| First Author | Sabouri Z | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 25 | Pages | E2567-75 |
| PubMed ID | 24821781 | Mgi Jnum | J:211030 |
| Mgi Id | MGI:5573053 | Doi | 10.1073/pnas.1406974111 |
| Citation | Sabouri Z, et al. (2014) Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity. Proc Natl Acad Sci U S A 111(25):E2567-75 |
| abstractText | 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 naive 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. |
