The role of IL-15 in central nervous system disorders.

IL-15 is a proinflammatory cytokine. It is produced by activated blood monocytes, macrophages, dendritic cells, and activated glial cells. It promotes T-cell proliferation, induction of cytolytic effector cells including natural killer and cytotoxic cells and stimulates B-cell to proliferate and secrete immunoglobulins. Little information is available on the exact role of IL-15 in the neurological diseases. Microglial cells are the main regulators of both innate and adaptive immune responses in the central nervous system (CNS). IL-15 may be involved in the inflammatory reactions and microglial activation of some common CNS disorders such as multiple sclerosis, Alzheimer's and Parkinson's disease, but its exact role in their pathogenesis is not clear.

Alterations of T cell subsets in ALS: a systemic immune activation?

INTRODUCTION: There is evidence that immunological factors may involved in pathogenetic mechanisms of amyotrophic lateral sclerosis (ALS). Few studies to date have explored the status of the systemic immune response in patients with ALS. PATIENTS AND METHODS: In order to examine whether systemic immune activation is observed in patients with ALS, we measured the number of T cell subsets by flow cytometry in 36 patients with ALS and 35 normal controls. RESULTS: CD8 cytotoxic T cells and natural killer (NK) T cells were significantly increased in our patients with ALS compared with the control group (P = 0.02 and P = 0.04, respectively). Treg cells were significantly reduced compared with normal controls (P = 0.01). Treg cells were also negatively correlated with progression of the disease (P = 0.017). CONCLUSIONS: Our results suggest a systemic immune activation in patients with ALS. The high production of CD8(+) T and NKT cells may suggest an immunological reaction to some unknown or undetected endogenous proteins or viruses. A probably dual (neurodestructive or neuroprotective) inflammatory function of Treg cells cannot be excluded.

Interleukin-17 and interleukin-23 are elevated in serum and cerebrospinal fluid of patients with ALS: a reflection of Th17 cells activation?

BACKGROUND: There is evidence that immunological factors may involved in pathogenetic mechanisms of amyotrophic lateral sclerosis (ALS). Th17 cells are characterized by predominant production of IL-17 and are suggested to be crucial in destructive autoimmunity. Interleukin-23 (IL-23) appears to play a supporting role in the continued stimulation and survival of Th17. PATIENTS AND METHODS: We measured by enzyme-like immunosorbent assay (ELISA) serum and cerebrospinal fluid (CSF) levels of IL-17 and IL-23 in 22 patients with ALS and 19 patients with other non-inflammatory neurological disorders (NIND) studied as a control group. IL-17 and IL-23 serum and CSF levels were also correlated with duration of the disease, the disability level and the clinical subtype of the disease onset in patients with ALS. RESULTS: IL-17 and IL-23 serum levels were higher in patients with ALS as compared with patients with NIND (P = 0.015 and P = 0.002 respectively). IL-17 and IL-23 CSF levels were also increased in patients with ALS (P = 0.0006 and P = 0.000001 respectively). IL-17 and IL-23 levels were not correlated with disease duration, disability scale or clinical subtype of the disease onset in ALS patients. CONCLUSIONS: Our findings suggest that these molecules may be involved in the pathogenetic mechanisms acting as potential markers of Th17 cells activation in ALS.

Circulating interleukin-10 and interleukin-12 in Parkinson's disease.

