Biomedical subjects

A K Lefvert

Publications and source records attributed to A K Lefvert.

At least 73 records · Page 4Linked to original sources

PubMed1996

Idiotype-induced T cell stimulation requires antigen presentation in association with HLA-DR molecules.

An important and yet unresolved question concerns the mode of T cell recognition of idiotypic epitopes on immunoglobulin molecules in humans. Results from murine and human studies show that some idiotype-specific T cells recognize conformational epitopes on immunoglobulin, and such T cells are not MHC-restricted. In the present study T cell stimulation induced by idiotypic determinants on the autologous monoclonal IgG (M-components) from patients with monoclonal gammopathies was studied. In parallel, T cell stimulation in response to a conventional antigen, purified protein derivative, was also examined. It is shown that, as with conventional antigen, idiotype-induced T cell stimulation requires the presence of antigen-presenting cells (APC; monocytes and/or B cells), and is MHC class II (DR)-restricted. B cells, but not monocytes, can present idiotypic determinants to T cells at very low antigen concentrations, while monocytes do so only when antigen is present at high concentrations. Antigen processing and presentation is abrogated by treatment of APC with chloroquine. In conclusion, our study demonstrates that human idiotype-specific T cells recognize processed idiotypic determinants presented by MHC class II (HLA-DR) molecules on APC, and that B cells require about 1000-fold less antigen that monocytes.

Antigen Presentation↗

PubMed1996

Presynaptic membrane receptor-reactive T lymphocytes in myasthenia gravis.

The majority of patients with myasthenia gravis were shown to have T and B cells specific for a beta-bungarotoxin binding protein, presynaptic membrane receptor (PsmR). Such autoreactive T cells may be subdivided into different subsets according to the pattern of cytokine production. In this study the authors examined the subpopulation of the T cells by analysing their IFN-gamma and/or IL-4 secretion pattern. T cell response to human muscle acetylcholine receptor (AChR) was examined in parallel. PsmR-stimulated IFN-gamma secretion was found in 60%, and IL-4 secretion in 48% of the patients. Cells stimulated to secrete both IFN-gamma and IL-4 or IFN-gamma only were the most common patterns. Treatment of the cells with a mouse anti-human HLA-DR antibody abolished the secretion of cytokines. There was a positive correlation between the numbers of PsmR-reactive and AChR-reactive T cells. In conclusion, the results show that PsmR-stimulated T cells secreted IFN-gamma and/or IL-4. This T cell response is MHC class II restricted. Thus, this study indicates that both Th1/Th2 or Th0 subsets of the T cells are involved in the autoimmune response in the disease.

Adolescent↗

PubMed1996

Anti-idiotypic T cells in early stages of myasthenia gravis: increase in the number and prevalence correlated to clinical improvement in patients.

An idiotypic network involving T and B cells bearing complementary structures has been suggested to be important for the regulation of immune response in healthy and disease situations. A previous study by the authors has demonstrated the presence of a relatively higher concentration of anti-idiotypic antibodies than of idiotypic in early myasthenia gravis (MG), suggesting that the development of an anti-idiotypic immunity is important in early MG. The present study was conducted to examine the cellular components of the idiotypic network in the same situation. T and B cells reactive to acetylcholine receptor (AChR) or to a disease-related idiotype and to an anti-idiotype were analysed in seven patients with early MG at various times after the start of the disease. The results show that a significant increase in the number of idiotype-reactive interferon-gamma-secreting T cells and a shift from AChR-reactive to idiotype- and/or anti-idiotype-reactive T cells in the patients at 6 month follow-up were noted. Such changes seem to correlate to a clinical improvement in the patients. The enhanced anti-idiotypic T-cell response and the clinical improvement in the patients may speak in favour of a role for the anti-idiotypic immunity in controlling the autoimmune response in MG, i.e., down-regulating autoantibody-producing B cells and idiotypic (AChR-specific) T cells. Thus, an immune intervention towards the enhancement of the anti-idiotypic immunity in patients might be a rewarding approach. Further studies with regard to cell interactions and immune regulations in the network are warranted.

Adolescent↗

PubMed1996

Induction of human cytotoxic T lymphocytes by oxidized low density lipoproteins.

Oxidized low density lipoproteins (oxLDL) stimulated human blood T cells to a specific cytotoxic response with autologous PHA activated blood mononuclear cells which had been pre-incubated with oxLDL. The cytotoxic reaction was exerted by CD8+ enriched cells but not by CD4+ enriched cells. Allogeneic target cells from HLA mismatched donors were not damaged and the reaction was consistently inhibited by monoclonal antibody against HLA class I. Antigen-specific cytotoxic T cells might contribute to lysis of cells in the atherosclerotic plaque that have taken up oxLDL and thus participate in the inflammatory process associated with atherosclerosis.

Cytotoxicity Tests, Immunologic↗

PubMed1996

Cerebrospinal fluid and blood lymphocyte subpopulations following subarachnoid haemorrhage.

