Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1
Department of Neurology, MC-2030, University of Chicago, 5841 South Maryland Ave., Chicago, IL 60637, USA. Journal of Neuroimmunology
(Impact Factor: 2.47).
08/2002; 129(1-2):205-15. DOI: 10.1016/S0165-5728(02)00182-0
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.
Available from: Frank Lammert
- "Impaired IFN signalling has been observed in multiple sclerosis and chronic hepatitis C infection , . Critchley-Thorne et al. identified defects in IFN signalling as a dominant mechanism of immune dysfunction in cancer patients , . "
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ABSTRACT: Autoantibodies against CD28 have been found in patients with autoimmune and atopic diseases. These antibodies may act as superagonists and activate T cells but may also be antagonistic or induce immunosuppressive effects by activating regulatory T cells. Autoimmunity in melanoma patients has been discussed controversially.
We investigated 230 melanoma patients for the occurrence of CD28 antibodies and the effect of the latter on overall and progress-free survival.
We constructed an ELISA assay to measure CD28 serum antibodies. 230 patients with melanoma and a control-group of 625 patients consistent of 212 patients with virus hepatitis b or c, 149 patients with allergies, 78 patients with psoriasis, 46 patients with plasmocytoma and 140 healthy blood donors were investigated for the occurrence of CD28 antibodies.
CD28 abs occur at a higher percentage in patients with melanoma and in patients with viral hepatitis than in other groups investigated (p<0.001). Occurrence of CD28 abs is significantly higher in patients receiving interferons independent from the underlying disease (p<0.001). In vitro CD28 serum antibodies have an inhibitory effect on the CD28 receptor as they lead to reduced stimulation of Jurkat cells. Presence of CD28 was correlated with a higher risk of dying from melanoma (p = 0.043), but not with a significantly shortened overall survival or progression-free survival.
Interferon therapy appears to induce the production of CD28 abs. In light of reports that these CD28 abs induce immunosuppressive Tregs and - as our data show - that they are inhibitors of CD28 receptor mediated stimulation, the continuation of therapies with interferons in melanoma patients developing CD28 antibodies should be critically reconsidered, since our data indicate a worse outcome of patients with CD28 abs.
Available from: Hans-Jürgen Thiesen
- "Our study is limited by the fact that we measured the gene expression in PBMCs at the mRNA level, which does not necessarily correlate with the amounts of active proteins due to post-transcriptional gene regulation, for example by microRNAs [54,55]. However, earlier studies at the protein level have already shown that the phosphorylation status of the ISGF3 component STAT1 correlates with the ISG expression in MS patients . "
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ABSTRACT: A subset of patients with multiple sclerosis (MS) shows an increased endogenous IFN-like activity before initiation of IFN-beta treatment. The molecular basis of this phenomenon and its relevance to predict individual therapy outcomes are not yet fully understood. We studied the expression patterns of these patients, the prognostic value of an elevated IFN-like activity, and the gene regulatory effects of exogenously administered IFN-beta.
Microarray gene expression profiling was performed for 61 MS patients using peripheral blood mononuclear cells obtained before and after 1 month of IFN-beta therapy. Expression levels of genes involved in pathways either inducing or being activated by IFN-beta were compared between patients with high (MX1(high) cohort) and low (MX1(low) cohort) endogenous IFN-like activity. Patients were followed for 5 years and relapses as well as progression on the expanded disability status scale (EDSS) were documented.
Before the start of therapy, 11 patients presented elevated mRNA levels of IFN-stimulated genes indicative of a relatively high endogenous IFN-like activity (MX1(high)). In these patients, pathogen receptors (for example, TLR7, RIG-I and IFIH1) and transcription factors were also expressed more strongly, which could be attributed to an overactivity of IFN-stimulated gene factor 3 (ISGF3, a complex formed by STAT1, STAT2 and IFN regulatory factor 9). After 1 month of IFN-beta therapy, the expression of many pathway genes was significantly induced in MX1(low) patients, but remained unaltered in MX1(high) patients. During follow-up, relapse rate and changes in EDSS were comparable between both patient groups, with differences seen between different types of IFN-beta drug application.
Therapeutic IFN-beta induces the transcription of several genes involved in IFN-related pathways. In a subgroup of MS patients, the expression of these genes is already increased before therapy initiation, possibly driven by an overexpression of ISGF3. Patients with high and low endogenous IFN-like activity showed similar clinical long-term courses of disease. Different results were obtained for different IFN-beta drug preparations, and this merits further investigation.
Available from: Frank Middleton
- "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). "
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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.
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