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Biomedical subjects

A K Lefvert

Publications and source records attributed to A K Lefvert.

At least 37 records · Page 2Linked to original sources
PubMed2000

Anticardiolipin antibodies are not an independent risk factor for stroke: an incident case-referent study nested within the MONICA and Västerbotten cohort project.

BACKGROUND AND PURPOSE: Anticardiolipin antibodies (aCL) have been proposed to be an independent risk factor for stroke. To test this hypothesis, a nested case-control study was performed to compare aCL with the other known risk factors for stroke. METHODS: Within the framework of the World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project and the Västerbotten Intervention Program (VIP) health survey, 44 725 men and women were enrolled and followed up from January 1, 1985, through August 31, 1996. Individuals free from cardiovascular events were followed up, and 123 developed stroke (on average, 34.1 months after blood sampling; 21 cerebral hemorrhage and 102 cerebral infarction); they were compared with 241 age- and sex-matched control subjects from the same population. ELISA was used for the analysis of IgG, IgM, and IgA aCL. RESULTS: IgM-aCL were present in 11.4% of patients (14/123) who developed stroke and in 4. 1% of individuals (10/241) who remained healthy (P=0.013, OR 2.97, 95% CI 1.28 to 6.89). The OR for the levels of IgM-aCL was 1.34 (P=0. 01, 95% CI 1.07 to 1.68) without adjustment for other risk factors and 1.24 when adjusted for hypertension, diabetes mellitus, cigarette smoking, and use of smokeless tobacco (P=0.077, 95% CI 0. 98 to 1.56). There was no difference between patients and controls for the prevalence or level of IgG-aCL and IgA-aCL and also no difference between patients with cerebral hemorrhage and cerebral infarction for the prevalence of all 3 isotypes of aCL. CONCLUSIONS: We conclude that aCL are associated with future stroke but do not constitute an independent risk factor.

Adult↗
PubMed2000

Polymorphisms in CTLA-4 but not tumor necrosis factor-alpha or interleukin 1beta genes are associated with Wegener's granulomatosis.

OBJECTIVE: The genetic factors predisposing to Wegener's granulomatosis (WG) are largely unknown. T cells are clearly involved in the disease, as are the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta). The cytotoxic T lymphocyte associated antigen-4 (CTLA-4) suppresses antigen-specific immune responses by opposing the CD28 pathway, and is crucial for a balanced T cell activation. Genetic variations in the TNF-alpha, IL-1beta, and CTLA-4 genes could thus be important in WG. METHODS: Polymorphisms in the genes coding for TNF-alpha, IL-1beta, and CTLA-4 were analyzed in 32 Swedish Caucasian patients and 109 ethnically matched controls. Results. A strong association of Ctla-4 (AT)n microsatellite to WG contrasts to the negative finding of associations between TNF-alpha NcoI, IL-1beta TaqI restriction fragment length polymorphism, and WG. The prevalence of the shortest Ctla-4 allele was decreased in patients with WG compared with healthy individuals (p < 0.0001, pc < 0.0016). CONCLUSIONS: This is the first report of a T cell related gene in association with WG. The Ctla-4 itself, or a gene close to Ctla-4, may thus contribute to the pathogenesis of WG by allowing an increased T cell activation by antigen.

Abatacept↗
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

C4 null alleles and myocardial infarction.

The classical risk factors, hypercholesterolemia, smoking, hypertension and diabetes, explain only a part of the epidemiological features of atherosclerotic coronary heart disease. Investigations in the past few years have shown involvement of immunological mechanisms in atherosclerosis. Circulating immune complexes accelerate atherosclerosis both in experimental animal models and in humans. The fourth component of complement (C4) plays an important role in the solubilisation and elimination of immune complexes. C4 consists of two allotypes, C4A and C4B. An earlier report showed an association between C4B null alleles (C4B*Q0) and myocardial infarction and to infarction related mortality. In the present investigation, C4A*Q0 and C4B*Q0 were studied in two population samples. The first (Group I) was a cross sectional study of 100 consecutive males with myocardial infarction before the age of 45 years and 164 population based healthy controls, age and sex matched. The second (Group II) was a nested case control study in which a cohort of 50 year-old males were followed for 20 years for development of myocardial infarction between 50-60 and 60-70 years, and the results compared with those who did not develop MI. We observed no association of homozygous and/or heterozygous C4A*Q0 or C4B*Q0 with myocardial infarction occurring in the age groups < 45, 50-60 and 60-70 years or with the infarction related mortality (P > 0.05). The prevalence/frequency of C4A*Q0 and C4B*Q0 was not related to the age at which MI occurred. The prevalence of C4A*Q0 was not affected by age. We thus conclude that partial deficiency of C4 does not appear to be a major risk factor for myocardial infarction.

