DISSECTING THE MOLECULAR MECHANISMS OF TCR ζ CHAIN DOWNREGULATION AND T Cell SIGNALING ABNORMALITIES IN HUMAN SYSTEMIC LUPUS ERYTHEMATOSUS

Abstract

Abnormal expression of key signaling molecules and defective function of T lymphocytes play a significant role in the pathogenesis of systemic lupus erythematosus (SLE). Probing on altered expression of genes that may predispose to SLE revealed that the expression of TCR ζ chain is defective in the majority of SLE patients. Current research has been directed towards understanding the molecular basis of TCR ζ chain deficiency and dissecting the T cell signalling abnormalities in SLE T cells. Latest developments suggest that interplay of abnormal transcriptional factor expression, aberrant mRNA processing/editing, unbiquitination, proteolysis, and the effects of oxidative stress as well as changes in chromatin structure invariably contribute to TCR ζ chain deficiency in SLE T cells. On the other hand, multiple factors, including altered receptor structure, modulation of membrane clustering, lipid-raft distribution of signaling molecules, and defective signal silencing mechanisms, play a key role in delivering the increased TCR/CD3-mediated intracellular calcium response in SLE T cells.

Keywords:

• systemic lupus erythematosus
• T cell receptor
• signaling
• gene transcription
• ubiquitination
• gene therapy