全身性エリテマトーデス患者T細胞に発現されるTCRζ鎖の異常に関する研究

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One of the earliest biochemical events after T cell receptor (TCR) stimulation is the tyrosine phosphorylation of the cellular proteins. Analysis of the tyrosine phosphorylation in T cells have provided us powerful means to investigate the defects in T cell function. To explore the molecular and cellular mechanism of T cell dysfunction observed in SLE, we utilized these systems and examined tyrosine phosphorylation of SLE T cells with or without TCR/CD3 and CD4 stimulation.When we analyze the tyrosine phosphorylation of total cellular lysates prepared from peripheral T cells with or without stimulation, the major bands migrating around 18, 56, 70, and 100KD were always detected in normal T cells. In contrst, tyrosine phosphorylation was diminished in pp18 and pp100 in SLE T, whereas it was normal to high level in 56KD band.Since pp18 seemed to be TCR zeta chain, it was immunoprecipitated from normal and SLE T cells and examined for its tyrosine phosphorylation and protein expression. Tyrosine phosphorylation of the TCR zeta chain and its expression was significantly decreased in more than 60% of the SLE patients. Among those patients, we identified an aberrant form of zeta chain without exon7, or with short exon8, which are presumably generated from alternative splicing.Along with the decreased zeta chain expression in SLE T cells, adaptor proteins and molecular scafold such as linkers for activation of T cells are continuously recruited in the raft fraction. These results may account for the chronic activated status of SLE T cells, through ineffective negative regulation with downregulated zeta chain and subsequent lack of protein tyrosine phosphatase such as SHP-2.