Adult↗
PubMed1999

Circulating immune complexes and complement C4 null alleles in patients in patients operated on for premature atherosclerotic peripheral vascular disease.

Circulating immune complexes can lead to vascular inflammation and premature atherosclerosis and the fourth component of complement, C4, plays an important role in the removal of immune complexes. The objective of this study was to analyze the relation between circulating immune complexes and C4 null alleles in patients operated on for peripheral vascular disease before the age of 50. The prevalence of circulating immune complexes and null alleles of C4 (C4Q0) was determined in 62 patients with peripheral atherosclerosis requiring surgery before 50 years of age and in a matched control group. C4A and C4B null alleles (C4A*Q0, C4B*Q0) were determined by electrophoresis of plasma, followed by immunofixation. C4A and C4B concentrations were measured by ELISA. Circulating immune complexes were determined by sucrose density gradient centrifugation and gel filtration. There was no difference in the distribution of C4Q0 between patients and controls. The patients had higher prevalences and levels of circulating immune complexes. This was correlated with the presence of C4Q0, especially C4A*Q0. There was an inverse correlation of concentration of circulating immune complexes with C4A levels and with ratio of C4A/B levels. Thus, a significant proportion of patients with premature peripheral atherosclerosis had circulating immune complexes and C4A*Q0 enhanced the propensity to immune complex formation. This might represent one mechanism for vascular damage in this patient group.

Adult↗
PubMed1999

Anti-cardiolipin antibodies and circulating immune complexes in type 1 diabetes mellitus: increased prevalence and relation to vascular complications.

Anti-cardiolipin antibodies, oxidatively modified low-density lipoproteins (oxLDL) and circulating immune complexes are humoral factors that have been linked to vascular damage. To analyse their possible role in the vascular complications in type 1 diabetes mellitus, we investigated patients with and without vascular complications (retinopathy, nephropathy, polyneuropathy, foot ulcers). The patients were matched for age, sex and duration of diabetes. The patients were also compared with 102 healthy individuals. Anti-cardiolipin antibodies of IgG and IgA type were more common in patients compared with healthy individuals. There was no difference between patients with and without vascular complications. There was no increased prevalence of IgM anti-cardiolipin antibodies, but the levels of these antibodies were higher in patients with vascular complications compared with patients without complications and controls. Eighty-three percent of patients had circulating immune complexes in comparison with 5% of healthy individuals. Such complexes were more common in patients with complications. Both the prevalence and the levels of immune complexes were higher in patients with null alleles of complement factor C4. Patients with vascular complications had higher prevalence of C4A than of C4B null alleles. Anti-cardiolipin antibodies were present in higher relative concentrations in immune complex form than in serum in all six patients analysed. There was no increased prevalence of antibodies against oxidatively modified LDL in the patients. The higher prevalence and levels of anti-cardiolipin antibodies and circulating immune complexes in patients with vascular complications suggests that these humoral factors might be involved in the vascular complications of type 1 diabetes mellitus.

Adult↗
PubMed1999

Autoantibodies against oxidatively modified LDL do not constitute a risk factor for stroke: a nested case-control study.

BACKGROUND AND PURPOSE: Autoantibodies against oxidatively modified LDL have been shown to be associated with atherosclerosis. Their possible pathogenic role is not yet fully understood, and earlier published data are inconsistent. In this prospective study, we have investigated the association of these antibodies with future stroke. METHODS: A prospective case-control study in which 44 725 men and women from the World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project and the Västerbotten Intervention Program (VIP) were enrolled and followed from January 1, 1985, to August 31, 1996. One hundred nineteen cases of stroke (male 75, female 44) were noted and compared with 233 age- and sex-matched controls from the same population. Antibodies against oxidatively modified LDL (copper-oxidized LDL and malonaldehyde [MDA]-LDL) were analyzed by ELISA. RESULTS: There was no difference in the levels or in the prevalence of IgG, IgA, and IgM autoantibodies against copper-oxidized LDL or MDA-LDL between patients and controls. Risk ratios for these antibodies, when adjusted for diabetes mellitus, hypertension, and smoking habits, did not confer a risk of stroke. Serum triglycerides (1.7 versus 1.4 mmol/L, P=0.01), fasting blood sugar, and systolic and diastolic blood pressures were significantly higher in the patient group than in the control group, as was the prevalence of hypertension (51.8% versus 27.4%, P<0.0001) and diabetes mellitus (9.6% versus 0.8%, P<0.001). CONCLUSIONS: Autoantibodies against oxidatively modified LDL do not constitute a risk factor for stroke in an adult population.

