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Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):1901-1906. doi: 10.1073/pnas.1711720115. Epub 2018 Feb 5.

Adaptive antibody diversification through N-linked glycosylation of the immunoglobulin variable region.

Author information

1
Sanquin Research, Department of Immunopathology, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands; s.vandebovenkamp@sanquin.nl.
2
Sanquin Research, Department of Immunopathology, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands.
3
Sanquin Research, Department of Experimental Immunohematology, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands.
4
Erasmus Medical Center, Department of Immunology, University Medical Center Rotterdam, 3015 CE, Rotterdam, The Netherlands.
5
Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000 Belgium.
6
Department of Rheumatology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
7
Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
8
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, 31400 Toulouse, France.

Abstract

A hallmark of B-cell immunity is the generation of a diverse repertoire of antibodies from a limited set of germline V(D)J genes. This repertoire is usually defined in terms of amino acid composition. However, variable domains may also acquire N-linked glycans, a process conditional on the introduction of consensus amino acid motifs (N-glycosylation sites) during somatic hypermutation. High levels of variable domain glycans have been associated with autoantibodies in rheumatoid arthritis, as well as certain follicular lymphomas. However, the role of these glycans in the humoral immune response remains poorly understood. Interestingly, studies have reported both positive and negative effects on antibody affinity. Our aim was to elucidate the role of variable domain glycans during antigen-specific antibody responses. By analyzing B-cell repertoires by next-generation sequencing, we demonstrate that N-glycosylation sites are introduced at positions in which glycans can affect antigen binding as a result of a specific clustering of progenitor glycosylation sites in the germline sequences of variable domain genes. By analyzing multiple human monoclonal and polyclonal (auto)antibody responses, we subsequently show that this process is subject to selection during antigen-specific antibody responses, skewed toward IgG4, and positively contributes to antigen binding. Together, these results highlight a physiological role for variable domain glycosylation as an additional layer of antibody diversification that modulates antigen binding.

KEYWORDS:

Fab glycosylation; antibody diversification; variable domain glycosylation

PMID:
29432186
PMCID:
PMC5828577
DOI:
10.1073/pnas.1711720115
[Indexed for MEDLINE]
Free PMC Article

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