George C. Tsokos, M.D. Laboratory
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.
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.
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 promoter 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. We use lupus-prone mice to carry our preclinical studies and we engineer genetically lupus-prone animals (e.g. MRL/ lprCamkiv-/-) to confirm findings in patients with SLE and better dissect the involved mechanisms.
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.
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.
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.
1. Deng GM, Beltran J, Chen C, Terhorst C, Tsokos GC. T Cell CD3? Deficiency Enables Multiorgan Tissue Inflammation. J Immunol. 2013 Oct 1; 191(7):3563-7.
2. Kannan L, Kis-Toth K, Yoshiya K, Thai TH, Sehrawat S, Mayadas TN, Dalle Lucca JJ, Tsokos GC. R-spondin3 prevents mesenteric ischemia/reperfusion-induced tissue damage by tightening endothelium and preventing vascular leakage. Proc Natl Acad Sci U S A. 2013 Aug 27; 110(35):14348-53.
3. Kyttaris VC, Kampagianni O, Tsokos GC. Treatment with anti-interleukin 23 antibody ameliorates disease in lupus-prone mice. Biomed Res Int. 2013; 2013:861028.
4. Paz Z, Tsokos GC. New therapeutics in systemic lupus erythematosus. Curr Opin Rheumatol. 2013 May; 25(3):297-303.
5. Ichinose K, Zhang Z, Koga T, Juang YT, Kis-Tóth K, Sharpe AH, Kuchroo V, Crispín JC, Tsokos GC. Brief Report: Increased expression of a short splice variant of CTLA-4 exacerbates lupus in MRL/lpr mice. Arthritis Rheum. 2013 Mar; 65(3):764-9.
6. Splicing factor SF2/ASF rescues IL-2 production in T cells from systemic lupus erythematosus patients by activating IL-2 transcription. Moulton VR, Grammatikos AP, Fitzgerald LM, Tsokos GC. Proc Natl Acad Sci USA. 2013 Jan 29;110(5):1845-50. doi: 10.1073/pnas.1214207110. Epub 2013 Jan. 14.
7. Increased Expression of a short splice variant of CTLA-4 exacerbates lupus in MRL/lpr mice. Ichinose K, Koga T, Juang YT, Kis-Toth K, Sharpe AH, Kuchroo V, Crispin JC, Tsokos GC. Arthritis Rheum. 2012 Nov 30. doi: 10.1002/art.37790.
8. Interleukin-2 in systemic autoimmunity hits the micro way. Tsokos GC, Thai TH. Arthritis Rheum. 2012 Nov;64(11):3494-7. doi: 10.1002/art.34597.
9. cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus. Hedrich CM, Crispin JC, Rauen T, Ioannidis C, Apostolidis SA, Lo MS, Kyttaris VC, Tsokos GC. Proc Natl Acad Sci USA. 2012 Oct 9;109(41):16606-11. doi: 10.1073/pnas.1210129109. Epub 2012 Sep 26.
10. Calcium/calmodulin-dependent protein kinase IV suppresses IL-2 production and regulatory T cell activity in lupus. Koga T, Ichinose K, Mizui M, Crispin JC, Tsokos GC. J Immunol. 2012 Oct 1;189(7):3490-6. Epub 2012 Aug 31.
11. The role of platelet factor 4 in local and remote tissue damage in a mouse model of mesenteric ichemia/reperfusion injury. Lapchak PH, Ioannou A, Rani P, Lieberman LA, Yoshiya K, Kannan L, Dalle Lucca JJ, Kowalska MA, Tsokos GC. PLoS One. 2012;7(7):e39934. doi: 10.1371/journal.pone.0039934. EPub 2012 Jul 6.
12. Cutting edge: protein phosphatase 2A confers susceptibility to autoimmune disease through an IL-17-dependent mechanism. Crispin JC, Apostolidis SA, Rosetti F, Keszei M, Wang N, Terhorst C, Mayadas TN, Tsokos GC. J Immunol. 2012 Apr 15;188(8):3567-71. doi: 10.4049/jimmunol.1200143. Epub 2012 Mar 14.
13. A novel isoform of the orphan receptor RORγt suppresses IL-17 production in human T cells. Rauen T, Juang YT, Hedrich CM, Kis-Toth K, Tsokos GC. Genes Immun. 2012 Jun;13(4):346-50. doi: 10.1038/gene.2011.85. Epub 2012 Jan 12.
14. Treatment of systemic lupus erythematosus: new advances in targeted therapy. Lo MS, Tsokos GC. Ann N Y Acad Sci. 2012 Jan;1247:138-52. doi: 10.1111/j.1749-6632.2011.06263.x. Epub 2012 Jan 11. Review.
15. Immunodeficiency and autoimmunity: lessons from systemic lupus erythematosus. Grammatikos AP, Tsokos GC. Trends Mol Med. 2012 Feb;18(2):101-8. doi: 10.1016/j.molmed.2011.10.005. Epub 2011 Dec 15. Review.
Members of the Tsokos Laboratory
Vasileios C. Kyttaris, MD
Jose Crispin, MD
Katalin Kis-Toth, PhD
Linda Lieberman, PhD
Vaishali Moulton, MD, PhD
To-Ha Thai, PhD
Gelareh Atefi, MD
Sokratis Apostolidis, MD
Denis Comte, MD
Trevor Davis, MD
Amy Devlin, MD
Nikolina Dioufa, MD
Lindsay Edwards, PhD
Mayya Geha, MD
Lakshmi Kannan, PhD
Maria Karampetsou, MD, PhD
Tomohiro Koga, MD
Christine Konya, MD
Mindy Lo, MD, PhD
Kotaro Otomo, MD
Masayuki Mizui, MD
Kamalpreet Nagpal, PhD
Lucia Novelli, MD
Pavel Riha, MD
Nobuya Yoshida, PhD
Michele Finnell, ANP
Noe Rodriguez-Rodriguez, MS
Robin Bosse, MS
Andrew Gillooly, BS
Nesta Ha, MS
Christina Ioannidis, BS – Lab Manager
Tran Nguyen, BS
Stacy Rivera, BS