Adult↗
PubMed1998

No evidence for interleukin-4 gene conferring susceptibility to myasthenia gravis.

A variable number of tandem repeat (VNTR) and a dinucleotide repeat polymorphism in IL-4 gene were examined in Swedish myasthenia gravis (MG) patients and ethnically matched healthy individuals. There were no associations between these polymorphisms and MG patients as a whole group or stratified by clinical and pathological parameters and genetic markers in MHC gene (TNF-alpha NcoI allele 2) and IL-1 gene (IL-1beta TaqI allele 2). This lack of association between the IL-4 gene and disease contrasts to our previous results showing that MG is associated with higher secretor phenotypes of two prototype proinflammatory cytokine (TNF-alpha and IL-1) genes.

Adult↗
PubMed1998

T-cell expansions with conserved T-cell receptor beta chain motifs in the peripheral blood of HLA-DRB1*0401 positive patients with necrotizing vasculitis.

T lymphocytes are implicated in the pathogenesis of systemic vasculitis such as Wegener's granulomatosis (WG) and polyarteritis nodosa (PAN). In the present study, we have characterized in detail the T-cell receptor (TCR) of peripheral blood T cells from eight vasculitis patients of known HLA class II genotypes. We used flow cytometry to outline the exact TCR V gene expression, complementarity determining region 3 (CDR3) fragment analysis to estimate the degree of clonality and cDNA sequencing to define the exact TCR or beta chain sequences. The TCR CDR3 region interacts with antigenic peptides presented by HLA molecules, and it is normally immensely diverse. It was therefore of particular interest to identify a common dominating TCR BV8-F/L-G-G-A/Q-G-J2S3 beta chain sequence in the CD4(+) T cells of four unrelated vasculitis patients. Furthermore, this BV8-associated CDR3 motif was linked to the HLA-DRB1*0401 allele, as well as to active disease and/or an established BV8(+) CD4(+) T-cell expansion. In contrast, age- and HLA-matched patients with rheumatoid arthritis did not harbor the described BV8 motif. These results strongly suggest that BV8(+) CD4(+) T cells with the described CDR3 motif recognize a specific antigen presented by DR4 molecules, indicating the existence of a common vasculitis-associated antigen.

Adult↗
PubMed1998

Antibodies against beta1 and beta2 adrenergic receptors in myasthenia gravis.

Patients with myasthenia gravis have antibodies and T cells that react with the beta1- and beta2-adrenergic receptors. These receptors, as well as other auto-antigens, are present on cardiomyocytes, skeletal muscle cells and lymphocytes and are of importance for the regulation of the functions of these organs. Antibodies against the beta1-adrenergic receptor have been implicated in dilated cardiomyopathies. Myasthenia gravis (MG) patients have been suggested to have a higher than normal prevalence of heart disease. We have analysed the isotypes, subclasses, and binding sites of the beta-adrenergic receptors antibodies in both MG patients and healthy individuals and the correlation between beta-adrenergic receptors antibodies and heart disease in MG patients. The patients have IgG antibodies that react with both beta1- and beta2-adrenergic receptors. The subclasses were predominantly IgG2 and IgG4. By using synthesised overlapping peptides representing the immunodominant regions on the receptors, it was shown that the antibodies bound to partially overlapping sites on both beta1- and beta2-adrenergic receptors, but not to peptides from the acetylcholine receptor. beta-adrenergic receptor antibodies were found in 34/125 MG patients. Seven out of these 34 patients had symptomatic heart disease, all seven were over 70 years of age and had arteriosclerotic heart disease. There was no difference in the prevalence of clinical heart disease in patients with and without beta-adrenergic receptor antibodies. However, patients with heart disease had significantly higher levels of antibodies than healthy individuals and other patients. Antibodies against beta-adrenergic receptors in patients with myasthenia gravis binds to both beta1- and beta2-adrenergic receptors and might be implicated in the few patients with myasthenia gravis who have heart disease.

Aged↗
PubMed1998

Polymorphism in tumor necrosis factor genes associated with myasthenia gravis.

The aim of this study was to analyze associations between myasthenia gravis (MG) and polymorphisms in the tumor necrosis factor (TNF) region in 79 Swedish patients and 155 unrelated controls. The frequency of the TNFa2 allele of a microsatellite located 3.5 kb upstream of the lymphotoxin alpha (LT-alpha) gene in the TNF region was found to be increased in overall MG patients compared to controls. The frequency of the short 5.5 kb fragment (TNFB * 1) of a bi-allelic NcoI RFLP polymorphism located at the first intron of the LT-alpha gene was increased in patients with an early onset of disease compared to patients with a later onset.

