Heterogeneous phenotypic manifestations of maternally inherited deafness associated with the mitochondrial A3243G mutation. Case report.

The A3243G mutation is one of the most frequent mutations of mitochondrial DNA. The phenotypic expression of the A3243G mutation is variable and causes a wide range of syndromic and non-syndromic clinical disorders. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is the most frequent syndromic manifestation of the A3243G mutation. Stroke-like episodes seem to be the dominant feature of MELAS. We have investigated the case of a family with A3243G mutation, in which a dominant symptom in three generations was the maternally inherited hearing loss with absence of stroke-like episodes. Besides deafness, we found also other clinical features such as myopathy, neuropathy, migraine, ataxia, short stature, diabetes mellitus, and cardiomyopathy.

Clinical study on CXCL13, CCL17, CCL20 and IL-17 as immune cell migration navigators in relapsing-remitting multiple sclerosis patients.

BACKGROUND: There has been a growing evidence for the role of chemokines in the pathology of multiple sclerosis. Recently, there has been great emphasis placed on humoral immunity and the T(H)-17 response, which has not yet been thoroughly described in MS. The aim of this study was to investigate the role of specific chemokines involved in B-cell migration (CXCL13) and in the T(H)-17 immune response (IL-17, CCL17, CCL20). METHODS: Using ELISA, the chosen chemokine concentrations were measured in the serum and cerebrospinal fluid of relapsing-remitting MS patients with both active and stable disease, and the relapse prediction rate was calculated. RESULTS: We found that the CSF concentrations of CXCL13 in patients with RRMS both, during relapse and remission, were significantly higher than in controls. CCL17 and CCL20 were not detected in CSF in either of the groups, whereas serum CCL20 level was significantly higher in remission than during relapse. Intravenous methylprednisolone treatment of patients with relapse did not influence serum CXCL13 and CCL20 levels. However, it did lower CCL17 and IL-17 concentrations. CONCLUSIONS: CXCL13 is an important mediator in MS that is strongly linked to the neuroinflammatory activity of the disease. However, more studies are needed for elucidating the roles of CCL17, CCL20 and IL-17 in MS pathology.

CCL5, CXCL10 and CXCL11 chemokines in patients with active and stable relapsing-remitting multiple sclerosis.

OBJECTIVE: Chemokines are involved in the migration of inflammatory cells to the central nervous system in multiple sclerosis (MS). The aim of our study was to estimate the concentrations of CCL5, CXCL10 and CXCL11 in serum and cerebrospinal fluid (CSF) samples of relapsing-remitting MS (RRMS) patients during both relapse and stable disease, and to compare the results with those of controls. We also decided to evaluate the effect of methylprednisolone (MP) therapy on CCL5, CXCL10 and CXCL11 serum concentrations in MS patients with relapse. METHODS: The study groups consisted of 17 RRMS patients during relapse, 30 RRMS patients in remission and 25 patients with tension headache with no symptoms of inflammatory disease as controls. In the group of relapsing MS patients, blood samples were obtained before steroid therapy and after a 5-day treatment with MP at a dose of 1 g i.v. once daily. Chemokine levels were measured by ELISA. RESULTS: CXCL10 levels were significantly higher in the CSF of MS patients both during relapse (mean ± SD, 298.2 ± 143.8 pg/ml) and stable disease (323.7 ± 183 pg/ml) in comparison with the control group (152.4 ± 97.7 pg/ml; p < 0.001). CSF levels of CCL5 were significantly higher in relapsing MS patients (8.74 ± 6.18 pg/ml) in comparison with stable MS patients (4.4 ± 3.9 pg/ml, p = 0.005). CXCL11 levels of MS patients did not significantly differ from control values. There was no effect of MP therapy on serum levels of CCL5, CXCL10 and CXCL11. CONCLUSIONS: These observations suggest involvement of CXCL10 and CCL5 but not CXCL11 in the pathogenesis of MS. CCL5 may induce the recruitment of inflammatory cells in acute-stage MS.

CXCL11 (Interferon-inducible T-cell alpha chemoattractant) and interleukin-18 in relapsing-remitting multiple sclerosis patients treated with methylprednisolone.

