Details

Autor(en) / Beteiligte

• Sabouri, Zahra
• Schofield, Peter
• Horikawa, Keisuke
• Spierings, Emily
• Kipling, David
• 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
• Goodnow, Christopher C

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2014-06, Vol.111 (25), p.E2567-E2575

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2014

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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 IgM ˡᵒʷ 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 IgM ˡᵒʷ IgD+ B cells form twice as many GC progeny as naïve IgM ʰⁱ 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.