TCR zeta chain lacking exon 7 in two patients with systemic lupus erythematosus

Abstract

To address the molecular mechanism underlying the functional defects of peripheral T cells in systemic lupus erythematosus (SLE), we focused on early signaling events. We demonstrated that protein expression of the TCR zeta chain was significantly decreased in peripheral T cells from patients with SLE compared to normal controls and patients with systemic sclerosis (SSc). Among those patients showing decreased TCR zeta chain expression, we found two patients with pronounced TCR zeta chain abnormalities, including an aberrant 14 kDa form in one and only trace expression in the other. RT-PCR, SSCP and subsequent cloning of the transcripts revealed that bases 468503, corresponding to exon 7, were deleted in both patients. Since exon 7 spans the GTP/GDP binding site and N-terminal tyrosine in the third ITAM domain of TCR zeta chain, the transcript lacking exon 7 may be responsible for altered signal transduction via TCR in these SLE patients.

Association of a four–amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: Molecular and functional analysis

“…Dysregulation of the BCR-mediated signaling pathway is likely to result in the breakdown of peripheral B cell tolerance and the development of SLE. In the case of the T cell receptor, the zeta chain of the CD3 complex is aberrantly expressed in a subset of SLE patients, which has been implicated in tolerance disruption (48,49). In fact, the phosphorylation patterns of several proteins of T and B lymphocytes are altered in patients with SLE (20)(21)(22)47,50), which suggests that signaling pathways, including protein kinases and phosphatases, are defective in these patients.…”

DNA Microarray Gene Expression Profile of T Cells with the Splice Variants of TCRζ mRNA Observed in Systemic Lupus Erythematosus

“…T cells are considered central to the pathogenesis of SLE, because a dysfunction in their regulatory action may be responsible for the altered immune responses and overproduction of autoantibodies (4). We and other groups have reported that a decrease in tyrosine phosphorylation and the diminished expression of the TCR -chain ( ) in the peripheral blood T cells (PBTs) of SLE patients may be responsible for the pathogenesis of SLE (5)(6)(7). SLE patients have several alterations in the mRNA open reading frame (8).…”

“…SLE patients have several alterations in the mRNA open reading frame (8). We previously reported the aberrant form of mRNA lacking exon 7 ( mRNA/exon 7Ϫ) observed in SLE patients (5). Moreover, we and other groups have demonstrated that an aberrant form of the mRNA 3Ј-untranslated region (3Ј UTR), which is alternatively spliced and 562 bp shorter than the WT 3Ј UTR, is predominantly expressed in SLE T cells ( mRNA/as-3Ј UTR) (9,10).…”

Abnormal expression of various molecular forms and distribution of T cell receptor ? chain in patients with systemic lupus erythematosus

“…Recently, we identified a decrease in the expression of TCR chain messenger RNA (mRNA) and the detergent-soluble form of TCR chain in a majority of SLE patients (3,11,12). Defective expression of the chain at both the protein and mRNA levels has also been reported by others (7,9). How the TCR engagement induces hyperphosphorylation of cytosolic proteins and a supranormal [Ca 2ϩ ] i response in SLE T cells remains poorly understood.…”