George C. Tsokos, MD 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.
Members of the Tsokos Laboratory
Vasileios C. Kyttaris, MD
Jose Crispin, MD
Christian Hedrich, MD
Katalin Kis-Toth, PhD
Linda Lieberman, PhD
Vaishali Moulton, MD, PhD
To-Ha Thai, PhD
Sokratis Apostolidis, MD
Trevor Davis, MD
Amy Devlin, MD
Nikolina Dioufa, MD
Lindsay Edwards, PhD
Mayya Geha, MD
Alexandros Grammatikos, MD
Antonis Ioannou, MD
Lakshmi Kannan, PhD
Tomohiro Koga, MD
Mindy Lo, MD, PhD
Anastasia Markopoulou, MD
Masayuki Mizui, MD
Takashi Muroya, MD
Kamalpreet Nagpal, PhD
Pavel Riha, MD
Nobuya Yoshida, MD
Noe Rodriguez-Rodriguez, MS
Michele Finnell, ANP
Jessica Beltran, BS - Lab manager
Robin Bosse, MS
Andrew Gillooly, BS
Christina Ioannidis, BS
Tran Nguyen, BS
Stacy Rivera, BS
1. 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 U S A. 2013 Jan 29;110(5):1845-50. doi: 10.1073/pnas.1214207110. Epub 2013 Jan 14.
2. Increased Expression of a short splice variant of CTLA-4 exacerbates lupus in MRL/lpr mice. Ichinose K, Zhang Z, Koga T, Juang YT, Kis-Tóth K, Sharpe AH, Kuchroo V, Crispín JC, Tsokos GC. Arthritis Rheum. 2012 Nov 30. doi: 10.1002/art.37790. [Epub ahead of print]
3. 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.
4. 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 U S A. 2012 Oct 9;109(41):16606-11. doi: 10.1073/pnas.1210129109. Epub 2012 Sep 26.
5. Calcium/calmodulin-dependent protein kinase IV suppresses IL-2 production and regulatory T cell activity in lupus. Koga T, Ichinose K, Mizui M, Crispín JC, Tsokos GC. J Immunol. 2012 Oct 1;189(7):3490-6. Epub 2012 Aug 31.
6. The role of platelet factor 4 in local and remote tissue damage in a mouse model of mesenteric ischemia/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.
7. Cutting edge: protein phosphatase 2A confers susceptibility to autoimmune disease through an IL-17-dependent mechanism. Crispín 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.
8. A novel isoform of the orphan receptor RORγt suppresses IL-17 production in human T cells. Rauen T, Juang YT, Hedrich CM, Kis-Tóth K, Tsokos GC. Genes Immun. 2012 Jun;13(4):346-50. doi: 10.1038/gene.2011.85. Epub 2012 Jan 12.
9. 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.
10. 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.
11. Systemic lupus erythematosus. Tsokos GC. N Engl J Med. 2011 Dec 1;365(22):2110-21. doi: 10.1056/NEJMra1100359. Review.
12. Cutting edge: Calcium/Calmodulin-dependent protein kinase type IV is essential for mesangial cell proliferation and lupus nephritis. Ichinose K, Rauen T, Juang YT, Kis-Tóth K, Mizui M, Koga T, Tsokos GC. J Immunol. 2011 Dec 1;187(11):5500-4. doi: 10.4049/jimmunol.1102357. Epub 2011 Oct 26.
13. cAMP-responsive element modulator (CREM)α protein induces interleukin 17A expression and mediates epigenetic alterations at the interleukin-17A gene locus in patients with systemic lupus erythematosus. Rauen T, Hedrich CM, Juang YT, Tenbrock K, Tsokos GC. J Biol Chem. 2011 Dec 16;286(50):43437-46. doi: 10.1074/jbc.M111.299313. Epub 2011 Oct 24.
14. Induction of PP2A Bβ, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus. Crispín JC, Apostolidis SA, Finnell MI, Tsokos GC. Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12443-8. doi: 10.1073/pnas.1103915108. Epub 2011 Jul 11.
15. Cytosolic DNA-activated human dendritic cells are potent activators of the adaptive immune response. Kis-Tóth K, Szanto A, Thai TH, Tsokos GC. J Immunol. 2011 Aug 1;187(3):1222-34. doi: 10.4049/jimmunol.1100469. Epub 2011 Jun 27.
16. Promoter hypomethylation results in increased expression of protein phosphatase 2A in T cells from patients with systemic lupus erythematosus. Sunahori K, Juang YT, Kyttaris VC, Tsokos GC. J Immunol. 2011 Apr 1;186(7):4508-17. doi: 10.4049/jimmunol.1000340. Epub 2011 Feb 23.
17. Suppression of autoimmunity and organ pathology in lupus-prone mice upon inhibition of calcium/calmodulin-dependent protein kinase type IV. Ichinose K, Juang YT, Crispín JC, Kis-Toth K, Tsokos GC. Arthritis Rheum. 2011 Feb;63(2):523-9. doi: 10.1002/art.30085.
18. Transcriptional activation of the cAMP-responsive modulator promoter in human T cells is regulated by protein phosphatase 2A-mediated dephosphorylation of SP-1 and reflects disease activity in patients with systemic lupus erythematosus. Juang YT, Rauen T, Wang Y, Ichinose K, Benedyk K, Tenbrock K, Tsokos GC. J Biol Chem. 2011 Jan 21;286(3):1795-801. doi: 10.1074/jbc.M110.166785. Epub 2010 Nov 19.
19. T cells as therapeutic targets in SLE. Crispín JC, Kyttaris VC, Terhorst C, Tsokos GC. Nat Rev Rheumatol. 2010 Jun;6(6):317-25. doi: 10.1038/nrrheum.2010.60. Epub 2010 May 11. Review.
20. Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice. Kyttaris VC, Zhang Z, Kuchroo VK, Oukka M, Tsokos GC. J Immunol. 2010 May 1;184(9):4605-9. doi: 10.4049/jimmunol.0903595. Epub 2010 Mar 22.