Search PubMed⌕ Search

Biomedical subjects

R Pirskanen

Publications and source records attributed to R Pirskanen.

At least 19 recordsLinked to original sources
PubMed2006

Expression of OX40 (CD134) on CD4+ T-cells from patients with myasthenia gravis.

Myasthenia gravis (MG) is commonly regarded as the prototype of an antibody-mediated, organ-specific autoimmune disease. Antibodies against the acetylcholine receptor (AChR) on the muscle endplate trigger its typical clinical manifestations of weakness and fatiguability. T-B cell interactions are thought to play a crucial role in the pathogenesis of MG. OX40 (CD134), a costimulatory molecule that is expressed on activated CD4+ T-cells, might contribute to the development or pathogenesis of immune-mediated diseases such as rheumatoid arthritis and graft-versus-host disease. In the present study, we investigated the expression of OX40 on CD4+ T-cells from patients with MG and healthy individuals. Results from 36 MG patients and 28 healthy controls revealed that more freshly isolated CD4+ T-cells from MG patients expressed OX40 than cells from healthy individuals. High levels of antibodies against the AChR, thymic hyperplasia and onset at an early age were associated with elevated expression of OX40. Upon activation by various concentrations of anti-CD3 antibodies, CD4+ T-cells from MG patients showed a tendency toward higher levels of OX40 expression than cells from healthy individuals. Given the role of OX40 in the immune system, we conclude that OX40 might contribute to the development of MG.

Adult↗
PubMed2006

Raised prolactin levels in myasthenia gravis: two case reports and a study of two patient populations.

OBJECTIVES: To describe two patients with myasthenia gravis (MG) and prolactinoma and analyze the associations between MG and prolactin (PRL) levels. DESIGN: Two case reports and a case-control study of PRL levels in 192 patients with MG. PARTICIPANTS: The Immunological Research Laboratory, Center for Molecular Medicine, Department of Medicine and the Department of Neurology, Karolinska Institutet, Stockholm, Sweden; St Petersburg Medical Academy for Postgraduate Studies, and St Petersburg State Medical Pediatric Academy, Russia. RESULTS: Two women with MG and thymic hyperplasia accompanied by prolactinomas are described. The levels of plasma PRL were raised in 101 women with MG, but not in 91 men. There was an association between high PRL levels and high levels of autoantibodies against the acetylcholine receptor. CONCLUSIONS: There is an association of MG with raised levels of PRL in women. PRL has stimulating effects on immune activation and the increased levels might thus be implied in the pathophysiology of MG.

Adult↗
PubMed2004

The autoimmune T and B cell repertoires in monozygotic twins discordant for myasthenia gravis.

Two pairs of monozygotic twins, discordant for myasthenia gravis (MG) for more than 30 years, were studied regarding T cell and antibody reactivity against disease related autoantigens, the acetylcholine receptor, one idiotypic and one anti-idiotypic human monoclonal antibody. The healthy and myasthenic twins had very similar autoantibody repertoires. IgG fractions from both healthy and myasthenic twins had the same capacity to decrease the free acetylcholine receptor content in mice after passive transfer. In comparison with their myasthenic sisters, the healthy twins had lower T cell responses against the acetylcholine receptor.

Adult↗
PubMed2004

Circulating CD4+CD25+ and CD4+CD25+ T cells in myasthenia gravis and in relation to thymectomy.

