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Krzysztof Selmaj

Publications and source records attributed to Krzysztof Selmaj.

At least 19 recordsLinked to original sources
PubMed2006

Linkage disequilibrium screening for multiple sclerosis implicates JAG1 and POU2AF1 as susceptibility genes in Europeans.

By combining all the data available from the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) project, we have been able to identify 17 microsatellite markers showing consistent evidence for apparent association. As might be expected five of these markers map within the Major Histocompatibility Complex (MHC) and are in LD with HLA-DRB1. Individual genotyping of the 12 non-MHC markers confirmed association for three of them--D11S1986, D19S552 and D20S894. Association mapping across the candidate genes implicated by these markers in 937 UK trio families revealed modestly associated haplotypes in JAG1 (p=0.019) on chromosome 20p12.2 and POU2AF1 (p=0.003) on chromosome 11q23.1.

Calcium-Binding Proteins↗
PubMed2006

Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis.

Plasmacytoid dendritic cells (pDCs) represent a DC subtype that exerts divergent functions in innate and adoptive immunity including the immediate reaction to microbial factors and the induction of immunoregulatory responses. It is thought that different DC subtypes may be critically involved in the pathogenesis of multiple sclerosis (MS). In our study we assessed the phenotype, maturation and functional properties of peripheral blood pDCs from 35 clinically stable, untreated multiple sclerosis patients, 30 healthy controls and 9 patients with pneumonia, which was used as a non-specific inflammatory condition (NIC). Ex vivo expression of CD86 and 4-1BBL was significantly lower on pDCs from multiple sclerosis patients than from controls and patients with NIC (22 versus 47 versus 41% and 12 versus 35 versus 32%, respectively). When stimulated with IL-3 and CD40L, pDCs of multiple sclerosis patients showed inefficient maturation as demonstrated by significantly lower or delayed upregulation of CD86, 4-1BBL, CD40 and CD83. Additionally, in multiple sclerosis, stimulation of pDCs by unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODN) resulted in a significantly lower interferon (IFN) alpha secretion than in controls. In multiple sclerosis, but not in controls, pDCs failed to upregulate proliferative responses and IFN-gamma secretion of autologous peripheral blood mononuclear cells (PBMC) in a co-culture system. Moreover, depletion of pDCs in multiple sclerosis patients, but not in controls, had no effect on generation of CD4+Foxp3+ regulatory T cells. We also provide data showing that glatiramer acetate (GA) treatment partially restores phenotype and function of pDCs in multiple sclerosis patients. These findings suggest functional abnormalities of pDCs in these patients, which might be of importance in the understanding of the development of immune dysregulation in this disease.

Antigens, CD↗
PubMed2006

TRAIL-induced death of human adult oligodendrocytes is mediated by JNK pathway.

Tumor necrosis-related apoptosis-inducing ligand (TRAIL) induces apoptosis of oligodendrocytes, target cells of immune attack in multiple sclerosis (MS). TRAIL-induced human oligodendrocyte (hOL) death depends on TRAIL ligation with its receptor 1 (TRAIL-R1). However, the intracellular signaling initiated with ligation of TRAIL-R1 in hOLs is unknown. We defined that intracellular transduction signaling involved in TRAIL-induced death of hOLs is associated with strong activation of c-jun NH2-terminal kinase (JNK) and a dominant negative mutant of MKK4/SEK1, MAP kinase upstream of JNK, inhibited TRAIL-induced apoptosis of hOLs. The immunoprecipitation experiments showed that JNK3 isoform was predominantly activated upon hOLs exposure to TRAIL and JNK-3 activation occurred before mitochondrial membrane dysfunction. The other mitogen-activated protein kinase p38 and ERK, as well as calpains and serine proteases, were not activated during TRAIL-induced hOL death. Accordingly, the calpain inhibitor, ZLLY.FMK, p38 kinase inhibitor, SB 203580, and serine proteases inhibitor, TPCK, did not protect hOLs from TRAIL-induced apoptosis. These results demonstrate that JNK pathway is critically involved in hOL death induced by TRAIL and might have significant importance in designing new molecules to protect immune-mediated hOLs demise.