Lymphocyte subpopulations from 10 patients who had had a subarachnoid haemorrhage were analysed. In CSF, an increase of CD3 cells was found in two of ten, CD4 in one of ten, CD8 in three of ten, and CD19 in three of ten patients. Three patients with delayed ischaemic deficit (DID) showed a statistically significant increase of intrathecal suppressor/cytotoxic/NK-cells. The cellular inflammation had been modulated within the CNS indicating a pathogenic role in the biochemical cascades following SAH.

Adult↗

PubMed1996

Prevalence of antibodies to cardiolipin in chronic ITP and reactivity with platelet membranes.

UNLABELLED: Anti-cardiolipin antibodies (ACLA) have been suggested to play a role in the pathogenesis of thrombocytopenia. When sera from 40 patients with chronic idiopathic thrombocytopenic purpura (ITP) were analyzed for ACLA, these autoantibodies were present in 12 (30%). In 4 sera the antibody activity was restricted to the IgG or IgM isotype, respectively, while 4 of the samples contained both IgG and IgM antibodies. To elucidate the interaction between platelets and ACLA, we studied the reactivity of sera from non-ITP patients with ACLA, with fragmented platelet membranes. None of them had a concurrent platelet deficiency, but sera from 8 (67%) of them showed increased IgG-binding to platelet membranes. Absorbtion with cardiolipin reduced membrane binding in 6 (50%). C3 levels were normal, while low C4 values occurred in both groups with significantly lower levels in ACLA-positive patients (p<0.05). Circulating immune complexes (CIC) were common in both groups. CONCLUSION: The prevalence of ACLA is increased in ITP and sera from non-ITP patients with ACLA react with fragmented platelet membranes. This reactivity is often decreased by absorption with cardiolipin, suggesting that ACLA bind to phospholipid epitopes on platelet membranes.

Adolescent↗

PubMed1996

Overexpression of select T cell receptor V beta gene families within CD4+ and CD8+ T cell subsets of myasthenia gravis patients: a role for superantigen(s)?

BACKGROUND: The principal symptoms of myasthenia gravis (MG), muscle weakness and fatigue due to impaired neuromuscular transmission, are caused by autoantibodies to the muscle nicotinic acetylcholine receptor (AChR). The mechanisms underlying the autoimmune response, however, appear to be initiated by activation of specific HLA class II-restricted CD4+ T lymphocytes. Thus, central to elucidating the causation of MG is determining how T cells are recruited to contribute to misguided immunological assaults on the major autoantigenic target, AChR. MATERIALS AND METHODS: By combining a polymerase chain reaction (PCR)-based strategy and Southern blot technique, we have analyzed the frequency of expression of 22 individual T cell receptor (TCR) V beta gene subfamilies in CD4+ and CD8+ peripheral blood T cell subsets derived from eight MG patients and seven healthy controls. The quantification of relative usage of individual TCR J beta gene segments was performed by hybridization of PCR-amplified products (specifically V beta 1-C beta) with a complete panel of 32P-5'-end-labeled J beta-specific oligonucleotide probes, followed by scanning analysis of autoradiographs. RESULTS: Comparisons of data obtained from V beta analyses of T cells from MG patients with those from healthy individuals established that MG patients significantly overexpressed V beta 1, V beta 13.2, V beta 17, and V beta 20 gene family members within both CD4+ and CD8+ T cell subpopulations. Moreover, analysis of the relative utilization of individual TCR J beta gene segments in V beta 1+/CD4+ and V beta 1+/CD8+ T lymphocytes revealed distribution patterns in patients indistinguishable from those recorded in the corresponding cell subsets derived from controls. CONCLUSIONS: T lymphocytes from MG patients displayed a biased overexpression of four TCR V beta gene segments: V beta 1, V beta 13.2, V beta 17, and V beta 20. The relative frequencies of association of individual V beta 1 (D beta) J beta combinations revealed that J beta gene usage in the V beta 1-over-represented T cell subsets had normal distribution patterns. It can thus be deduced that J beta gene segment products appear not to have a selective effect on the process leading to overexpression of V beta 1 exons in MG patients. Hence, our observations suggest a possible role for superantigen(s) in the T cell activation in MG patients.

Adult↗

PubMed1995

Idiotype-reactive T-cell subsets and tumor load in monoclonal gammopathies.

