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

Sabouria, Z, Schofield, P, Horikawa, K, Spierings, E, Kipling, D, Randall, KL, Langley, D, Roome, B, Vazquez-Lombardi, R, Rouet, R, Hermes, J, Chan, TD, Brink, R, Dunn-Walters, D, Christ, D and Goodnow, CC (2014) Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity PNAS, 111 (25). E2567-E2575.

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Abstract

The best-understood mechanisms for achieving antibody self/nonself 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
Subjects : Biosciences and Medicine
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
AuthorsEmailORCID
Sabouria, ZUNSPECIFIEDUNSPECIFIED
Schofield, PUNSPECIFIEDUNSPECIFIED
Horikawa, KUNSPECIFIEDUNSPECIFIED
Spierings, EUNSPECIFIEDUNSPECIFIED
Kipling, DUNSPECIFIEDUNSPECIFIED
Randall, KLUNSPECIFIEDUNSPECIFIED
Langley, DUNSPECIFIEDUNSPECIFIED
Roome, BUNSPECIFIEDUNSPECIFIED
Vazquez-Lombardi, RUNSPECIFIEDUNSPECIFIED
Rouet, RUNSPECIFIEDUNSPECIFIED
Hermes, JUNSPECIFIEDUNSPECIFIED
Chan, TDUNSPECIFIEDUNSPECIFIED
Brink, RUNSPECIFIEDUNSPECIFIED
Dunn-Walters, DUNSPECIFIEDUNSPECIFIED
Christ, DUNSPECIFIEDUNSPECIFIED
Goodnow, CCUNSPECIFIEDUNSPECIFIED
Date : 12 May 2014
Identification Number : 10.1073/pnas.1406974111
Copyright Disclaimer : Copyright 2014 National Academy of Sciences
Uncontrolled Keywords : self-tolerance, affinity maturation, clonal selection, autoimmunity
Depositing User : Symplectic Elements
Date Deposited : 06 Jul 2016 14:40
Last Modified : 06 Jul 2016 14:40
URI: http://epubs.surrey.ac.uk/id/eprint/811133

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