Apoptosis Regulatory Proteins↗
PubMed2005

Inhibition of Notch signaling enhances tissue repair in an animal model of multiple sclerosis.

Oligodendrocytes (OLs) fail to regenerate myelin destroyed by the immune attack in multiple sclerosis (MS) and lesion areas are eventually largely occupied by astrocytic scar tissue. Loss of OLs in MS does not account for the limited myelin repair as lesions contain a considerable number of OL precursor cells (OPC). Activation of the Notch pathway has been shown to provide inhibitory signals for OPC and to hamper their ability to produce myelin during CNS development. Here we show that gamma-secretase inhibition of Notch signaling within OL of CNS of SJL/J mice with experimental autoimmune encephalomyelitis (EAE) significantly enhanced clinical recovery and in the CNS, promoted remyelination and reduced axonal damage. Functional assays confirmed decreased Notch signaling in inhibitor-treated groups. Therefore, gamma-secretase inhibition led to an environment more conducive to myelin repair and axonal survival. Our results suggest that manipulation of the environment associated with Notch activation in the mature CNS provides a promising therapeutic target in MS.

Amyloid Precursor Protein Secretases↗
PubMed2005

Tumour necrosis factor-induced death of adult human oligodendrocytes is mediated by apoptosis inducing factor.

Tumour necrosis factor (TNF)-induced death of oligodendrocytes, the cell type targeted in multiple sclerosis, is mediated by TNF receptor p55 (TNFR-p55). The ligation of TNFR-p55 induces several signal transduction pathways; however, the precise mechanism involved in human oligodendrocyte (hOL) death is unknown. We defined that TNF-induced death of hOLs is non-caspase dependent, as evidenced by lack of generation of caspases 8, 1 and 3 active subunits; lack of cleavage of caspases 1 and 3 fluorogenic substrates; and lack of hOL death inhibition by the general caspase inhibitor, ZVAD.FMK. Electrophoresis of TNF-exposed hOL DNA revealed large-scale DNA fragmentation characteristic of apoptosis-inducing factor (AIF)-mediated cell death, and co-localization experiments showed that AIF translocation to the nucleus occurred upon exposure to TNF. AIF depletion by an antisense strategy prevented TNF-induced hOL death. These results indicate that TNF-induced death of hOLs is dependent on AIF, information of significance for the design strategies to protect hOLs during immune-mediated demyelination.

Adult↗
PubMed2004

Differential prevention of experimental autoimmune encephalomyelitis with antigen-specific DNA vaccination.

We compared the potential therapeutic effect of vaccination with DNA constructs encoding two encephalitogenic proteins, PLP and MOG, on the outcome of subsequent sensitization of EAE induced in SJL/J and C57/B6 mice. Early sensitization for EAE (4 weeks after DNA vaccination) caused recipient animals to develop enhanced disease with DNA-encoding PLP but not with DNA-encoding MOG. Late sensitization (more than 10 weeks) resulted in an amelioration of EAE in animals vaccinated with both PLP and MOG DNA constructs. These results, confirming the DNA-mediated ameliorating effect on EAE, also indicate significant differences in the kinetics of development of EAE tolerance in response to vaccination with different DNA-encoding myelin antigens. Since PLP and MOG require different MHC presentation and induce different EAE models, the results point to potential differences in immune system requirements for efficient DNA-induced amelioration of the autoimmune response.

Animals↗
PubMed2003

TNF-alpha microinjection upregulates chemokines and chemokine receptors in the central nervous system without inducing leukocyte infiltration.

Chemokines (chemoattractant cytokines) are key players in the initiation of inflammatory cell accumulation in the central nervous system (CNS). Mechanisms leading to upregulation of chemokines in CNS pathologic conditions remain largely unknown. Numerous in vitro studies showed that inflammatory cytokines stimulate cultured CNS cells to produce chemokines. The main goal of this study was to analyze if an individual proinflammatory cytokine is sufficient to upregulate the chemokine system in the adult CNS in vivo. We analyzed CC chemokine ligand and receptor expression in brains from two different strains of mice (SJL and BALB) after stereotaxic, intracerebral injection of tumor necrosis factor-alpha (TNF-alpha). In both strains, we detected similarly increased expression of chemokines RANTES/CCL5, macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL3, MIP-1beta/CCL4, and MIP-2, as well as chemokine receptors CCR1, CCR2, and CCR5. Interestingly, we did not observe parenchymal leukocyte infiltrates after local TNF-alpha delivery. This observation shows that upregulation of chemokines by TNF-alpha is not sufficient to cause accumulation of leukocytes in the CNS parenchyma in both strains of mice.

