Spleen Tyrosine Kinase (Syk) Regulates Systemic Lupus Erythematosus (SLE) T Cell Signaling

Abstract

Engagement of the CD3/T cell receptor complex in systemic lupus erythematosus (SLE) T cells involves Syk rather than the zeta-associated protein. Because Syk is being considered as a therapeutic target we asked whether Syk is central to the multiple aberrantly modulated molecules in SLE T cells. Using a gene expression array, we demonstrate that forced expression of Syk in normal T cells reproduces most of the aberrantly expressed molecules whereas silencing of Syk in SLE T cells normalizes the expression of most abnormally expressed molecules. Protein along with gene expression modulation for select molecules was confirmed. Specifically, levels of cytokine IL-21, cell surface receptor CD44, and intracellular molecules PP2A and OAS2 increased following Syk overexpression in normal T cells and decreased after Syk silencing in SLE T cells. Our results demonstrate that levels of Syk affect the expression of a number of enzymes, cytokines and receptors that play a key role in the development of disease pathogenesis in SLE and provide support for therapeutic targeting in SLE patients.

γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program

“…The kinase domain of Zap70 has been shown to exert lower catalytic activity than that of Syk (42). It is also possible that Syk and Zap70 have different specificities to target proteins, because the ectopic expression of Syk in human αβT cells can result in altered gene expression downstream of TCR signaling (43). The Src homology 2 (SH2) domains of Syk may be more structurally flexible than those of Zap70 (44), possibly leading to a higher accessibility of Syk to the immunoreceptor tyrosinebased activation motifs (ITAMs) in γδTCR-CD3 complexes.…”

FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression

“…Syk high / ZAP-70 Ϫ T-cells show decreased Erk, JNK, and MAPK activity, suggesting a distinct signaling (17). T E cells in SLE patients show up-regulation of FcR␥-Syk signaling (18). T E populations, T H 1, and T H 17 that produce interferon-␥ (IFN-␥) and interleukin-17 (IL-17) contribute to autoimmune pathology (19,20).…”

T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity

“…Eventually, small-molecule drugs and/or gene targeting to correct the expression of molecules only in patients in whom they are abnormally expressed should be expected to meet success. Along these lines a gene expression array has been developed (101,102) to determine the aberrant expression of signaling molecules in patients with SLE, pointing to the possibility that patients with SLE can be stratified along their molecular profiles.…”