B cell receptor-independent stimuli trigger immunoglobulin (Ig) class switch recombination and production of IgG autoantibodies by anergic self-reactive B cells

Phan, TG; Amesbury, M; Gardam, S; Crosbie, J; Hasbold, J; Hodgkin, PD; Basten, A; Brink, R

Author(s): Phan, TG; Amesbury, M; Gardam, S; Crosbie, J; Hasbold, J; Hodgkin, PD; Basten, A; Brink, R;
Details: Publication Year 2003-04-07,Volume 197,Issue #7,Page 845-860
Journal Title: JOURNAL OF EXPERIMENTAL MEDICINE
Publication Type: Journal Article
Abstract: In both humans and animals, immunoglobulin (Ig)G autoantibodies are less frequent but more pathogenic than IgM autoantibodies, suggesting that controls over Ig isotype switching are required to reinforce B cell self-tolerance. We have used gene targeting to produce mice in which hen egg lysozyme (HEL)-specific B cells can switch to all Ig isotypes (SWHEL mice). When crossed with soluble HEL transgenic (Tg) mice, self-reactive SWHEL B cells became anergic. However, in contrast to anergic B cells from the original nonswitching anti-HEL x soluble HEL double Tg model, self-reactive SWHEL B cells also displayed an miniature phenotype, reduced lifespan, and exclusion from the splenic follicle. These differences were not related to their ability to Ig class switch, but instead to competition with non-HEL-binding B cells generated by V-H gene replacement in SWHEL mice. When activated in vitro with B cell receptor (BCR)-independent stimuli such as anti-CD40 monoclonal antibody plus interleukin 4 or lipopolysaccharide (LPS), anergic SWHEL double Tg B cells proliferated and produced IgG anti-HEL antibodies as efficiently as naive HEL-binding B cells from SWHEL Ig Tg mice. These results demonstrate that no intrinsic constraints to isotype switching exist in anergic self-reactive B cells. Instead, production of IgG autoantibodies is prevented by separate controls that reduce the likelihood of anergic B cells encountering BCR-independent stimuli. That bacteria-derived LPS could circumvent these controls may explain the well-known association between autoantibody-mediated diseases and episodes of systemic infection.
Publisher: ROCKEFELLER UNIV PRESS
Keywords: ANTI-DNA ANTIBODIES; LYMPHOCYTES-B; BONE-MARROW; TRANSGENIC MICE; MRL/LPR MICE; LIFE-SPAN; ACTIVATION; EXPRESSION; GENE; TOLERANCE
Publisher's Version: https://doi.org/10.1084/jem.20022144
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2003-04-07 12:00:00