Animals↗
PubMed2003

TNF-induced death of adult human oligodendrocytes is mediated by c-jun NH2-terminal kinase-3.

Tumour necrosis factor (TNF) induces death of oligodendrocytes, the putative cell target in multiple sclerosis. We defined that the intracellular transduction pathway involved in TNF-induced death of human adult oligodendrocytes (hOLs) is dependent on c-jun NH(2)-terminal kinase (JNK) activation, but not the other mitogen-activated protein kinase (MAPK), p38. JNK activation, measured by c-jun phosphorylation and induction of the phosphorylated form of JNK, was enhanced, prolonged and correlated with cell death in hOLs exposed to TNF. Comparative autoradiographic analysis revealed that JNK-3, but not JNK-1 or JNK-2, is responsible for prolonged JNK activation in TNF exposed hOLs. Expression of a dominant-negative mutant of JNK upstream kinase, MKK4/SEK1, inhibited apoptosis induced by TNF, whereas expression of a constitutive active mutant of MEKK1, an upstream kinase to JNK, accelerates TNF-induced apoptosis. JNK activation occurred prior to changes of mitochondrial membrane potential in hOLs exposed to TNF. These results demonstrate that TNF-induced death in adult hOLs depends on prolonged JNK-3 activation, and that this apoptosis requires the mitochondrial dysfunction that occurs after JNK activation. This is the first evidence that a JNK-3 isoform is involved in oligodendrocyte death and might have significant importance in designing new molecules to protect hOLs demise in multiple sclerosis.

Adult↗
PubMed2002

MTR discloses subtle changes in the normal-appearing tissue from relatives of patients with MS.

The presence of normal-appearing brain tissue (NABT) changes was investigated in 30 first-degree relatives of patients with MS, using magnetization transfer ratio (MTR) histograms. When compared with controls, relatives of patients with familial (p = 0.01) and sporadic (p = 0.01) MS had lower NABT MTR histogram peak heights. This study suggests a reduction of truly normal NABT in asymptomatic relatives of patients with MS.

Adult↗
PubMed2002

Experimental autoimmune encephalomyelitis: CC chemokine receptor expression by trafficking cells.

Chemokines are chemotactic cytokines, which stimulate migration of inflammatory cells towards tissue sites of inflammation. The largest chemokine group, termed CC chemokines (CCLs), act primarily on T cells and monocytes, through CC chemokine receptors (CCRs) belonging to the superfamily of G-protein coupled seven transmembrane domain receptors. CCR expression is a critical determinant of cellular responses to CCLs. In this report, we describe the expression pattern of mRNA encoding selected CCRs in the spinal cord and spleen of perfused and non-perfused mice at different stages of chronic-relapsing EAE (ChREAE). We detected increased expression of receptors (CCR1, CCR5) associated with T helper-1 (Th1) but not those (CCR3, CCR4) associated with Th2 T cells in spinal cord during initial attack and relapse of ChREAE. Expression of these CCRs correlated temporally and spatially with reported previously expression of corresponding CCLs. The principal cells expressing CCR5 were inflammatory cells invading the spinal cord. Our results supported the implication of Th1-associated CCRs in the CNS-specific inflammatory reaction of ChREAE.