Studies in experimental animal models of human autoimmune diseases have revealed that CD4(+)CD25(+) T regulatory (Tr) cells are of thymic origin and have potentials in preventing auto-aggressive immunity. Myasthenia gravis (MG) is the best-characterized autoimmune disease. Changes in the thymus are found in a majority of patients with MG. Thymectomy has beneficial effects on the disease severity and course in a substantial proportion of MG patients. But the occurrence and characteristics of Tr cells have not yet been defined in MG. We determined the frequencies and properties of circulating CD4(+)CD25(+) versus CD4(+)CD25(-) cells in MG patients and healthy controls (HCs), with special focus on the effect of thymectomy on CD4(+)CD25(+) cells. CD4(+)CD25(high) cells comprise only about 2% of blood lymphocytes in both MG patients and HCs. Frequencies of CD4(+)CD25(high) cells were similar in MG patients irrespective of treatment with thymectomy. CD4(+)CD25(+) cells in both MG patients and HCs are mainly memory T cells and are activated to a greater extent than CD4(+)CD25(-) cells, as reflected by high levels of CD45RO and human leucocyte antigen (HLA)-DR-positive cells. In both MG patients and HCs, CD4(+)CD25(+) cells also contained a high proportion of CD95-expressing cells as possible evidence of apoptosis-proneness. Upon stimulation with anti-CD3/CD28 monoclonal antibodies, CD4(+)CD25(+) cells responded more vigorously than CD4(+)CD25(-) cells in MG, irrespective of treatment with thymectomy, as well as in HCs. Although CD4(+)CD25(-) cells are mainly naïve T cells, in non-thymectomized MG patients, they are activated to a greater extent as reflected by higher expression of HLA-DR and CD95 on the surface compared to HCs. The data thus show that there is no deficiency of CD4(+)CD25(+) cells in MG, nor is the proportion of CD4(+)CD25(+) cells influenced by thymectomy.

Adolescent↗
PubMed2002

Peripheral neuropathy in acrodermatitis chronica atrophicans - effect of treatment.

Forty-seven patients with the late borrelial manifestation acrodermatitis chronica atrophicans (ACA) and with objective neurological and/or neurophysiological findings were followed up after antibiotic treatment with dermatological, serological, neurological and neurophysiological controls. Despite a good therapeutic effect on ACA lesions, specific antibody values and symptoms of irritative nerve lesions, the objective neurological and neurophysiological findings of nerve deficit remained unchanged. There was no progress of neuropathy findings during the follow-up time. Our interpretation of the results is that the remaining neuropathy signs after treatment of ACA are neurological sequelae and not manifestations of persisting Borrelia infection.

Acrodermatitis↗
PubMed2002

CDS1 and promoter single nucleotide polymorphisms of the CTLA-4 gene in human myasthenia gravis.

The cytotoxic T lymphocyte associated protein 4 (CTLA-4) gene (Ctla-4) is a candidate gene for autoimmune disease. We here report results of two single nucleotide polymorphisms (SNPs) in the Ctla-4, a +49 A/G SNP in CDS1 and a C/T promoter SNP at position -318. There were no differences in these two SNPs between patients and healthy individuals. The frequency of allele G and genotype G/G at position +49 in CDS1 was increased in patients with thymoma when compared with patients with normal and hyperplastic thymic histopathology. Patients with the G/G genotype had signs of immune activation manifested as higher levels of serum IL-1beta and higher percentage of CD28(+) T lymphocytes. There was a strong linkage between the 86bp allele in the 3'-UTR and the A(+49) allele in CDS1. Our results suggest that the SNP at position +49 in CDS1 might be associated with the manifestations of MG.

3' Untranslated Regions↗
PubMed2001

Elevated levels of soluble Fas and Fas ligand in cerebrospinal fluid of patients with AIDS dementia complex.

We measured the levels of sFas and sFasL in CSF and serum of HIV-1 infected patients and related them to AIDS dementia complex (ADC). Specimens were obtained from 51 HIV-1 infected individuals (29 with ADC) and 39 HIV negative individuals. The sFas was detectable in all sera and 98% of CSF specimens. Measurable levels of sFasL were found in 79% of the CSF and 98% of sera samples. According to the presence or absence of ADC, we observed significant differences in CSF sFas (median and IQR 116, 132 vs. 30, 23 pg/ml, P<0.001) and sFasL (median and IQR 127, 290 vs. 15, 73 pg/ml, P<0.001) levels. The sFas in serum differed significantly between HIV-1 infected subjects and non-infected controls (P<0.001), with no correlation to ADC. On the contrary, sFasL in serum differed among HIV-1 infected subjects according to clinical signs of ADC. In the cross-sectional study, the number of cells present in CSF and CD4+ T cell counts in blood did not correlate to the levels of CSF sFas and sFasL. Interestingly, the number of HIV RNA copies in CSF correlated significantly to the levels of CSF sFasL (P=0.001) but not to sFas in the same compartment. Antiretroviral therapy reduced viral load and sFas levels in CSF in the majority of patients. sFas is a useful marker for ADC diagnosis and follow-up during antiviral treatment.

