Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1
ABSTRACT Multiple sclerosis is an immune-mediated brain disease ameliorated by interferon-beta therapy. Immune responses to IFN-alpha and IFN-beta are sometimes subnormal in MS peripheral blood mononuclear cells (MNCs), suggesting an underlying defect in type I IFN signaling. We studied IFN-beta regulation of mRNA and protein induction for IFN regulatory factor-1 (IRF-1) and IRF-2, which control multiple IFN-stimulated genes, and for 2',5'-oligoadenylate synthetase (2',5'-OAS) and MxA, which are antiviral proteins. First, mRNA levels in resting MNC from untreated patients with clinically active MS contained IRF-1 at 38% of normal controls, 45% for IRF-2, 44% for 2',5'-OAS (all p<0.005), and 46% for MxA protein (p<0.007). Stable MS patients had intermediate levels of 2',5'-OAS and MxA. IFN-beta-1b therapy increased IRF-1, IRF-2, and 2',5'-OAS mRNA in resting MNC-but only up to levels seen in unstimulated control cells. In untreated patients with active MS, serine phosphorylation of the STAT1 transcription factor was markedly reduced, suggesting a mechanism for the low levels of IFN-induced genes. Secondly, in untreated patients with stable MS, culture with IFN-beta induced excessive tyrosine phosphorylation of STAT1, and this correlated with low SHP1 tyrosine phosphatase levels. Excessive P-Tyr-STAT1 responses could induce inflammatory cytokines and demyelination in MS, as in motheaten mice, which have defects in SHP-1 function. Abnormal IFN signaling may predict the course of MS and responses to therapy.
- SourceAvailable from: Frank Middleton
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- "We and others previously described that the anti-inflammatory gene SHP-1 is reduced in PBMC of MS compared to normal subjects both at the mRNA and protein levels which may relate to increased inflammatory activity of these cells in the CNS. Further analysis indicated that both lymphocytes and myeloid cells of MS patients have lower amounts of SHP-1 protein (Christophi et al., 2008c, Feng et al., 2002). Moreover, decreased SHP-1 correlated with specific repression of promoter 2 (hematopoietic specific) relative to promoter 1 (epithelial specific) (Tsui et al., 2002) transcripts (Christophi et al., 2008a, Christophi et al., 2009a). "
ABSTRACT: The protein tyrosine phosphatase, SHP-1, is a negative regulator of proinflammatory signaling and autoimmune disease. We have previously reported reduced SHP-1 expression in peripheral blood leukocytes of subjects with multiple sclerosis (MS). Recent evidence indicates that virus-induced DNA methylation of the SHP-1 promoter is responsible for aberrant silencing of SHP-1 expression and function in hematopoietic cells that might relate to inflammatory diseases. In the present study, bisulfite sequencing of the SHP-1 promoter demonstrated that over a third of MS subjects had abnormally high promoter methylation. As SHP-1 is deficient in MS leukocytes and SHP-1-regulated proinflammatory genes are correspondingly upregulated, we propose that increased SHP-1 promoter methylation may relate in part to decreased SHP-1 expression and increased leukocyte-mediated inflammation in MS.Journal of neuroimmunology 03/2012; 246(1-2):51-7. DOI:10.1016/j.jneuroim.2012.03.003 · 2.79 Impact Factor
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- "Interestingly, IFN-β, a mainstay of MS treatment, has been recently shown to increase the level and activity of SHP-1 in MS patients (Christophi et al. 2009). In support of this, phosphorylation of STAT1, which mediates interferon signaling and is elevated in MS patients, has been reported to be linked to SHP-1 levels (Feng et al. 2002). These findings therefore support further study of the role of SHP-1 in controlling low-functional-avidity T cell responses, with direct applicability to the treatment of EAE and MS. "
ABSTRACT: The development of antigen-specific therapies for the selective tolerization of autoreactive T cells remains the Holy Grail for the treatment of T-cell-mediated autoimmune diseases such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). This quest remains elusive, however, as the numerous antigen-specific strategies targeting myelin-specific T cells over the years have failed to result in clinical success. In this review, we revisit the antigen-based therapies used in the treatment of myelin-specific CD4+ T cells in the context of the functional avidity and the strength of signal of the encephalitogenic CD4+ T cell repertoire. In light of differences in activation thresholds, we propose that autoreactive T cells are not all equal, and therefore tolerance induction strategies must incorporate ligand strength in order to be successful in treating EAE and ultimately the human disease MS.Journal of Neuroimmune Pharmacology 11/2009; 5(2):176-88. DOI:10.1007/s11481-009-9181-3 · 3.17 Impact Factor
- 01/1988; 1989(1). DOI:10.1109/OCEANS.1988.794913