George C Tsokos, MD
Division Chief
Rheumatology
Contact Information
| Office: | CL-0937 |
| Phone: | 617-735-4160 |
| Fax: | 617-735-4170 |
| Email: | gtsokos@bidmc.harvard.edu |
| Address: | 330 Brookline Ave; CL-0937
Boston, MA 02215 |
Research Lab Team Members
| Ingrid Avalos MD | Michele Finnell NP | Vasileios Kyttaris MD |
Major Research Theme
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The Tsokos laboratory is interested in studies of immune cell signaling and gene transcription in human SLE, as well as in mechanisms of tissue injury. By exploring the molecular origin of the multiple immune cell abnormalities in SLE, the studies identify novel biomarkers for the diagnosis of the disease and therapeutic targets. 1. Studies on SLE T cell signaling. SLE T cells express decreased amounts of T cell receptor (TCR) zeta chain. A number of mechanisms have been identified as contributing to the decreased expression of TCRzeta chain including increased caspase-3-mediated degradation, increased production of alternatively spliced products that are unstable, and decreased transcriptional activity of TCRzeta chain promoter activity. The function of the missing TCRzeta chain is assumed by the FcRgamma chain which is upregulated in SLE T cells. 2. Studies on the decreased production of interleukin-2 (IL-2) in human SLE T cells. The Tsokos Lab has established that decreased transcriptional activity of the IL-2 promotes leads to decreased production of IL-2 by SLE T cells. We have found that the suppressor CREMalpha is expressed in increased amounts in SLE T cells and binds to the IL-2 promoter. After binding, CREMalpha recruits HDAC1, which deacetylates histones and confers a �closed� chromatin structure. CREMalpha activation and binding to the IL-2 promoter was found to be caused by CaMKIV which is also increased in SLE T cells. In parallel studies we found that SLE T cells express increased amounts of PP2Ac which dephosphorylates CREB and thus deprives the IL-2 promoter of a putative transcriptional enhancer. 3. Development of T cell-based biomarkers for SLE. While performing our studies we have identified markers that we plan to develop as biomarkers. Specifically, aggregated lipid rafts on the surface membrane of SLE T cells represent a disease specific and highly sensitive phenomenon. Expression of aggregated lipid rafts and molecules that are included in the rafts, such as FcRgamma, Syk, CD44, and complement components, is being studied with a goal of using them as disease biomarkers. 4. Autoantibody-mediated tissue injury. We have demonstrated, using a mouse model of mesenteric ischemia/reperfusion (I/R) model that autoantibodies such, as anti-DNA, cardiolipin, histones and RNP, infused in mice resistant to RI, Rag1-/-, do not cause any tissue injury unless the mice undergo I/R. We have shown that these antibodies bind to neoantigens expressed on IR-stressed tissues, activate complement and execute pathology. In brief, we study immune cell signalling and gene transcription aberrations in SLE patients to: 1) Understand how immune cells function, 2) Identify molecules that can serve as therapeutic targets 3) Identify new diagnostic tools for SLE |
Publications
External Recognition
| Chair, HAI Study Section, CSR, NIH Chair, ALR Study Section Past President, Clinical Immunology Society Associate Editor-In-Chief, Clinical Immunology; Editor, Autoimmunity; Associate Editor, Frontiers in B cell molecules; Section Editor, Cellular and Molecular Immunology; Chair, Committee on Journals and Publications, American College of Rheumatology; Master, ACP; Fellow, AAAS; Member AAP. |
Major Collaborative Activities
| Cox Terhorst, BIDMC Ping Lu, BIDMC Tanya Mayadas, BWH Maria Kontaridis, BIDMC Jean-Pierre Kinet, BIDMC Betty Tsao, UCLA |
Investigator's Lab Web Site
| Research Lab URL | None listed |
| Harvard Catalyst Site: | Tsokos Harvard Catalyst Web Site |
