Altered pattern of TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of the T cell receptor zeta chain.

Abstract

Cellular immunity aberrations in patients with SLE are underscored by the abnormal early Ag receptor-mediated lymphocyte signal transduction pathway. To further characterize the T cell receptor (TCR)/CD3-initiated signaling defects, we studied 22 patients with SLE, 12 patients with other systemic rheumatic diseases, and 14 normal donors. The early (1 min) TCR/CD3-mediated tyrosine phosphorylation of cellular proteins with a molecular size between 36 and 64 kD was increased in 15 of 21 SLE patients, compared to normal or disease control subjects. The deficiency or absence of a band with a molecular size of approximately 16 kD in the immunoblots of SLE patients led us to investigate the expression of the TCRzeta chain. In immunoblots using anti-zeta antibodies we found that 10 of 22 lupus patients tested lacked the expression of TCRzeta, which was always present in control subjects (P < 0.001). Flow cytometric studies using permeabilized cells confirmed the deficiency or absence of the TCRzeta chain in lupus T cells. Using Northern blots we found that for eight patients tested, the TCRzeta mRNA was missing in three, decreased in three, and apparently normal in two patients (P < 0.003), but was always present in control subjects. Reverse transcriptase-PCR verified Northern blot results. We conclude that TCRzeta chain expression is either decreased or absent in the majority of patients with SLE, but not in patients with other systemic rheumatic diseases, regardless of disease activity, treatment status, or clinical manifestations. The previously described increases in TCR-initiated Ca2+ responses and the herein described increases in TCR-induced protein tyrosine phosphorylation and deficient TCRzeta expression may represent intrinsic defects modulating lupus T cell function.

Analysis of gene expression profiles in human systemic lupus erythematosus using oligonucleotide microarray

“…There were many reports about TCR/CD3 defects in SLE patients. 23,38,39 In our study, we also found the TCRs pathways, TCRa, TCRd, and Zap-70 associated protein kinase 70 kDa) had lower expression in SLE patients. So, an inverse relationship between TSA-1 and CD3 expression on thymocytes may reflect abnormal activated lymophocytes in 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.…”

Modulation of TcR/CD3-zeta chain expression by a circulating factor derived from ovarian cancer patients

“…T-cells with suppressed zeta chain have been demonstrated to exhibit diminished proliferation and production of cytokines. Decreased zeta chain expression occurs in other disease states, including chronic infections and systemic lupus erythematosus, where deficient zeta chain expression has been proposed to aberrantly modulate T-cell functions (Liossis et al, 1998).…”