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.
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.
|Comte, Denis; Karampetsou, Maria P; Kis-Toth, Katalin et al. (2016) Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus. Proc Natl Acad Sci U S A 113:9321-6|
|Karampetsou, Maria P; Comte, Denis; Kis-Toth, Katalin et al. (2016) Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production. J Immunol 196:4915-24|
|SuÃ¡rez-Fueyo, Abel; Bradley, Sean J; Tsokos, George C (2016) T cells in Systemic Lupus Erythematosus. Curr Opin Immunol 43:32-38|
|Moulton, Vaishali R; Tsokos, George C (2015) T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity. J Clin Invest 125:2220-7|
|Edwards, Lindsay J; Mizui, Masayuki; Kyttaris, Vasileios (2015) Signal transducer and activator of transcription (STAT) 3 inhibition delays the onset of lupus nephritis in MRL/lpr mice. Clin Immunol 158:221-30|
|Comte, D; Karampetsou, M P; Tsokos, G C (2015) T cells as a therapeutic target in SLE. Lupus 24:351-63|
|Bradley, Sean J; Suarez-Fueyo, Abel; Moss, David R et al. (2015) T Cell Transcriptomes Describe Patient Subtypes in Systemic Lupus Erythematosus. PLoS One 10:e0141171|
|Deng, Guo-Min; Tsokos, George C (2015) Pathogenesis and targeted treatment of skin injury in SLE. Nat Rev Rheumatol 11:663-9|
|Walter, Jolan E; Lo, Mindy S; Kis-Toth, Katalin et al. (2015) Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis. J Allergy Clin Immunol 135:272-3|
|Moulton, Vaishali R; Gillooly, Andrew R; Perl, Marcel A et al. (2015) Serine Arginine-Rich Splicing Factor 1 (SRSF1) Contributes to the Transcriptional Activation of CD3Î¶ in Human T Cells. PLoS One 10:e0131073|
Showing the most recent 10 out of 115 publications