Dr. Linda Spatz
My laboratory has been studying the regulation of anti-dsDNA B cells in mice transgenic for the IgM heavy chain of an anti-dsDNA antibody. In patients with the autoimmune disease Systemic Lupus Erythematosus (SLE), pathogenic anti-dsDNA antibodies are produced and deposited in many organs of the body where they induce many symptoms including rashes, arthritis and nephritis. Normally anti-dsDNA antibodies are downregulated by mechanisms of tolerance. Using our transgenic mouse model, we have observed that one mechanism of tolerance that serves to regulate anti-dsDNA B cells is anergy in which the anti-dsDNA B cells become functionally incapable of secreting antibody in response to antigen activation.
In an effort to understand some factors that can lead to a breakdown of B cell tolerance and the development of autoimmune disease, we have bred our transgenic mice to mice that overexpress genes involved in B cell signaling or B cell survival. We have observed that tolerance is lost in transgenic anti-dsDNA B cells in mice that overexpress CD19 a cell surface molecule that lowers the threshold for B cell activation. We have demonstrated that the anti-dsDNA B cells can spontaneously secrete antibody in these mice although they still maintain an anergic phenotype and cannot be activated by antigen. However, they can be activated by signaling through innate immune receptors suggesting that innate mechanisms may play a role in the breakdown of tolerance. More recently we have demonstrated that transgenic anti-dsDNA mice overexpressing BAFF, a molecule involved in B cell survival, display a loss of B cell tolerance and have elevated frequencies of transgenic anti-dsDNA secreting B cells.
In addition, we are investigating the possible role of the Epstein Barr Virus in the etiology of Systemic Lupus Erythematosus (SLE), in collaboration with Dr. Paul Gottlieb. We have demonstrated that mice injected with a major nuclear protein from the Epstein Barr Virus, known as EBNA-1, can develop antibodies to dsDNA. We have shown that many of these anti-dsDNA antibodies also recognize or cross-react with the EBNA-1 protein suggesting that these antibodies see some structural similarity between dsDNA and EBNA-1.
Dr. Linda Spatz
Department of Biology
City College of New York
138th Street & Convent Avenue
New York, NY 10031
t. 212.650.7703 – Office, MR-909
t. 212.650.7772 – Lab, MR-611