Age of Onset↗
PubMed1998

Genetic association of Ctla-4 to myasthenia gravis with thymoma.

Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) plays a pivotal role in downregulating both the cellular and the humoral response by suppressing ongoing responses of activated T cells. Our earlier study showed that genetic variations in interleukin-1 genes confer susceptibility to myasthenia gravis, especially in patients having the lowest risk from major histocompatibility complex genes. Here we describe an association of Ctla-4 gene to the disease with thymoma and a higher prevalence of CTLA-4 gene polymorphism allele 104 in patients positive for IL-1beta TaqI allele 2, an IL-1beta 'high secretor' phenotype. There was no association in patients with hyperplasia and normal thymic histology. These results further advocate that MG is a polygenetic disease and suggest that co-stimulators such as CTLA-4 and CD28 might have an important role in the pathogenesis of the disease.

Abatacept↗
PubMed1998

Idiotype immunization combined with granulocyte-macrophage colony-stimulating factor in myeloma patients induced type I, major histocompatibility complex-restricted, CD8- and CD4-specific T-cell responses.

Idiotypic structures expressed on the myeloma Ig protein might be regarded as a tumor-specific antigen. Five patients with IgG myeloma were immunized with the purified serum M-component by repeated intradermal injections together with soluble granulocyte-macrophage colony-stimulating factor (GM-CSF). All patients developed an idiotype (Id)-specific T-cell immunity, defined as blood T cells predominantly secreting interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) (type I cells). Id-specific DNA synthesis was induced in one patient. Delayed-type hypersensitivity against the Id was not evoked. The specific IFN-gamma/IL-2 T-cell response was inhibited (46% to 100%) by a major histocompatibility complex (MHC) class I monoclonal antibody (MoAb) in all five patients. A 5% to 37% inhibition by an MHC class II MoAb was seen in four patients. CD4+ as well as CD8+ T cells enriched by magnetic microbeads contained Id-specific cells. The T cells recognized peptides corresponding to the complementarity-determining regions 1, 2, and 3 of the heavy chain of the Id. There was a transient rise of B cells producing IgM anti-idiotypic antibodies in all patients. The results indicate that immunization of myeloma patients using the autologous M-component and soluble GM-CSF may evoke an Id-specific predominantly MHC class I-restricted type I T-cell response.

Aged↗
PubMed1998

Cytokine production from colonic T cells in patients with ulcerative colitis with and without primary sclerosing cholangitis.

PURPOSE: Only five percent of all patients with ulcerative colitis develop primary sclerosing cholangitis. T cells accumulate at the sites of the colonic and bile duct inflammation in both ulcerative colitis and primary sclerosing cholangitis. T helper cell populations comprise functionally distinct subsets characterized by the cytokines they produce. Several alterations in cytokine production have been described in patients with ulcerative colitis. The aim of this study was to investigate possible differences in T helper subsets and cytokine production in peripheral blood and colonic mucosa among ulcerative colitis patients with and without primary sclerosing cholangitis. METHODS: Eleven patients with primary sclerosing cholangitis and extensive ulcerative colitis, 11 patients with extensive ulcerative colitis and no liver disease, and 5 patients without any history of liver disease who underwent routine colonoscopy because of previous polypectomy were included in the study. Colonoscopy with multiple biopsies was performed on all patients. Lamina propria mononuclear cells and peripheral blood mononuclear cells were isolated. A modified version of solid-phase enzyme-linked immunospot assay was used for the separate counting of cells producing interferon-gamma, interleukin-2 (T helper 1), and interleukin-4 (T helper 2). RESULTS: No differences in spontaneous production of cytokines from peripheral blood mononuclear cells was found among the three groups. Patients with primary sclerosing cholangitis compared with patients with ulcerative colitis without liver disease showed a significant increase in the number of cells secreting interferon-gamma after purified protein derivative stimulation (P < 0.02). More cells secreting interferon-gamma were found in the two ulcerative colitis groups than in the cell populations from healthy controls (P < 0.03). The number of cells secreting interferon-gamma in the primary sclerosing cholangitis group was significantly lower than in the ulcerative colitis group without liver disease (P < 0.04). The number of cells secreting interleukin-4 was lower in the primary sclerosing cholangitis group than among the patients with ulcerative colitis only (P = 0.05). CONCLUSION: Isolated lymphocytes from colonic mucosa differ in cytokine production in patients with ulcerative colitis with and without primary sclerosing cholangitis.

Cholangitis, Sclerosing↗