MUTATIONS IN T-CELL RECEPTOR ZETA-CHAIN MESSENGER-RNA OF PERIPHERAL T-CELLS FROM SYSTEMIC LUPUS-ERYTHEMATOSUS PATIENTS

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown aetiology. Although it has been reported that T cells might b e responsible for the pathogenesis of SLE, it remains unclear whether immune aberrations of SLE T cells are the primary event in this pathol ogical process. We have recently reported that tyrosine phosphorylatio n and expression of the T cell receptor zeta chain (TCR zeta) was sign ificantly decreased in SLE T cells and that two SLE patients exhibited a 36 bp, exon 7 deletion of the TCR zeta mRNA. To investigate further common mutations in TCR zeta mRNA among SLE patients, mRNA was isolat ed from the peripheral blood T cells of two normal controls, two syste mic sclerosis (SSc) patients, and eight SLE patients. TCR zeta cDNA wa s amplified by RT-PCR Five out of the eight SLE patients exhibited abn ormal migration patterns of the TCR zeta cDNA in PCR single stranded c onformational polymorphism analysis. PCR products were ligated into pU C18 and five clones obtained were sequenced. Analysis of the nucleotid e sequences revealed that all of the five pUC18 clones from the normal controls and SSc patients had the normal nucleotide sequence, whereas all eight SLE patients had mutations in TCR zeta cDNA accompanied by predicted amino acid substitutions. Mutations found in six of these pa tients corresponded to those of the third immunoreceptor tyrosine-base d activation motif (ITAM) domain or the GTP/GDP binding site in TCR ze ta. Thus, these mutations in TCR zeta mRNA could be responsible for th e decreased expression of the TCR zeta protein in SLE T cells. (C) 199 8 Academic Press