BACKGROUND: Interleukin (IL)-12 is a heterodimeric cytokine produced by activated blood monocytes, macrophages and glial cells. It enhances differentiation and proliferation of T cells and increases production of proinflammatory cytokines. IL-10 is a pleiotropic cytokine produced by both lymphocytes and mononuclear phagocytes including microglia. Recent studies demonstrated the neuroprotective effect of IL-10. There is little information about the involvement of IL-12 or IL-10 in the pathophysiology of Parkinson's disease (PD). OBJECTIVES: The objective of our study was to assess the role of IL-12 as a potential marker of immune reactions in patients with PD and to investigate whether IL-10, an immunosuppressive cytokine, may have a neuroprotective effect in the pathogenesis of PD. PATIENTS AND METHODS: We measured using immunoassay serum IL-12 and IL-10 levels in 41 patients with PD in comparison with serum levels in 19 healthy subjects (controls) age and sex matched. IL-12 and IL-10 levels were tested for correlation with sex, age, disease duration, Hoehn and Yahr stage and the UPDRS III score. RESULTS: The PD group presented with significantly increased IL-10 levels when compared with the control group (P = 0.02). The increase observed was not affected by the treatment status. A strong and significant correlation between IL-10 and IL-12 levels was observed in patients with PD (R(S) = 0.7, P < 0.000001). CONCLUSIONS: Our findings suggest that IL-10 may be involved in the pathogenetic mechanisms of PD. The elevation of IL-10 and the significant correlation between IL-10 and IL-12, a proinflammatory cytokine, may suggest that immunological disturbances and neuroprotective mechanisms are involved in patients with PD.

Chronic inflammatory demyelinating polyneuropathy: a 6-year retrospective clinical study of a hospital-based population.

We reviewed the clinical, electrophysiological, laboratory and neuroimaging features of 25 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) admitted to Aeginition Hospital from 1996 to 2001. We also investigated the response to several treatment modalities. The aim was to reveal the clinical spectrum of the disease; the diagnostic criteria developed by the Ad Hoc Subcommittee of the American Academy of Neurology (AAN) in 1991 were used. The subjects consisted of 17 men (68%) and eight women (32%) aged 18-81 years (mean age: 48.5 years) with CIDP. Eighteen patients (72%) had a symmetric neuropathy, whereas seven (28%) had an asymmetric neuropathy. Two patients (8%) had a pure sensory neuropathy. Nine (36%) presented with cranial nerve involvement and only one (4%) had central nervous system demyelination. Most patients had a satisfactory response after treatment with corticosteroids, intravenous immunoglobulins, plasma exchange and azathioprine. In conclusion, CIDP is a clinically heterogeneous disorder. It is one of the few serious chronic neuropathies that has a good (although not permanent) treatment response.

IL-15 is elevated in serum and cerebrospinal fluid of patients with multiple sclerosis.

UNLABELLED: Interleukin-15 (IL-15) is a novel proinflammatory cytokine having similar biological activities to IL-2 which is implicated in the pathogenesis of multiple sclerosis. It is produced by activated blood monocytes, macrophages and glial cells. There is little information about the involvement of IL-15 in the development of multiple sclerosis (MS). The objective of our study was to measure IL-15 serum and cerebrospinal fluid (CSF) levels in MS patients and to correlate serum and CSF IL-15 concentrations with clinical parameters of the disease. CSF IL-15/Serum IL-15 ratio (c/s IL-15 ratio) was introduced to assess the origin of elevated IL-15 levels. MATERIALS AND METHODS: We measured serum and CSF IL-15 levels in 52 patients with MS and 36 age and gender matched patients with inflammatory (IND) and non-inflammatory neurological diseases (NIND) studied as control groups. IL-15 levels were correlated with clinical parameters as duration, disability, MRI activity and clinical subtypes of the disease. RESULTS: MS patients were found to have significantly higher serum IL-15 levels compared with IND (p=0.00016) and NIND patients (p=0.00045). Elevated levels of IL-15 were also found in CSF samples from MS patients compared with patients with IND (p=0.00034) and NIND (p=0.0003). Among MS subgroups there were no statistically different IL-15 serum and CSF concentrations. No significant correlation of serum and CSF IL-15 concentrations with MRI activity, disability assessed by EDSS score and duration of the disease were also found. C/S IL-15 ratio was found lower in MS patients compared with IND (p=0.01) and not significantly different compared with NIND patients (p=0.14) suggesting that systemic activation might be the source of high CSF IL-15 levels in MS patients. CONCLUSIONS: Our findings suggest a possible role of IL-15 in the immunopathogenetic mechanisms of MS.

IL-15 is elevated in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia.

