Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Interferon-beta (IFN-beta) therapy for MS is hypothesized to cause short-term and long-term changes in gene expression that shift the inflammation from Th1 to Th2. In vivo gene induction to define kinetics of response to IFN-beta therapy in a large cohort of MS patients is described. Differential gene expression in peripheral blood mononuclear cells (PBMCs) obtained from relapsing-remitting MS patients (RRMS) was assessed using high content microarrays. Rapid onset of gene expression appeared within 4 h of subcutaneous IFN-beta administration, returning to baseline levels at 42 h in clinically stable RRMS. IFN-beta therapy in vivo rapidly but transiently induced strong upregulation of genes mediating immune modulation, IFN signaling, and antiviral responses. RT-PCR showed significant patient-to-patient variation in the magnitude of expression of multiple genes, especially for IFN-beta-inducible genes, such as MxA, IRF7, and CCL8, a Th1 product. Variation among patients in IFN-beta-induced RNA transcription was not explained by neutralizing antibodies or IFN receptor expression. Surprisingly, genes regulated in vivo by IFN-beta therapy do not support a simple Th1 to Th2 shift. A complex interplay between both proinflammatory and anti-inflammatory immune regulatory genes is likely to act in concert in the treatment of RRMS.
The mechanism of action of interferon (IFN)-beta therapy in multiple sclerosis (MS) is only partially known, and its efficacy changes with disease stage. In different forms of MS, we determined how IFN-beta regulates mononuclear cell production of the important anti-inflammatory Th2 cytokine - IL-10, the Th1 cytokine - IFN-gamma, and the brain-derived neurotrophic protein - BDNF. Activated T cells and monocytes from therapy-naïve patients secreted more IL-10 than healthy controls. During IFN-beta therapy, however, T cells produced less IL-10. In vitro, IFN-beta stimulated IL-10 production by activated T cells, but inhibited IL-10 secretion by activated monocytes, a richer source of IL-10 than T cells. The form of MS also affected cytokine production. IL-10 and BDNF levels in MNC were high during relapsing/remitting (RR) MS, but low in progressive MS. Surprisingly, IFN-beta therapy increased BDNF levels in antidepressant-naïve patients, but BDNF was lower during concurrent antidepressant drug therapy, suggesting an interaction between MS, depression, and neurodegeneration. IFN-beta in vitro strongly induced IL-10 and IFN-gamma in activated T cells in RRMS, but not in progressive MS, suggesting IFN resistance. IFN-beta effects are specific for disease state and immune subsets, possibly explaining why IFN-beta therapy is most effective in early T cell-regulated RRMS, but less beneficial in progressive MS, where chronic plaques contain few T cells and high numbers of monocytes.
This study was planned to investigate the dysfunction of the autonomic nervous system in fibromyalgia syndrome (FM) using sympathetic skin responses (SSR) and RR interval analysis. Thirty-four FM and 22 healthy subjects were recruited for the study. They were questioned for symptoms that are characteristic for FM and medical outcome study short form-36 (SF-36) was used to determine the quality of life of the subjects. Tender points were counted and the disease duration was noted. SSR was recorded from palm and sole with stimulation of contralateral median and tibial nerves respectively. R-R interval variation was evaluated at rest (R%) and during deep breathing (DR%). The mean ages of the patients were 37+/- 10.2 and 37+/-10.6, respectively. The mean tender point count was 14.9+/-2.3 and the disease duration was 16.6+/-12.1 months. The symptoms were discrepant in FM (P<0.001). The scores of the eight items of SF-36 in FMS patients were significantly lower than the control group (P<0.001). We could not elicit SSR in five FM patients (15%) from the sole and in two patients (6%) from the palm. The latencies of SSR recorded from both palms and soles of FM patients were significantly longer than healthy subjects (P<0.001). The mean amplitude of SSR recorded from both palm and sole was not statistically different from control subjects (P>0.05). RRIV obtained from FM and the control subjects at rest and during deep breathing showed that the decrease in DR% was significant compared to normal subjects (P<0.001). As a result, we can state that sympathetic as well as parasympathetic nervous system dysfunction occurs in FM patients and this abnormality could be determined by SSR and RRIV analysis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.