George Tsokos
Beth Israel Deaconess Medical Center
330 Brookline Ave.
Center for Life Sciences, Room 937
Phone: 617-735-4161
Fax: 617-735-4170
email: gtsokos@bidmc.harvard.edu
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 increased T cell receptor (TCR)-mediated early signaling response. Lipid rafts are aggregated on the surface membrane of T cells while the TCR is rewired with the FcRgamma chain assuming the function of the zeta chain. Additional signaling molecules are present in the lipid rafts including Syk and the adhesion molecule CD44 which signals though pERM. pERM is phosphorylated by Rho kinase. Reconstitution of the missing CD3zeta chain, inhibition of its degradation, inhibition of Syk or Rho kinase activity all result in normalization of T cell effector function.
2. Studies on the decreased production of interleukin-2 (IL-2) in human SLE T cells. We have 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. IL23/IL17 axis in SLE - Double negative (CD3+CD4-CD8-) T cells are expanded in SLE patients and we found to produce IL-17 and more interestingly to populate the kidneys of patients with lupus nephritis. In humans, double negative T cells appear to arise from CD8+ cells and in mice they expand under the influence of IL23. Ongoing studies in humans and in genetically engineered mice will determine the origin, developmental requirements and pathogenicity of double negative cells.
4. 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.
5. Tissue Injury Program. 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. The goal of these studies is to decipher mechanisms of tissue injury and develop approaches to limit damage.
References:
Kyttaris, V. C., Zhang, Z. Kuchroo, V. K., Oukka, M. and Tsokos, G. C. IL-23 receptor deficiency prevents the development of lupus nephritis in B6/lpr mice. J. Immunol. (Cutting Edge). 184:4605-9.
Moulton, V. R. and Tsokos, G. C. (2010). The splicing factor ASF/SF2 regulates the expression of the human T cell receptor CD3 zeta chain. J. Biol. Chem. 23:285:12490-6.
Deng, G. M., Liu, L., Kyttaris, V.C. and Tsokos, G. C. (2010). Lupus serum immunoglobulin G induces skin inflammation through TNFR1 signaling pathway. J. Immunol. 184: 4154-61.
Crispin, J, Liossis, SNC, Kis-Toth, K., Lieberman L A., Kyttaris, V.C. Juang, Y. T. and Tsokos, G. C. (2010). Recent developments in the pathogenesis of systemic lupus erythematosus. Trends Mol. Med. 16: 47-57.
Li, Y., Harada, T., Juang, Y. T., Kyttaris, V. C., Wang, Y., Zidanic, M., Tung, K., and Tsokos, G. C. (2007). Anti-CD3/TCR autoantibodies induce p-ERM and trigger T cell polarization, adhesion and migration into inflamed SLE kidney. J. Immunol. 178: 1938-1947. Highlighted In This Issue, J. Immunol, 178:1226.
Immunology webpage updated 7/12/2010