Interleukin-15 is a novel proinflammatory cytokine. It is produced by activated blood monocytes, macrophages, and glial cells. The objective of our study was to assess the role of interleukin-15 as a marker of increased proinflammatory activity in patients with Alzheimer's disease and frontotemporal dementia. We measured cerebrospinal fluid interleukin-15 levels in 17 patients with Alzheimer's disease and 7 patients with frontotemporal dementia in comparison with 17 patients with amyotrophic lateral sclerosis and 15 patients with Parkinson's disease. Patients with Alzheimer's disease and frontotemporal dementia had significantly higher cerebrospinal fluid interleukin-15 levels compared with patients with noninflammatory neurological diseases (P < .05 and P < .01, respectively). In Alzheimer's disease, a significant positive correlation was noted between interleukin-15 levels and age of onset (R = .48, P = .05). Our findings suggest that interleukin-15 may be implicated in the pathophysiology of Alzheimer's disease and frontotemporal dementia.

Serum uric acid and multiple sclerosis.

UNLABELLED: Peroxynitrite (PN) has been implicated in multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis. Uric acid (UA) serum levels of MS patients, a natural scavenger of PN, were found lowered in some recent studies. OBJECTIVE/PURPOSE: The objective of our study was to correlate UA serum levels and several clinical parameters of MS. We also tried to investigate serum UA changes during treatment with immunomodulating or immunosuppressing drugs in the last 6 months. PATIENTS AND METHODS: We measured UA serum levels in 190 patients with MS and 58 age and gender matched patients with inflammatory (IND) and non-inflammatory diseases (NIND) studied as control groups. UA levels were correlated with clinical parameters as type of the disease, duration, disability, magnetic resonance imaging (MRI) activity and female gender. RESULTS: In the overall MS group, patients were found to have significantly lower mean serum uric acid levels compared with the IND (p = 0.0029) and the NIND group (p < 0.0001). UA serum concentrations were not inversely correlated with duration of the disease (p = 0.87), with disability as assessed by Expanded Disability Status Scale (EDSS) score (p = 0.67) and MRI activity (p = 0.36). Treatment with immunomodulating or immunosuppressing drugs had no influence in UA levels (p = 0.85). Patients with Clinically Isolated Syndromes (CIS) were found to have significantly lower UA concentrations compared with IND and NIND patients (p = 0.009 and <0.001, respectively). CONCLUSIONS: Our findings suggest that lower serum UA levels in MS patients may represent a primary, constitutive loss of protection against nitric oxide and the development of CNS inflammation and tissue damage may not have a direct effect to UA serum levels. They also provide support that the earlier increase of UA serum levels might be beneficial in the future treatment of MS.

The role of soluble intercellular adhesion molecules in neurodegenerative disorders.

UNLABELLED: Immunological disturbances have been implicated in the pathogenesis of some neurodegenerative disorders like Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Adhesion molecules are markers of activated endothelial cells upregulated by action of cytokines. MATERIALS AND METHODS: To investigate the activation or not of the vascular cells in AD and ALS, serum soluble intercellular adhesion molecule-1 (ICAM-1) and soluble E-selectin were evaluated (enzyme-like immunosorbent assay, ELISA) in 22 patients with Alzheimer's disease (AD), 20 patients with amyotrophic lateral sclerosis (ALS), 34 patients with non-inflammatory neurological diseases (NIND) and 15 control subjects. RESULTS: Patients with AD had higher s-ICAM-1 levels compared to NIND patients and control subjects (p<0.0027 and p<0.04, respectively). Patients with ALS had not higher s-ICAM-1 levels compared to NIND patients and control subjects (p<0.21 and p<0.31, respectively). Soluble-E-selectin levels in AD and ALS patients were not statistically different compared to NIND patients and controls (p<0.4, p<0.9 and p<0.3, p<0.19, respectively). CONCLUSIONS: The presence of high s-ICAM values may be related to immunological processes involved in pathogenetic mechanisms of AD. The not statistically significant values of s-E selectin, a glycoprotein considered an exclusive marker of endothelial activation, seem to suggest the neural rather than the endothelial s-ICAM origin in patients with AD. The low values of s-ICAM-1 and sE-selectin in the serum of ALS patients do not exclude the presence of an unconventional immunological abnormality in this disorder.