AIDS Dementia Complex↗
PubMed2000

Dinucleotide repeat expansion in the CTLA-4 gene leads to T cell hyper-reactivity via the CD28 pathway in myasthenia gravis.

CD28 is required to promote T cell proliferation and cytokine production, while the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) functions as a negative modulator for T cell activation. We previously reported that alleles with longer PCR products (designated as allele xx) in an (AT)n polymorphism in Ctla-4 are associated with myasthenia gravis with thymoma, while the shortest allele, 86, is negatively associated with the disease. Here, we demonstrate that serum IL-2 sRalpha increases parallel to the length of (AT)n in Ctla-4. Periphereal blood mononuclear cells (PBMC) from patients with Ctla-4 xx/xx contained higher activity of telomerase than patients bearing Ctla-4 86/86. Blockade of CTLA-4 increased the telomerase activity in PBMC stimulated by acetylcholine receptor in vitro. There was a positive correlation between the expression of CD28 and CTLA-4 on anti-CD3 activated PBMC, suggesting a balance between CD28 and CTLA-4. Cells from patients with Ctla-4 xx/xx had the highest level of T cell proliferative responses upon the addition of anti-CD28 antibodies to the anti-CD3 containing culture system while cells from patients with Ctla-4 86/xx had an intermediate and cells from patients with Ctla-4 86/86 the lowest increase. The current results point to the (AT)n in Ctla-4 as a myasthenia gravis facilitating mutation under certain permissive environments by influencing the T cell reactivity via the CD28 pathway.

Abatacept↗
PubMed2000

Altered expression of costimulatory molecules in myasthenia gravis.

To characterize the involvement of costimulatory pathways in the pathogenesis of myasthenia gravis (MG), a multiparameter flow cytometry assay was adopted to enumerate blood mononuclear cells (MNC) expressing CD28, CD80, CD86, CD40, and CD40L molecules in patients with MG and healthy subjects. Patients with MG had lower percentages of CD8(+)CD28(+) cells, augmented percentages of CD4(+)CD80(+), CD4(+)CD86(+), CD8(+)CD80(+), CD8(+)CD86(+), CD14(+)CD80(+), and CD14(+)CD86(+) cells, and similar levels of cells expressing CD40 and CD40L and of B cells expressing CD80 and CD86 compared to the controls. Patients with early onset of MG (<40 years) had lower percentages of CD3(+)CD86(+), CD4(+)CD86(+), CD8(+)CD86(+) T cells and CD20(+)CD86(+) B cells compared to those with late onset (>40 years). There was a positive correlation between the patients' age and percentages of CD86(+) cells. The data indicate that the CD28/CD80-CD86 costimulatory pathway is involved in MG. The high percentages of CD80 and CD86 positive T cells and monocytes may reflect persistent activation of T and B cells, whereas the low CD28 expression may be the result of chronic exposure to CD80 and CD86. These molecules could be the focus for new and improved immunomodulating therapies of MG.

Adult↗
PubMed2000

Polyneuropathy in late Lyme borreliosis - a clinical, neurophysiological and morphological description.

In a prospective study, detailed clinical and neurophysiological examinations were performed in 17 patients with polyneuropathy associated with the late borrelial manifestation acrodermatitis chronica atrophicans (ACA). Similar clinical and neurophysiological signs were found in most of the patients. The findings were those of a sensory polyneuropathy, mainly affecting large nerve fibres. Marked abnormality of vibration threshold was a common finding and in 4 patients this raised a suspicion of spinal cord engagement, in addition to a polyneuropathy. Sural nerve biopsy, performed in 3 of the patients, showed a mainly axonal neuropathy. Biopsy findings did not confirm earlier reports of vasculitis of epineural vessels in ACA-associated polyneuropathy.

Acrodermatitis↗
PubMed2000

beta2-adrenergic receptor gene polymorphisms in myasthenia gravis (MG).

