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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.

SUBMITTER: Grammatikos AP

PROVIDER: S-EPMC3754955 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Spleen tyrosine kinase (Syk) regulates systemic lupus erythematosus (SLE) T cell signaling.

Grammatikos Alexandros P AP Ghosh Debjani D Devlin Amy A Kyttaris Vasileios C VC Tsokos George C GC

PloS one 20130827 8

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 ...[more]

PMID: 24013589

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Project description:An in-depth literature review of up to 2023 reveals 330 risk loci found by genetic association at p ≤ 5 × 10-8, with systemic lupus erythematosus (SLE) in at least one study of 160 pertinent publications. There are 225 loci found in East Asian (EAS), 106 in European (EU), 11 in African-American (AA), 18 Mixed American (MA), and 1 in Egyptian ancestries. Unexpectedly, most of these associations are found to date at p ≤ 5 × 10-8 in a single ancestry. However, the EAS and EU share 40 risk loci that are independently established. The great majority of the identified loci [250 (75.8%) of 330] do not contain a variant that changes an amino acid sequence. Meanwhile, most overlap with known regulatory elements in the genome [266 (80.6%) of 330], suggesting a major role for gene regulation in the genetic mechanisms of SLE. To evaluate the pathways altered by SLE-associated variants, we generated gene sets potentially regulated by SLE loci that consist of the nearest genes, published attributions, and genes predicted by computational tools. The most useful insights, at present, suggest that SLE genetic mechanisms involve (1) the regulation of both adaptive and innate immune responses including immune cell activation and differentiation; (2) the regulation of production and response to cytokines, including type I interferon; (3) apoptosis; (4) the sensing and removal of immune complexes and apoptotic particles; and (5) immune response to infections, including Epstein-Barr Virus, and symbiont microorganisms. These mechanisms affected by SLE genes involve multiple cell types, including B cells/plasma cells, T cells, dendritic cells, monocytes/macrophages, natural killer cells, neutrophils, and endothelial cells. The genetics of SLE from GWAS data reveal an incredibly complex profusion of interrelated molecular processes and interacting cells participating in SLE pathogenesis, mostly unified in the molecular regulation of inflammatory responses. These genetic associations in lupus and affected molecular pathways not only give us an understanding of the disease pathogenesis but may also help in drug discoveries for SLE treatment.

Dataset Information

Spleen tyrosine kinase (Syk) regulates systemic lupus erythematosus (SLE) T cell signaling.

Publications

Spleen tyrosine kinase (Syk) regulates systemic lupus erythematosus (SLE) T cell signaling.

Similar Datasets

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