inositol-1-4-5-trisphosphate and Lupus-Erythematosus--Systemic

Topics: Active Transport, Cell Nucleus; Animals; Autoimmune Diseases; Calcium Signaling; Chromosomes, Human, Pair 7; Cyclic AMP Response Element Modulator; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; DNA-Binding Proteins; Genetic Predisposition to Disease; Humans; Inositol 1,4,5-Trisphosphate; Interleukin-2; Isoenzymes; Leukocyte Common Antigens; Lupus Erythematosus, Systemic; MAP Kinase Signaling System; Membrane Proteins; Mice; Mice, Inbred MRL lpr; Models, Immunological; NF-kappa B; Phosphorylation; Protein Processing, Post-Translational; Receptors, Antigen, T-Cell; Repressor Proteins; Signal Transduction; T-Lymphocyte Subsets; Transcription Factor RelA

We studied the TCR/CD3 complex-mediated signal transduction pathway in freshly isolated T cells and T cell lines from patients with systemic lupus erythematosus (SLE). The peak and 5-min anti-CD3 mAb-mediated free intracytoplasmic Ca2+ concentration ([Ca2+]i) increase was statistically significant higher in fresh T cells from SLE patients than in control T cells. Increased CD3-mediated [Ca2+]i responses were observed in T cells from patients with SLE but not in T cells from other rheumatic diseases. Furthermore, significantly increased CD3-mediated [Ca2+]i responses were observed in T cell lines from SLE patients but not from controls. Although the [Ca2+]i response did not correlate with the global SLE disease activity or individual clinical manifestations, it was significantly higher in the group of patients who were not on treatment. Both CD4+ and CD8+ T cell subsets from peripheral blood cells and T cell lines displayed higher CD3-mediated [Ca2+]i responses than their normal counterparts. The peak of the response occurred earlier in the patient than in the normal group. The amount of Ca2+ that was released from the intracellular stores was higher in lupus than control T cells. The TCR/CD3-induced production of inositol phosphate metabolites in SLE cells was comparable with controls. The sarcoplasmic and endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin-induced [Ca2+]i response was similar in both SLE and normal T cells. Our experiments demonstrate for the first time a definite abnormality in the early steps of the TCR/CD3-mediated signal transduction pathway in T cells from SLE patients that involves increased release of Ca2+ from intracellular stores.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Calcium; Cell Line; Female; Humans; Inositol 1,4,5-Trisphosphate; Lupus Erythematosus, Systemic; Male; Middle Aged; Receptor-CD3 Complex, Antigen, T-Cell; Signal Transduction; T-Lymphocytes; Terpenes; Thapsigargin