The beta2-adrenergic receptor (beta2-AR) belongs to the group of G-protein coupled receptors and is present mainly on skeletal and cardiac muscle cells and lymphocytes. The gene encoding beta2-AR (ADRB2) displays a moderate degree of heterogeneity in the human population. The distribution of polymorphisms at amino acid positions 16, 27 and 164 is changed in asthma, hypertension and obesity. We have earlier reported a decreased density of the beta2-AR on peripheral blood mononuclear cells and the presence of beta2-AR antibodies in patients with MG. Since certain polymorphisms affect the function of the beta2-AR, it was of interest to analyse these in MG. Using allele-specific polymerase chain reaction amplification, we revealed an over-representation of homozygosity for Arg16 and a lower prevalence of homozygosity for Gly16 in MG patients compared with healthy individuals. The increased frequency of homozygosity for Arg16 was due to a contribution from patients with generalized MG but not from patients with only ocular disease. Homozygosity for Glu27 was negatively associated with both the presence of beta2-AR antibodies and severity of disease. Moreover, acetylcholine receptor (AChR) antibodies were more often present in patients being homozygous for Gln27. Our results imply that homozygosity for Arg16 confers susceptibility to generalized MG, and that certain polymorphisms at amino acid position 27 are associated with subgroups of patients.

Adolescent↗
PubMed2000

Decreased mRNA expression of TNF-alpha and IL-10 in non-stimulated peripheral blood mononuclear cells in myasthenia gravis.

Myasthenia gravis (MG) is characterized by T cell-dependent autoantibodies to the acetylcholine receptor on the post-synaptic membrane of the neuromuscular junction. The production of autoantibodies is regulated by T cells via cytokines. To investigate the involvement of interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha), interleukin-4 (IL-4) and interleukin-10 (IL-10) in MG, the mRNA levels of these cytokines in peripheral blood mononuclear cells without stimulation in vitro were quantified by competitive reverse transcription polymerase chain reaction technique. The mRNA level of TNF-alpha was significantly lower (P = 0.0004) in the overall group of MG patients compared with controls. IL-10 was also lower in MG patients (P = 0.008), most markedly in non-thymectomized patients (P = 0.016). There were no significant differences in IFN-gamma and IL-4 between patients and healthy controls, but the mRNA levels of IL-4 in non-thymectomized patients was significantly lower than in controls (P = 0.02) and in thymectomized patients (P = 0.03). These results, reflecting the in vivo expression pattern of these cytokines in the periphery, suggest an altered cytokine expression at the systemic level in MG.

Adult↗
PubMed1999

Polymorphisms at - 174 and in the 3' flanking region of interleukin-6 (IL-6) gene in patients with myasthenia gravis.

We examined the bi-allelic polymorphism at - 174 in the promoter region and the polymorphism in the 3' flanking AT rich region of the interleukin-6 (IL-6) gene in Swedish patients with myasthenia gravis (MG) and ethnically matched healthy individuals. There was no association between the polymorphisms and the disease. There was no relation of the polymorphisms to the clinical variables, the thymic histopathologies, the level of serum acetylcholine receptor antibodies or the concentrations of IgG and its subclasses. Our data yield no evidence for the IL-6 gene contributing to the disease susceptibility.

AT Rich Sequence↗
PubMed1999

Antibody dependent cell-mediated cytotoxicity--an additional mechanism in human autoimmune myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease characterised by serum anti-acetylcholine receptor (AChR) antibodies and several pathogenic mechanisms for the action of these antibodies have been elucidated. In this study, we have analysed a possible additional mechanism for these antibodies, namely antibody-dependent cell-mediated cytotoxicity (ADCC). Using as target cells a cell line expressing AChR, we could show an increased ADCC mediated by sera from MG patients. Sera with AChR antibodies induced a higher cytotoxicity than sera from patients without these antibodies or healthy individuals. Sera from MG patients with thymoma induced a higher cytotoxic effect than sera from other patients. There was a strong positive correlation between the concentration of AChR antibodies and cytotoxicity mediated by purified IgG fractions from thymoma patients. In addition, there was a higher cytotoxicity mediated by sera from thymoma patients with extended dinucleotide repeats, (AT)n repeats, in the CTLA-4 gene. ADCC mediated by AChR antibodies may thus be another possible pathogenic mechanism that could operate in MG patients, especially in patients with thymoma.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1999

Markers in the promoter region of interleukin-10 (IL-10) gene in myasthenia gravis: implications of diverse effects of IL-10 in the pathogenesis of the disease.

