Systemic lupus erythematosus afflicts 1 to 2 million Americans and is associated with significant morbidity and mortality. While wise use of steroids and cytotoxics drugs along with effective use of antibiotics overall survival and quality of life have increased significantly over the last 30 years, we still lack specific treatment, and among others, the lack of full understanding of involved pathogenic mechanisms and of proper disease biomarkers are to be blamed for this. Immune cell and cytokine abnormalities in patients with systemic lupus erythematosus (SLE) are diverse and involve among others decreased cytotoxic responses, decreased activation induced cell death, decreased T regulatory function, increased dendritic cell function, increased IFNa, IL-6 and decreased IL-2, IFN? and TNFa production. Distinct molecular and biochemical abnormalities may account for several cell and cytokine abnormalities. Among peripheral T cells an expanded population of T cells missing CD4 and CD8 from the surface (double negative (DN) T cells exists which when placed in coculture with autologous B cells promoted the production of immunoglobulin and anti-dsDNA. We have recently found that this DN T cell population in SLE patients can be expanded in vitro and that it produces IL- 17 and more importantly, IL-17 producing DN T cells infiltrated kidney tissue of patients with lupus nephritis. We propose, accordingly, that an expanded DN T cell population in patients with SLE produces IL-17 and participates in target organ damage. We will test our thesis in experiments outlined in this application and grouped in four specific aims: In the first aim we will establish the presence of CD4+ and expanded DN T cells producing IL-17 in patients with SLE-determine clinical correlations. In the second we will determine the origin of DN T cells is SLE patients, the requirements for expansion, their early and late signaling profile and their susceptibility to cellular control mechanisms. In the third we will determine the requirements for the generation of TH17 in SLE. In the last aim we study the nature of T cells that infiltrate target tissues in SLE and explore mechanisms which are responsible for the inappropriate homing. These studies intend to propose IL-17 as a novel treatment target in SLE patients and will generate information which will propose Th17 cells as a biomarker of disease activity.
Systemic lupus erythematosus afflicts more than one million Americans most of whom are women in the child bearing age. Diagnosis is frequently delayed and the disease has significant morbidity and mortality. Current treatment is based primarily on indiscriminate immunosuppression. This proposal will identify IL-17 as a novel treatment target and will generate information to introduce Th17 cells as a biomarker of disease activity.
|RodrÃguez-RodrÃguez, NoÃ©; Apostolidis, Sokratis A; Fitzgerald, Lauren et al. (2016) Pro-inflammatory self-reactive TÂ cells are found within murine TCR-Î±Î²(+) CD4(-) CD8(-) PD-1(+) cells. Eur J Immunol 46:1383-91|
|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|
|RodrÃguez-RodrÃguez, NoÃ©; Apostolidis, Sokratis A; Penaloza-MacMaster, Pablo et al. (2015) Programmed cell death 1 and Helios distinguish TCR-Î±Î²+ double-negative (CD4-CD8-) T cells that derive from self-reactive CD8 T cells. J Immunol 194:4207-14|
|Hedrich, Christian M; CrispÃn, JosÃ© C; Rauen, Thomas et al. (2014) cAMP responsive element modulator (CREM) Î± mediates chromatin remodeling of CD8 during the generation of CD3+ CD4- CD8- T cells. J Biol Chem 289:2361-70|
|Koga, Tomohiro; Mizui, Masayuki; Yoshida, Nobuya et al. (2014) KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase IV, promotes generation and function of Foxp3âº regulatory T cells in MRL/lpr mice. Autoimmunity 47:445-50|
|Mizui, Masayuki; Koga, Tomohiro; Lieberman, Linda A et al. (2014) IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4-CD8- IL-17-producing T cells. J Immunol 193:2168-77|
|Kyttaris, Vasileios C; Kampagianni, Ourania; Tsokos, George C (2013) Treatment with anti-interleukin 23 antibody ameliorates disease in lupus-prone mice. Biomed Res Int 2013:861028|
|Hedrich, Christian M; Rauen, Thomas; Crispin, Jose C et al. (2013) cAMP-responsive element modulator Î± (CREMÎ±) 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|
|Hedrich, Christian M; Crispin, Jose C; Rauen, Thomas et al. (2012) cAMP response element modulator Î± controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus. Proc Natl Acad Sci U S A 109:16606-11|
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