J. Exp. Med., Volume 186, Number 11, December 1, 1997 1923-1931

CD19-Regulated Signaling Thresholds Control Peripheral Tolerance and Autoantibody Production in B Lymphocytes

By Makoto Inaoki,^* Shinichi Sato,^* Bennett C. Weintraub, Christopher C. Goodnow, and Thomas F. Tedder^*

From the ^* Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710; and  Department of Microbiology and Immunology and Howard Hughes Medical Institute, Beckman Center, Stanford University School of Medicine, Stanford, California 94305

The CD19 cell surface molecule regulates signal transduction events critical for B lymphocyte development and humoral immunity. Increasing the density of CD19 expression renders B lymphocytes hyper-responsive to transmembrane signals, and transgenic mice that overexpress CD19 have increased levels of autoantibodies. The role of CD19 in tolerance regulation and autoantibody generation was therefore examined by crossing mice that overexpress a human CD19 transgene with transgenic mice expressing a model autoantigen (soluble hen egg lysozyme, sHEL) and high-affinity HEL-specific IgM^a and IgD^a (Ig^HEL) antigen receptors. In this model of peripheral tolerance, B cells in sHEL/Ig^HEL double-transgenic mice are functionally anergic and do not produce autoantibodies. However, it was found that overexpression of CD19 in sHEL/Ig^HEL double-transgenic mice resulted in a breakdown of peripheral tolerance and the production of anti-HEL antibodies at levels similar to those observed in Ig^HEL mice lacking the sHEL autoantigen. Therefore, altered signaling thresholds due to CD19 overexpression resulted in the breakdown of peripheral tolerance. Thus, CD19 overexpression shifts the balance between tolerance and immunity to autoimmunity by augmenting antigen receptor signaling.

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