Dissecting the molecular mechanisms of TCR zeta chain downregulation and T cell signaling abnormalities in human systemic lupus erythematosus.
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 zeta chain is defective in the majority of SLE patients. Current research has been directed towards understanding the molecular basis of TCR zeta 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 zeta 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.
Nambiar
Madhusoodana P
MP
Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, and Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
Juang
Yuang-Taung
YT
Krishnan
Sandeep
S
Tsokos
George C
GC
D000595:Amino Acid Sequence; D002843:Chromatin / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology; D015536:Down-Regulation; D015316:Genetic Therapy; D006801:Humans; D007139:Immunoglobulin epsilon-Chains / Q000235:genetics / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000502:physiology
D002843:Chromatin; D004268:DNA-Binding Proteins; D007139:Immunoglobulin epsilon-Chains; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C054979:antigen T cell receptor, zeta chain