CTGF/CCN2 has a possible detrimental role in the inflammation and the remyelination failure in the early stages of multiple sclerosis.

Connective tissue growth factor (CTGF/CCN2) is a proinflammatory and an oligodendrocyte-differentiating blocking agent. It is found in MS lesions, which raises the possibility of involvement in MS pathogenesis. We found that its CSF and serum levels were higher in RR-MS patients than in controls and for serum compared to PP and SP-MS.

Specific Blockade of Bone Morphogenetic Protein-2/4 Induces Oligodendrogenesis and Remyelination in Demyelinating Disorders.

Oligodendrocyte precursor cells (OPCs) are present in demyelinated lesions of multiple sclerosis (MS) patients. However, their differentiation into functional oligodendrocytes is insufficient, and most lesions evolve into nonfunctional astroglial scars. Blockade of bone morphogenetic protein (BMP) signaling induces differentiation of OPCs into myelin-producing oligodendrocytes.

Increased Expression of Ephrins on Immune Cells of Patients with Relapsing Remitting Multiple Sclerosis Affects Oligodendrocyte Differentiation.

The effect of the inflammatory response on regenerative processes in the brain is complex. This complexity is even greater when the cause of the tissue damage is an autoimmune response. Multiple sclerosis (MS) is an immune-mediated disease in which demyelination foci are formed in the central nervous system.

Fingolimod Increases Brain-Derived Neurotrophic Factor Level Secretion from Circulating T Cells of Patients with Multiple Sclerosis.

Background: The pathophysiology of multiple sclerosis involves an autoimmune and a neurodegenerative mechanism. Central nervous system-infiltrating immune cells in multiple sclerosis also possess a neuroprotective activity through secretion of neurotrophins, such as brain-derived neurotrophic factor. Fingolimod was shown to slow the progression of disability and loss of brain volume.

Reduced levels of Coco in sera of multiple sclerosis patients: A potential role in neuro-regeneration failure.

Demyelination, axonal loss and failure of tissue repair characterize MS lesions. Bone morphogenetic proteins (BMPs) signaling is associated with remyelination failure. Coco is one of the BMP antagonists.

Natural and induced immunization against CCL20 ameliorate experimental autoimmune encephalitis and may confer protection against multiple sclerosis.

Th-17 type immune response that occurs in multiple sclerosis (MS) is linked to CCR6-CCL20 interaction. We confirmed the dependency on CCR6 in EAE development. Vaccination of mice with hCCL20, but not mCCL20, produced anti-murine CCL20 and ameliorated EAE.

High serum levels of BMP-2 correlate with BMP-4 and BMP-5 levels and induce reduced neuronal phenotype in patients with relapsing-remitting multiple sclerosis.

Blockage of bone morphogenetic protein (BMP) signaling is required for differentiation of neurons and oligodendrocytes from neural stem cells (NSCs). Sera of untreated relapsing-remitting multiple sclerosis (RR-MS) patients expressed significantly higher levels of BMP-2 compared to sera of healthy controls. BMP-2 levels correlated with BMP-4 and -5 levels only in sera of untreated MS patients.

Differential screening-selected gene aberrative in neuroblastoma (DAN) is increased in the CSF of patients with MS and may be induced by therapy with interferon-β.

Bone morphogenic proteins (BMPs) signaling blockade induce neurogenesis and oligodendrogenesis. Differential screening-selected gene aberrative in neuroblastoma (DAN) is a glycoprotein that antagonizes BMPs. We found that DAN levels were higher in CSF compared to serum in all participants.

Increased neutralization capacity of TNF-α in sera of relapsing remitting multiple sclerosis patients is not related to soluble TNF-α receptors or anti-TNF-α autoantibody levels.

The increased TNF-α levels in active lesions and CSF of multiple sclerosis (MS) patients and the beneficial effect of TNF-α blockade in animal models of MS led to the therapeutic usage of TNF-α antagonists. However, systemic TNF-α blockade exacerbated MS activity and was associated with new-onset MS when implemented for treating other autoimmune disorders. We employed a TNF-α neutralization bioassay and demonstrated that the capacity of sera from untreated and IFN-β-treated relapsing remitting MS patients to neutralize TNF-α is significantly higher than that of matched healthy controls.

Treatment with Anti-EGF Ab Ameliorates Experimental Autoimmune Encephalomyelitis via Induction of Neurogenesis and Oligodendrogenesis.