Tumour necrosis factor alpha is elevated in serum and cerebrospinal fluid in multiple sclerosis and inflammatory neuropathies.

Tumour necrosis factor alpha (TNFalpha) is a peptide that is derived from T lymphocytes and macrophages and is used as a marker of activated cellular immune responses. TNFalpha was measured in paired sera and cerebrospinal fluid (CSF) from 30 patients with multiple sclerosis (MS) with worsening disability, 54 patients with other neurological diseases, and 20 normal subjects. A sensitive enzyme-linked immunosorbent assay was used to determine the TNFalpha levels. We found significantly elevated serum and CSF levels in 12 (40%) and 6 (20%) MS patients, respectively, compared with healthy controls (P < 0.007 and P < 0.05). Among the 18 patients with neuropathy, we also found high serum and CSF TNFalpha values in 3 (17%) and 5 (28%) patients, respectively (P < 0.04 and P < 0.002). Our study shows that TNFalpha is probably involved in the pathogenetic mechanisms of MS and other inflammatory neurological diseases.

Hereditary neuropathy with liability to pressure palsies: the same molecular defect can result in diverse clinical presentation.

Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral nerve disorder characterized by autosomal dominant inheritance, recurrent pressure palsies, reduced motor and sensory conduction velocities and sausage-like swellings (tomacula) of myelin sheaths in nerve biopsy. Two young adult patients are reported as index cases of two families in which HNPP was diagnosed. The first patient presented with recurrent pressure palsies, whereas the second suffered from fasciculations and myokymias in his right hand, with difficulty in writing, and upper and lower limb paraesthesias of 3 years' duration. Electrodiagnostic studies revealed slowing of conduction primarily in common sites of compression in both patients. Sural nerve biopsy revealed the characteristic tomaculous swellings in both patients. DNA analysis showed that both patients have a deletion in chromosome 17p11.2 which is found in the majority of HNPP cases. In light of the common molecular defect, the different clinical symptomatology of the two patients is discussed.

Serum levels of soluble intercellular adhesion molecule-1 and soluble endothelial leukocyte adhesion molecule-1 in Alzheimer's disease.

Serum soluble intercellular adhesion molecule-1 (s-ICAM-1) and soluble E-selectin (s-ELAM-1) were evaluated in 25 patients with Alzheimer's disease (AD), 54 patients with noninflammatory neurological diseases (NIND), and 15 control subjects. Patients with AD had a higher s-ICAM-1 level compared with the NIND patients and the control subjects (P< .001 and P< .04, respectively). The presence of high s-ICAM-1 values may be related to immunological processes involved in pathogenetic mechanisms of AD. The not statistically significant values of (s-ELAM-1), a glycoprotein considered an exclusive marker of endothelial activation, compared with the NIND patients and healthy subjects (P< .47 and P< .17, respectively), seem to suggest the neural rather than the endothelial s-ICAM origin in patients with AD.

Superficial siderosis of central nervous system mimicking multiple sclerosis.

INTRODUCTION: Superficial siderosis of the central nervous system is a neurologic disorder mainly characterized by cerebellar involvement, myelopathy, neurosensory hearing loss, and possibly progressive cognitive impairment. Root avulsion due to traumatic plexus injury has been recognized as an extremely rare cause of hemosiderin deposition on leptomeninges and subpial layers of brain and spinal cord parenchyma. CASE REPORT: A 49-year-old man presented with progressively evolving ataxia and spastic paraparesis. CSF oligoclonal bands were indicative of an underlying inflammatory process and raised the possibility of a demyelinating disorder. However, spinal cord and brain MRI revealed hemosiderin deposition along the entire neuraxis. A rigorous electrophysiologic study confirmed a functional impairment in many different levels of the nervous system. CONCLUSION: The demonstration of CSF oligoclonal bands in the reported patient implies that inflammation might be involved in the pathogenesis of superficial siderosis. The diagnosis of this newly recognizable entity needs a high clinical suspicion, but further research is needed to fully elucidate the involved mechanisms.