Animals↗
PubMed2002

TRAIL induces death of human oligodendrocytes isolated from adult brain.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to induce apoptosis in various tumour cell lines and, recently, also in normal cells. TRAIL interacts with four receptors: two signalling receptors (TRAIL-R1 and TRAIL-R2) and two decoy receptors (TRAIL-R3 and TRAIL-R4). We have shown that both signalling receptors are present on the surface of oligodendrocytes isolated from adult human brain (ahOL), whereas the decoy receptors are expressed at a low level on ahOL. TRAIL induces ahOL apoptosis--as characterized by Annexin V staining prior to propidium iodide cell uptake--under conditions of protein synthesis inhibition. However, pre-treatment of ahOL with interferon gamma (IFNgamma) evoked susceptibility to TRAIL-induced death, which did not require inhibition of protein synthesis. A blocking experiment with monoclonal antibodies directed against TRAIL-R1 and TRAIL-R2 revealed that TRAIL-R1 is mainly involved in TRAIL-induced apoptosis of ahOL. In contrast to ahOL, microglial cells were completely resistant to cell death induced by TRAIL. Microglial cells had high surface expression of the decoy receptor TRAIL-R3, suggesting that resistance of these glial cells to TRAIL-induced death depends on the presence of the protective effect of TRAIL-R3. Stimulation of microglia with TRAIL increased further expression of TRAIL-R3, but it had no effect on the expression of TRAIL receptors by ahOL. This result may implicate TRAIL as an effector-immune molecule in selective ahOL demise in inflammatory/demyelinating conditions.

Annexin A5↗
PubMed2002

Hyperintense basal ganglia on T1-weighted magnetic resonance images in a patient with common variable immunodeficiency associated with elevated serum manganese.

The authors report on a 32-year-old man with common variable immunodeficiency and high signal intensity in basal ganglia on T1-weighted images. No signal alteration on T2-weighted and postcontrast images was observed. The patient had elevated levels of manganese in the serum. The authors conclude that the unusual hyperintensity in the basal ganglia area on T1-weighted images resulted from manganese deposition due to liver dysfunction.

Adult↗
PubMed2002

[Immunotherapy of intravenous immunoglobulin preparations in neurologic diseases].

Intravenous immunoglobulin (IVIG) has been used in a wide range of neurological conditions. Clinical effect of IVIG has been shown in controlled trials in patients with Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, dermatomyositis and recently in multiple sclerosis. This article aims to provide clinicians with an overview of the potential benefits of intravenous immunoglobulins in neurological practice.

Adult↗
PubMedDate not supplied

Treatment with soluble tumor necrosis factor receptor (sTNFR):Fc/p80 fusion protein ameliorates relapsing-remitting experimental autoimmune encephalomyelitis and decreases chemokine expression.

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease with pathological and clinical similarities to the major human demyelinating disease multiple sclerosis (MS). Multiple lines of evidence in recent years implicate the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of both EAE and MS. TNF-alpha cellular responses are mediated by signaling through receptors, which are expressed in two functional forms, designated according to molecular weight p55/60 and p75/80. We report a treatment trial using the extracellular domain of the p80 TNFR in a bivalent fusion construct designated soluble tumor necrosis factor receptor (sTNFR):Fc to treat EAE. sTNFR:Fc/p80, given after the onset of clinical signs, reduced the clinical deficit of the first attack of relapsing-remitting EAE (RR-EAE) and the exacerbation rate for subsequent attacks. The effect was reversible as mice treated with sTNFR:Fc/p80 reverted to an exacerbation rate and disease severity typical of placebo-treated animals after treatment was discontinued. Treatment of RR-EAE with sTNFR:Fc/p80 decreased expression of chemokines MIP-1alpha (Monocyte Inflammatory Protein)/CCL3, MIP-1beta/CCL4 and MIP-2/CXCL1-2 in the central nervous system. This treatment trial reveals an important function of TNF in the pathogenesis of RR-EAE and propose the mechanism of beneficial action of sTNFR:Fc/p80 in this disease.

Animals↗
PubMedDate not supplied

[Antemortem diagnosis of Balo's concentric sclerosis based on MRI. Case report].

Balo's concentric sclerosis is a rare variant of multiple sclerosis. It is pathologically characterized by alternating rings of demyelination and spared myelin. Recently, MRI was applied to demonstrate characteristic patterns in this disease. We report a case of Balo's concentric sclerosis diagnosed by the typical MRI findings of concentric rings of demyelination.

