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

Abstract

The best understood mechanisms for achieving antibody selfnonself 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 centres (GCs). Analysis of human antibody sequences by deep sequencing of isotypeswitched 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 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-nonself discrimination by somatic mutation away from self-reactivity, and reveal how varying the efficiency of N-glycosylation provides a mechanism to modulate antibody avidity.

Type Journal
Authors Sabouri Z, Schofield PR, Horikawa K, Spierings E, Kipling E, Randall K, Langley D, Roome B, Vazquez-Lombardi R, Rouet R, Hermes J, Chan T, Brink R, Dunn-Walters DK, Christ D and Goodnow CC
Garvan Authors A/Prof Daniel Christ , Dr David Langley , Jana Hermes , Dr Peter Schofield , Prof Robert Brink , Rodrigo Vazquez-Lombardi , Romain Rouet , Dr Tyani Chan
Publisher Name P NATL ACAD SCI USA
Published Date 2014-06-24 00:00:00
Status Published