Background. The neural stem cells (NSCs) migrate to the damaged sites in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). However, the differentiation into neurons or oligodendrocytes is blocked.

Dysregulated production of leukemia inhibitory factor in immune cells of relapsing remitting multiple sclerosis patients.

Leukemia inhibitory factor (LIF) is known to potentiate the differentiation and survival of neuronal and oligodendrocyte precursors. Systemic therapy with LIF reportedly ameliorated the severity of experimental autoimmune encephalomyelitis and prevented oligodendrocyte death. We studied the secreted LIF levels from immune cells of relapsing remitting multiple sclerosis (RR-MS) patients compared to age- and gender-matched healthy controls (HCs).

Elevated and dysregulated bone morphogenic proteins in immune cells of patients with relapsing-remitting multiple sclerosis.

The abundance of neural stem cells (NSCs) in multiple sclerosis (MS) lesions with extensive astrogliosis suggests that fate factors of NSCs, such as the bone morphogenic protein (BMP) signaling maybe defective in MS. We found an elevated mRNA expression and protein secretion of BMP-2,4,5 but not of BMP-7. This was primarily in T cells.

High and dysregulated secretion of epidermal growth factor from immune cells of patients with relapsing-remitting multiple sclerosis.

We studied the secretion and regulation of epidermal growth factor (EGF) from immune cells of patients with relapsing remitting multiple sclerosis (RR-MS), and the relevance of these levels to neuronal morphology and survival. Our data suggest that the immune-mediated neuronal and oligodendroglial regeneration may be defective by the increased EGF secretion from immune cells of RR-MS patients. We also suggest an increased neurotoxicity of the immune response in RR-MS via high levels of EGF secretion.

Low and dysregulated production of follistatin in immune cells of relapsing-remitting multiple sclerosis patients.

One of the mechanisms known to play a key role in neuronal and oligodendroglial fate specification of neural stem cells (NSCs) is restriction of bone morphogenic proteins (BMP) signaling by BMP antagonists. Here, we demonstrate that follistatin mRNA and protein secreted levels in peripheral blood mononuclear cells (PBMCs) of relapsing-remitting multiple sclerosis (RR-MS) patients are significantly reduced compared to healthy controls (HC). We also observed a different profile of regulation mechanisms.

Reduced production of noggin by immune cells of patients with relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) plaques are characterized by neurodegeneration, astrogliolis, the presence of immature oligodendrocytes and infiltrating immune cells. Recent studies revealed a putative role for noggin in both neurogenesis and oligodenrocytes development. In order to study the potential of peripheral immune cells to contribute to neurogenesis in MS, we studied the mRNA expression, protein secretion and regulation profile of noggin in peripheral blood mononuclear cells (PBMCs) of untreated patients with relapsing-remitting MS (RR-MS), interferon-β (IFN-β) treated RR-MS patients compared to matched healthy controls (HC).

Dysregulated neurotrophin mRNA production by immune cells of patients with relapsing remitting multiple sclerosis.

Recent studies have suggested a neuroprotective activity of the lesion-infiltrating immune cells in multiple sclerosis (MS) by secretion of neurotrophins. We had earlier reported that immune cells from relapsing remitting MS (RR-MS) patients secrete low levels of brain-derived neurotrophic factor (BDNF), and that its secretion is dysregulated after CD40 stimulation. Here, we measured mRNA levels for BDNF, NT3 and NGF-beta mRNA in unstimulated PBMCs and found levels lower in untreated RR-MS patients than in healthy controls (HC).

Interferon-beta therapy up-regulates BDNF secretion from PBMCs of MS patients through a CD40-dependent mechanism.

We had reported that immune cells from relapsing remitting multiple sclerosis (RR-MS) patients secrete low levels of BDNF and that there is a defective regulation of its secretion via DC40. We now studied the effect of interferon-beta (IFN-beta1) on the secretion and regulation of BDNF from immune cells in patients with RR-MS. The PBMCs of IFN-beta1a treated RR-MS patients secreted higher BDNF levels vs.

The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+CD25+ T cells.

Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are in widespread use due to their LDL reducing properties and concomitant improvement of clinical outcome in patients with and without preexisting atherosclerosis. Considerable evidence suggests that immune mediated mechanisms play a dominant role in the beneficial effects of statins. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) have a key role in the prevention of various inflammatory and autoimmune disorders by suppressing immune responses.