Brain↗
PubMedDate not supplied

[Open trial of the effectiveness of interferon beta 1a (Avonex) in multiple sclerosis. Clinical assessment using motor coordination tests].

OBJECTIVE: The aim of the study was to evaluate clinical efficacy and safety of interferon beta 1A (Avonex) in the Polish population of remitting-relapsing multiple sclerosis (RR MS) patients. MATERIAL AND METHODS: The study was organized as an open, multi-center trial with 126 RR MS patients. Intramuscular Avonex was administered once a week in the dose of 30 mcg. The treatment duration was 24 months. The annual relapse rate (ARR), proportion of relapse-free patients, the average change in EDSS scores between the baseline and the study completion, and the proportion of patients who deteriorated on the EDSS scale during the treatment were used as evaluation parameters. Additionally, to obtain quantitative data, the 9HPT and 25 FW test results were taken into account. RESULTS: A significant decrease in the ARR was noted in the course of treatment (from 1.47 in the 2-year period preceding the study to 0.38). The mean EDSS score for the whole group was higher by 0.13 on the study completion. However, patients without motor deficits (EDSS < 2.0) at baseline improved by 0.25 on the EDSS during the treatment, while those with motor deficits (EDSS 2.0 to 4.0)--deteriorated by 0.65. In the period under study 45.8% of the patients remained stable, 26.7% improved and 27.5% deteriorated on the EDSS. The mean duration of the 9HPT test performance increased by 0.67 sec for the dominant, and by 0.97 sec for the non-dominant hand from the baseline to post-treatment evaluation. But again, in patients without any motor deficits the mean time of 9HPT test performance was shorter post-treatment than at baseline for the dominant and non-dominant hand, while in those with motor deficits it was longer for both hands on the study completion. The mean performance time on the 25 FW test was longer by 0.74 sec on the study completion for the whole group, but in patients without motor deficits the increase in the 25 FW performance time was significantly smaller than in those with baseline EDSS scores ranging from 2.0 to 4.0. Avonex did not cause any significant abnormalities in laboratory parameters monitored during the treatment, and no significant side effects were observed except for flu-like symptoms following an Avonex injection. CONCLUSION: Results of this study confirmed a beneficial effect of 1FNb 1A (Avonex) in the dose of 30 mcg per week on the clinical status of MS patients. The findings indicate a better treatment outcome in patients with less pronounced neurological deficits at baseline.

Adjuvants, Immunologic↗
PubMedDate not supplied

[Open trial of the effectiveness of interferon beta 1a (Avonex) in the treatment of multiple sclerosis in Poland: MRI results].

OBJECTIVE: To assess the effect of interferon-beta 1A (IFNb 1A, Avonex) treatment on magnetic resonance (MR) image in patients with remitting-relapsing multiple sclerosis (RR MS) who participated in the Polish Avonex trial. PATIENTS AND METHODS: RR MS patients (N = 126) participated in a two-year randomized open trial of Avonex treatment administered in the dose of 30 mcg once a week. MRI was performed twice in each case: shortly before the patient's enrollment in the study and within a month from the study completion. Changes in T2-weighted lesion volume and T1-weighted gadolinium-enhanced lesion volume, as well as the number of new T2-weighted and T1-weighted gadolinium-enhanced lesions were measured. RESULTS: Over the two-year treatment period the mean volume of T2-weighted lesions decreased by 3.9% (p = 0.83) while that of T1-weighted gadolinium-enhanced lesions decreased by 79% (p = 0.084%) as compared to the baseline MRI evaluation. The mean number of enhanced lesions after two years of Avonex therapy was reduced by 46.1% (p = 0.0035). The total number of enhanced lesions decreased by 49.8% (p = 0.0078). Both the number of new T2-weighted lesions, 3.7 per patient, and that of new T1-weighted gadolinium-enhanced lesions, 0.7 per patient, were comparable with the results obtained in other Avonex trials. CONCLUSION: The results confirmed that interferon beta-1a (Avonex) has a significant effect in MS patients, slowing down the progress of their disease. This effect is particularly visible in T1-weighted contrast-enhanced images, indicating an impact of the treatment particularly on the inflammatory stage of the demyelination process.

Adjuvants, Immunologic↗