Circulating interleukin-15 and RANTES chemokine in Parkinson's disease.

UNLABELLED: Interleukin-15 promotes T-cell proliferation, induction of cytolytic effector cells including natural killer (NK) and cytotoxic cells and stimulates B-cell to proliferate and secrete immunoglobulins. RANTES is a C-C beta chemokine with strong chemoattractant activity for T lymphocytes and monocytes. OBJECTIVES: The objective of our study was to find out whether IL-15 and RANTES are involved in the possible inflammatory reactions of PD. PATIENTS AND METHODS: We measured by immunoassay serum IL-15 and RANTES levels in 41 patients with PD in comparison with serum levels in 19 healthy subjects age and sex-matched. IL-15 and RANTES levels were correlated with sex, age, disease duration. H-Y stage and the UPDRS III score in all the studied groups and were also correlated with treatment status in PD patients. RESULTS: The PD group presented with significantly increased RANTES levels as compared to the control group (P = 0.0009). No difference was observed as regards IL-15 levels. A strong and significant correlation between RANTES levels and UPDRS III score was observed in PD patients (R(s) = 0.42, P = 0.007). Untreated patients had significantly higher RANTES levels as compared to the controls. CONCLUSIONS: Our findings may suggest a recruitment of activated monocytes, macrophages and T lymphocytes to sites of inflammation in the central nervous system of PD patients.

Serum levels of soluble intercellular adhesion molecule-1 (s-ICAM-1) and soluble endothelial leukocyte adhesion molecule-1(s-ELAM-1) in amyotrophic lateral sclerosis.

Immunological disturbances have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Adhesion molecules are markers of activated endothelial cells up-regulated by action of cytokines. To investigate the activation or inactivation of the vascular cells in ALS, serum soluble intercellular adhesion molecule-1 (s-ICAM-1) and soluble E-selectin (s-ELAM-1) were evaluated (ELISA) in 16 patients with ALS, 30 patients with non-inflammatory neurological diseases (NINDS) and 15 healthy control subjects. Patients with ALS had no higher s-ICAM-1 levels compared with the NINDS patients and the control subjects (p<0.31 and p<0.21, respectively). s-ELAM levels were not statistically significant compared with the NINDS patients and healthy subjects (p<0.21 and p<0.24, respectively). We conclude that the low values of s-ICAM-1 and s-ELAM-1 in the serum of ALS patients do not exclude the presence of immunological abnormality in this disorder. Soluble E-selectin is a glycoprotein which is considered an exclusive marker of endothelial activation. Its low level in our study may suggest a neural rather than an endothelial s-ICAM origin in patients with ALS.

An unusual case of insomnia associated with Whipple encephalopathy: first case reported from Greece.

Whipple disease is a relapsing systemic illness caused by Tropheryma whippelii. Central nervous system involvement occurs in 5%-40% of all patients. Hypothalamic manifestations occur in 31% of Whipple encephalopathy, including polydipsia, hyperphagia, change in libido and insomnia. We report a case of a 48-year-old man with severe insomnia, depression, dementia, dysarthria, myoclonic movements of the limbs and ophthalmoplegia. The diagnosis of Whipple encephalopathy was confirmed by PCR analysis of blood and faeces. He received a full dose of antibiotic treatment. Despite clinical improvement, resolution of the lesions detected in MRI scan of the brain and negative results of the PCR in blood, faeces and cerebrospinal fluid six months later, insomnia persisted and finally subsided after the administration of carbamazepine (600 mg/day). Our case supports the finding that carbamazepine might be useful in the treatment of insomnia associated with Whipple encephalopathy.

Exclusion mapping of the benign hereditary chorea gene from the Huntington's disease locus: report of a family.

A Greek family is presented in which seven members suffered from benign hereditary chorea (a rare autosomal dominant non-progressive chorea without dementia). All patients and three informative healthy relatives were submitted to DNA analysis using probes from loci linked to Huntington's disease. The results confirm one previous suggestion that these two disorders are not allelic and that they should be considered as two distinct genetic entities.