics, Leiden University Medical Center, Netherlands
  • 7Poznan University of Medical Sciences, Poland
  • 8Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria
  • 9Division of Pediatric Hemato-Oncology, Department of Pediatric and Adolescent Medicine, University Hospital Graz, Austria
  • 10Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Netherlands
  • 11Immunology, Leiden University Medical Center, Netherlands

The generation of high affinity antibodies depends on somatic hypermutation (SHM). SHM is initiated by the activation induced cytosine deaminase (AID) which generates uracil (U) lesions in the B-cell receptor (BCR) encoding genes. Error-prone processing of U lesions creates a typical spectrum of point mutations during SHM. The aim of this study was to determine the molecular mechanism of SHM in humans, since current knowledge on SHM in humans is limited and is predominantly based on mice data. We collected a unique cohort of ten well-defined patients with bi-allelic mutations in genes involved in base excision repair (UNG), or mismatch repair (MSH2, MSH6, or PMS2) and are the first to present next generation sequencing data of the BCR, allowing us to study SHM extensively in humans. Analysis using ARGalaxy revealed selective skewing of SHM mutation patterns specific for each genetic defect, which are in line with the five pathway model of SHM that was recently proposed based on mice data. However, trans-species comparison revealed differences in the role of PMS2 and MSH2 in strand targeting between mice and man. In conclusion, our results indicate a role for UNG, MSH2, MSH6 and PMS2 in the generation of SHM in humans comparable to their function in mice. However, we observed differences in strand targeting between humans and mice, emphasizing the importance of studying molecular mechanisms in the human setting. The here developed method combining NGS and ARGalaxy analysis of BCR mutation data forms the basis for efficient SHM analyses of other immune deficiencies.

Keywords: B-cells, Somatic Hyper Mutation, DNA Repair, mismatch repair (MMR), base excision repair (BER), immunoglobulin, B-cell receptor (BCR), constitutional mismatch repair deficiency (CMMRD)

Received: 31 May 2019; Accepted: 29 Jul 2019.

Copyright: © 2019 IJspeert, Van Schouwenburg, Pico-Knijnenburg, Brugieres, Driessen, Blattmann, Suerink, Januszkiewicz-Lewandowska, Azizi, SEIDEL, Jacobs and van der Burg. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Mirjam van der Burg, Leiden University Medical Center, Immunology, Leiden, 3015 GE, Netherlands, m.van_der_burg@lumc.nl