Activation-induced deaminase contributes to the antibody-independent role of B cells in the development of autoimmunity

Abstract

B cells contribute to autoimmunity both as secretors of pathogenic antibodies and through the activation of autoreactive T cells. B cells and antibodies acquire higher affinity to self-antigen through a process known as immunoglobulin hypermutation or SHM. The contribution of SHM to pathogenic antibody development in lupus has been established in various autoimmune mouse models and by examining antibodies from patients. However, its role in the antibody-independent contribution of B cells to autoimmunity has not been examined. Herein, we generate lupus-prone MRL/lpr mice with a limited IgM-only B cell repertoire, no secreted antibodies and no SHM. This enabled us to isolate the role of somatic hypermutation in B cell-mediated autoimmunity. We found that SHM-deficiency correlated with a reduction in autoreactive B cells, a decrease in T cell activation and a decrease in kidney lymphocytic infiltration. These data establish AID as an important contributor to the antibody-independent role of B cells in autoimmunity.

Keywords::

• Somatic hypermutation
• AID
• B cells
• T cells
• lupus

Acknowledgements

We are grateful to Michael Fessler and Donald Cook for helpful suggestions and critical reading of the manuscript. Special thanks to Ronald Herbert, Natasha Clayton, and Tiwanda Masinde, for histology, and to Maria Sifre and Carl Bortner for assistance with flow cytometry.

Declaration of Interests: The authors declare no conflict of interest. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. Project Z01 ES101603.