Systemic lupus erythematosus (SLE) is characterized by diverse clinical and laboratory findings and multiple, frequently opposing cellular and cytokine aberrations. The T cell receptor (TCR) 6 chain is decreased in SLE T patients because of limited promoter activity, instability of an alternatively spliced TCR 6 mRNA missing crucial AU response elements and increased degradation by caspase 3. Its pace in the CD3 complex is taken by the FcR3 chain which signals through Syk. Lipid rafts form aggregates on the surface of T cells and together with the rewired TCR account for the aberrant signaling process in SLE T cells. In the lipid aggregates the adhesion molecule is present in increased amounts, which signal through ezrin. CD44 and phosphorylated ezrin positive cells are found in the kidneys of patients with lupus nephritis. It is hypothesized that altered cell surface membrane-mediated signaling in SLE T cells results in aberrant T cell function including inappropriate expression of adhesion molecules and homing to inflamed tissues. The objective of the proposed studies is to explore the role of TCR rewiring (FcR3 ->CD36) in effector SLE T cell function and establish the central role of Syk-mediated signaling in the expression of the SLE T cell phenotype and disease pathology. In addition, the contribution of cell membrane-mediated signaling in upregulating the expression of the adhesion molecule CD44 that results in inappropriate homing of T cells to the kidney will be studied. The proposed studies suggest the presence of molecular targets that can be modulated with gene transfer or drugs and have the potential to complement existing therapeutic modalities. In addition, they will identify several potential T cell based biomarkers. The long term goal of the ongoing and proposed research is the establishment of a "molecular signature" for each patient, or subgroups of SLE patients that will help the diagnosis and personalized treatment.

Public Health Relevance

Systemic lupus erythematosus afflicts more than one million Americans most of whom are women in the child bearing age. Current treatment is based primarily on indiscriminate immunosuppression. This application will explore the presence of molecular targets that can be modulated with gene transfer or drugs and have the potential to complement existing therapeutic modalities.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Johnson, David R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Hedrich, Christian M; Crispin, Jose C; Rauen, Thomas et al. (2014) cAMP responsive element modulator (CREM) * mediates chromatin remodeling of CD8 during the generation of CD3+ CD4- CD8- T cells. J Biol Chem 289:2361-70
Hedrich, Christian M; Rauen, Thomas; Apostolidis, Sokratis A et al. (2014) Stat3 promotes IL-10 expression in lupus T cells through trans-activation and chromatin remodeling. Proc Natl Acad Sci U S A 111:13457-62
Moulton, Vaishali R; Gillooly, Andrew R; Tsokos, George C (2014) Ubiquitination regulates expression of the serine/arginine-rich splicing factor 1 (SRSF1) in normal and systemic lupus erythematosus (SLE) T cells. J Biol Chem 289:4126-34
Grammatikos, Alexandros P; Kyttaris, Vasileios C; Kis-Toth, Katalin et al. (2014) A T cell gene expression panel for the diagnosis and monitoring of disease activity in patients with systemic lupus erythematosus. Clin Immunol 150:192-200
Muroya, Takashi; Kannan, Lakshmi; Ghiran, Ionita C et al. (2014) C4d deposits on the surface of RBCs in trauma patients and interferes with their function. Crit Care Med 42:e364-72
Hedrich, Christian M; Rauen, Thomas; Crispin, Jose C et al. (2013) cAMP-responsive element modulator * (CREM*) trans-represses the transmembrane glycoprotein CD8 and contributes to the generation of CD3+CD4-CD8- T cells in health and disease. J Biol Chem 288:31880-7
Deng, Guo-Min; Beltran, Jessica; Chen, Chen et al. (2013) T cell CD3ýý deficiency enables multiorgan tissue inflammation. J Immunol 191:3563-7
Davis, Trevor E; Kis-Toth, Katalin; Szanto, Attila et al. (2013) Glucocorticoids suppress T cell function by up-regulating microRNA-98. Arthritis Rheum 65:1882-90
Grammatikos, Alexandros P; Ghosh, Debjani; Devlin, Amy et al. (2013) Spleen tyrosine kinase (Syk) regulates systemic lupus erythematosus (SLE) T cell signaling. PLoS One 8:e74550
Ghosh, Debjani; Tsokos, George C; Kyttaris, Vasileios C (2012) c-Jun and Ets2 proteins regulate expression of spleen tyrosine kinase in T cells. J Biol Chem 287:11833-41

Showing the most recent 10 out of 94 publications