Interleukin-10 (IL-10) is an important pleiotropic cytokine with both anti-inflammatory and B lymphocyte stimulating functions. The expression of IL-10 is tightly controlled. A bi-allelic polymorphism and 2 CA repeat microsatellites located in the promoter region of IL-10 gene were analysed in Swedish myasthenia gravis (MG) patients and ethnically matched healthy individuals. The prevalence of a 'high secretor' phenotype of IL-10 (IL-10 1 G/G) was higher in IL-1beta TaqI polymorphism allele 2 positive healthy individuals ('high secretor' phenotype for IL-1beta) than in healthy individuals negative for this allele. No such balance was found in MG patients. In one of the microsatellites, IL10.R, allele 112 was associated with patients having normal thymic histology. No relation of IL10.R allele 112 to proinflammatory cytokine gene polymorphisms and serum IgG, IgM and autoantibodies against nicotinic acetylcholine receptor (nAchR-Ab) was found. In another microsatellite, IL10.G, allele 134 was associated with patients having higher level of nAchR-Ab in their circulation. Our results demonstrated novel genetic markers within IL-10 gene indicating different mechanisms for IL-10 involved in the disease.

Alleles↗
PubMed1999

Tumour necrosis factor-alpha polymorphism and secretion in myasthenia gravis.

The mechanism behind the association between MHC genes and myasthenia gravis (MG) is not fully understood. In the present study we studied the associations with polymorphisms at HLA-DR3, HLA-B8 and TNF-alpha genes in Swedish patients and healthy individuals. The TNF-alpha-308 allele 2 was associated with female patients having disease onset before the age 40 and with thymic hyperplasia. Analysis of strongest associations between MG and alleles close to TNF-alpha indicated that the association of TNF-alpha was possibly stronger than for HLA-DR3 and nearly the same as for HLA-B8. Peripheral blood mononuclear cells from patients positive for TNF-alpha -308 allele 2 had higher secretion of TNF-alpha when stimulated by anti-CD3 antibodies. Our results indicate that a subgroup of MG patients who have been previously shown to be associated with MHC genes may have a higher inducible TNF-alpha level in vivo, thus resulting the pathological changes in the thymus and the early onset of MG.

Adult↗
PubMed1999

Increased levels of circulating acetylcholine receptor (AChR)-reactive IL-10-secreting cells are characteristic for myasthenia gravis (MG).

Antibodies to the nicotinic AChR are pivotal in the immunopathogenesis of MG. Cytokines produced by T-helper cells are important regulators of humoral immune responses. IL-10 is considered an anti-inflammatory cytokine, but it promotes B cell activation and worsens experimental autoimmune MG in Lewis rats, an experimental model of MG. To study IL-10 and, as a control, interferon-gamma (IFN-gamma) in MG, we used an enzyme-linked immunospot (ELISPOT) assay, thereby assessing numbers of blood mononuclear cells (MNC) secreting IL-10 and IFN-gamma spontaneously and after stimulation with AChR. Low numbers of IL-10-secreting cells were regularly found in peripheral blood from patients with MG as well as in controls with other neurological diseases and healthy subjects. However, only MG patients had elevated blood levels of AChR-reactive IL-10- and IFN-gamma-secreting cells. The MG patients showed no responses to the control autoantigen myelin basic protein, underlining the specificity of the IL-10 and IFN-gamma responses. Immunosuppressive treatment reduced numbers of AChR-reactive IFN-gamma-secreting cells but increased the numbers of IL-10-secreting cells. The numbers of IL-10-secreting cells tended to be higher in patients with generalized versus ocular MG, further suggesting that the augmented IL-10 responses may be important in the pathogenesis and perpetuation of MG.

Adult↗