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Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity

Sabouri, Zahra, Schofield, Peter, Horikawa, Keisuke, Spierings, Emily, Kipling, David Glyn, Randall, Katrina L., Langley, David, Roome, Brendan, Vazquez-Lombardi, Rodrigo, Rouet, Romain, Hermes, Jana, Chan, Tyani D., Brink, Robert, Dunn-Walters, Deborah K., Christ, Daniel and Goodnow, Christopher C. 2014. Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity. Proceedings of the National Academy of Sciences of the United States of America 111 (25) , E2567-E2575. 10.1073/pnas.1406974111

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Abstract

The best-understood mechanisms for achieving antibody self/non-self discrimination discard self-reactive antibodies before they can be tested for binding microbial antigens, potentially creating holes in the repertoire. Here we provide evidence for a complementary mechanism: retaining autoantibodies in the repertoire displayed as low levels of IgM and high IgD on anergic B cells, masking a varying proportion of autoantibody-binding sites with carbohydrates, and removing their self-reactivity by somatic hypermutation and selection in germinal centers (GCs). Analysis of human antibody sequences by deep sequencing of isotype-switched memory B cells or in IgG antibodies elicited against allogeneic RhD+ erythrocytes, vaccinia virus, rotavirus, or tetanus toxoid provides evidence for reactivation of anergic IgMlow IgD+ IGHV4-34+ B cells and removal of cold agglutinin self-reactivity by hypermutation, often accompanied by mutations that inactivated an N-linked glycosylation sequon in complementarity-determining region 2 (CDR2). In a Hy10 antibody transgenic model where anergic B cells respond to a biophysically defined lysozyme epitope displayed on both foreign and self-antigens, cell transfers revealed that anergic IgMlow IgD+ B cells form twice as many GC progeny as naïve IgMhi IgD+ counterparts. Their GC progeny were rapidly selected for CDR2 mutations that blocked 72% of antigen-binding sites with N-linked glycan, decreased affinity 100-fold, and then cleared the binding sites of blocking glycan. These results provide evidence for a mechanism to acquire self/non-self discrimination by somatic mutation away from self-reactivity, and reveal how varying the efficiency of N-glycosylation provides a mechanism to modulate antibody avidity.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: self-tolerance; affinity maturation; clonal selection; autoimmunity
Publisher: National Academy of Sciences
ISSN: 0027-8424
Date of First Compliant Deposit: 23 November 2016
Date of Acceptance: 16 April 2014
Last Modified: 04 Jun 2017 09:07
URI: http://orca-mwe.cf.ac.uk/id/eprint/90749

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