BACKGROUND/AIMS: Chemokines may play a role in the pathogenesis of multiple sclerosis (MS), facilitating the trafficking of immune cells across the blood-brain barrier. Interferon-inducible T-cell alpha-chemoattractant (CXCL11) recruits activated Th1 cells to sites of inflammation. In this study, we wanted to estimate the levels of CXCL11 chemokine and interleukin-18 (IL-18), a proinflammatory cytokine, in sera of relapsing-remitting MS (RRMS) patients, both before and after methylprednisolone (MP) treatment, and to compare the results with those in the control group. MATERIALS AND METHODS: Serum CXCL11 and IL-18 concentrations were measured by the ELISA method in 30 RRMS patients during relapse both before and after MP treatment, and in 20 healthy blood donors. RESULTS: We found significantly increased CXCL11 and IL-18 serum levels in RRMS patients as compared with controls. Additionally, no influence of MP therapy on the serum levels of CXCL11 and IL-18 was observed. CONCLUSION: We suggest that CXCR3 receptor ligand, CXCL11, may be involved in MS pathogenesis.

Chemokines and chemokine receptors in multiple sclerosis. Potential targets for new therapies.

Multiple sclerosis (MS) is a chronic demyelinating disease of the human central nervous system of a still unknown etiology. The autoimmune inflammatory process is believed to be essential for the development of the disease. Several different studies have shown that chemokines and chemokine receptors are involved in the pathogenesis of MS. Chemokines can mediate the trafficking of immune cells across the blood-brain barrier, and regulate their transfer to lesion sites. Chemokines were detected in actively demyelinating lesions and were found to be elevated in the cerebrospinal fluid of patients with MS during relapse. Different pairs of chemokine receptors and their ligands seem to play a pathogenic role in MS (e.g., CXCR3 and CXCL9, CXCL10; CCR1 and CCL3, CCL4, CCL5; CCR2 and CCL2; CCR5 and CCL3, CCL4, CCL5). Interfering with the chemokine system may be an effective therapeutic approach in MS. In this review we briefly summarize the results of the previous studies and identify the most important findings in the field.

[Infectious agents in the pathogenesis of multiple sclerosis]. / Czynniki infekcyjne w patogenezie stwardnienia rozsianego.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) of a still unknown etiology. Genetic factors, environmental agents and an autoimmune response may play an important role in the pathogenesis of MS. In the paper the current opinion on the role of infectious agents in the pathogenesis of MS is presented. The results of epidemiological and serological studies are discussed as well as the results of viral isolation attempts and the search for virus structures in the CNS of MS patients. The most important findings in the field e.g. a potential role of Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6) and bacteria Chlamydia pneumoniae in MS are presented. Postulated mechanisms of virus-induced demyelination are also described.

Effect of methylprednisolone treatment on expression of sPECAM-1 and CXCL10 chemokine in serum of MS patients.

In order to elucidate the mechanism of intravenous methylprednisolone (IVMP) therapy of relapses in multiple sclerosis (MS) patients, we have undertaken a study on the expression of the chemokines: soluble platelet endothelial cell adhesion molecule (sPECAM-1) and interferon gamma-inducible protein (CXCL10), before and after treatment. As more becomes known about the mechanism of methylprednisolone (MP) action, it may be possible to find a more specific treatment as well for the individual patients as the phase of the disease. The mean level of sPECAM-1 in our material was almost identical in either the MS and control subjects. After a 5-day therapy with IVMP, no changes were found in comparison with the starting value. The serum concentration of CXCL10 in MS patients was found to be higher compared to that in sera from control subjects. After therapy with IVMP the mean level of CXCL10 was diminished to the initial value and occasionally was even lower than in the control group. The findings established in our present study indicate that IVMP diminished significantly the elevated expression of CXCL10, which seems to be an important factor in the mechanism of this drug action on MS relapses. It is important to stress that the reaction is not a general one because there was no effect on the expression of sPECAM-1.

Long-term effect of IFN-beta 1a therapy on CCL2 (MCP-1) chemokine in patients with multiple sclerosis.

Chemokines play an important role in pathogenesis of multiple sclerosis (MS), mediating migration of leukocytes into the central nervous system. CCL2 (MCP-1) chemokine is expressed in astrocytes in MS lesions. The aim of the study was to evaluate the effect of a two-year treatment with IFN-beta 1a on serum CCL2 level in MS patients. CCL2 concentration in sera of 18 relapsing-remitting MS (RR-MS) patients, and of 16 healthy controls was measured by ELISA. MS patients were treated with interferon-beta 1a (Avonex) in a dose of 30 microg i.m. once weekly. Significantly lower serum CCL2 level was found in MS patients in comparison with results of the control group. CCL2 concentration increased significantly after one year of therapy with IFN-beta, and remained high after the two-year treatment. The therapy of relapsing-remitting MS patients with interferon beta 1a is associated with a significant increase in CCL2 serum concentration.