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.
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.
Liossis
S N
SN
Department of Clinical Physiology, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
Ding
X Z
XZ
Dennis
G J
GJ
Tsokos
G C
GC
D000328:Adult; D000368:Aged; D005260:Female; D015870:Gene Expression; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D008875:Middle Aged; D019000:Phosphotyrosine / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*
D008565:Membrane Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D019000:Phosphotyrosine