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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Alloimmunity and Transplantation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1438285

Antigen-Antibody Complexes Density and Antibody Induced HLA Protein Unfolding Influences FC-Mediated Antibody Effector Function

Provisionally accepted
Tanusya Murali Murali Tanusya Murali Murali 1,2,3*Yue Gu Yue Gu 1,2Rabiatul Adawiyah Minhat Rabiatul Adawiyah Minhat 4Jiawei Yap Jiawei Yap 1,2Kathryn Wood Kathryn Wood 5Cheng-I Wang Cheng-I Wang 4Nick Gascoigne Nick Gascoigne 1,2Anantharaman Vathsala Anantharaman Vathsala 6,7Paul MacAry Paul MacAry 1,2,3
  • 1 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
  • 2 Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Singapore, Singapore
  • 3 NUS-Cambridge Cell Phenotyping Centre, National University of Singapore, Singapore, Singapore
  • 4 Singapore Immunology Network (A*STAR), Singapore, Singapore
  • 5 Transplantation Research Immunology Group, University of Oxford, Transplantation Research Immunology Group, University of Oxford,, Oxford, United Kingdom
  • 6 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
  • 7 National University Centre for Organ Transplantation, National University Hospital, Singapore, Singapore

The final, formatted version of the article will be published soon.

    Donor-specific antibodies (DSA) targeting mismatched HLA molecules are one of the principal threats to long-term graft survival in solid organ transplantation. However, many patients with long-term circulating DSA do not manifest rejection responses suggesting a degree of heterogeneity in their pathogenicity and related functional activity. Immunologic risk stratification of transplant recipients is complicated by challenges intrinsic to defining alloantibody responses that are potentially pathogenic versus those that are not. Thus, a comprehensive understanding of how human alloantibodies target and interact with donor HLA molecules is vital for the development and evaluation of new strategies aimed at reducing antibodymediated rejection responses. In this study, we employ hydrogen-deuterium exchange mass spectrometry (HDXMS), molecular dynamics (MD) simulations, advanced biochemical and biophysical methodologies to thoroughly characterize a panel of human monoclonal alloantibodies and define the influence of Fc-region biology, antibody binding kinetics, target antigen density and structural characteristics on their ability to potentiate the forms of immune effector mechanisms that are strongly implicated in transplant rejection.Our findings have significant implications for our understanding of the key biologic determinants that underlie the pathogenicity or lack thereof of human alloantibodies.

    Keywords: Alloantibodies, Transplantation, Antibody mediated rejection, human leukocyte antigen, Antibody pathogenicity

    Received: 25 May 2024; Accepted: 28 Nov 2024.

    Copyright: © 2024 Murali, Gu, Minhat, Yap, Wood, Wang, Gascoigne, Vathsala and MacAry. 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) or licensor 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: Tanusya Murali Murali, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.