The presence of idiotype-reactive T-cell subsets and their relation to the tumor load were analyzed in 9 patients with monoclonal gammopathy of undetermined significance (MGUS), in 12 patients with multiple myeloma (MM) clinical stage I, and in 9 patients with MM stage II/III. An enzyme-linked immunospot assay was used to identify interferon-gamma (IFN-gamma)-, interleukin-2 (IL-2)-, or IL-4-secreting T cells after stimulation by F(ab')2 fragments of monoclonal IgG. The response to autologous IgG was significantly higher than that induced by isotypic monoclonal IgG. Comparable results were obtained in a proliferation assay (3H-thymidine incorporation). A total of 8 of 9 patients with MGUS, 7 of 12 patients with MM stage I, and 3 of 9 with MM stage II/III had T cells secreting IFN-gamma and/or IL-2 (T helper [Th1] type-1 cells), whereas cells secreting both Th1 and Th2 or Th0 types of cytokines were more frequent in patients with MM, particularly in those with MM stage II/III. The number and frequency of Th1-type cells were significantly higher in MGUS patients as compared with those of MM stage II/III. The results indicate that idiotype-reactive T cells of the Th1 and Th2 or Th0 subsets were present in MGs and might provide indirect evidence that idiotype-reactive Th1-type cells may have a regulatory impact on the human tumor B cells.

Adult↗

PubMed1995

Idiotype-specific T cells in multiple myeloma stage I: an evaluation by four different functional tests.

Idiotype-specific T cells were characterized in patients with multiple myeloma stage I by analysing idiotype-induced DNA synthesis (3H-thymidine incorporation), IL-2 and IFN-gamma production at the single cell level (ELISPOT) (in vitro tests) and delayed type hypersensitivity (DTH) skin reaction (in vivo test). In seven out of eight patients at least one of the four tests was positive. In five patients three or more tests were positive. One patient was negative in all four tests. Six patients had both IL-2 and IFN-gamma-secreting cells and three of them also a DTH response. Furthermore, those three patients with a proliferative response also had IL-2 and IFN-gamma-secreting cells induced by the idiotype. The data indicate that part of the idiotype-specific T cell fraction belongs to the CD4 Th1 cell population. Whether CD8-specific T cells also were present could not be ruled out. The present study provides further support for the existence of idiotype-specific T cells in multiple myeloma. Such cells might be an important target for an immune-mediated therapeutic approach.

Aged↗

PubMed1995

Autoantibodies against oxidized low density lipoproteins (oxLDL): characterization of antibody isotype, subclass, affinity and effect on the macrophage uptake of oxLDL.

Circulating antibodies against oxLDL are present in several inflammatory and autoimmune conditions. Such antibodies are also present in patients with atherosclerosis, although the pathogenic significance of the antibodies is still not known. We have characterized the antibodies with regard to isotype, subclass, affinity and effect on macrophage uptake of oxLDL. Antibodies of IgG and IgM isotype were most common and found both in patients with atherosclerosis and in normal individuals. The subclass of IgG antibodies was mainly IgG2 and IgG3. Scatchard analyses of IgG and IgM antibodies showed that IgG antibodies were heterogeneous with regard to affinity, whereas only one population of high-affinity antibodies was found in the IgM antibody population. The high-affinity populations had an average equilibrium constant (K0) of 8.84 x 10(9) M-1 for IgG antibodies and of 1.65 x 10(9) M-1 for IgM antibodies. Incubation of 125I-oxLDL with purified IgG and IgM from sera with high amounts of antibodies enhanced the uptake of 125I-oxLDL in the monocyte-like U937 cell line. Antibody preparations from sera containing no anti-oxLDL antibodies and from sera with antibodies against LDL had less effect on this uptake. The increased uptake was competitively decreased by adding unlabelled oxLDL. This study shows that antibodies against oxLDL are mainly IgG2, IgG3 and IgM. Both IgG and IgM antibodies have a high affinity for the antigen and increase the uptake of oxLDL in a monocyte-like cell line.

Antibody Affinity↗

PubMed1995

T cell receptor (TCR) V gene usage in patients with systemic necrotizing vasculitis.

Wegener's granulomatosis (WG) and polyarteritis nodosa (PAN) are systemic necrotizing vasculitides of unknown etiology. These disorders run a fatal course if untreated. T lymphocytes are implicated in the pathogenesis of WG, since they have been found to infiltrate affected organs, and sIL-2R correlates with disease activity. To elucidate further the role of T cells in necrotizing vasculitis, we have used a panel of 12 TCR V-specific MoAbs to investigate the number of cells expressing certain V alpha and V beta gene segments in the CD4+ and CD8+ subsets of altogether 11 patients with WG or PAN. In the group of patients, we found abnormal expansions of T cells using particular TCR V alpha or V beta gene products. These T cell expansions were more numerous, of a dramatically higher magnitude, and frequently more often found in the CD4 subset, compared with T cell expansions identified in healthy individuals. In long-term studies of the T cell expansions for up to 18 months, a heterogeneous pattern was revealed, with no obvious correlation to clinical features such as disease activity or treatment. Studies of TCR V gene usage in this group of patients may help in understanding the pathogenesis of necrotizing vasculitis, and in the identification of unknown antigens, and may open the possibility to a highly selective immunotherapy by targeting disease-mediating T cells.

Aged↗

PubMed1995

Antibodies against endothelial cells and cardiolipin in young patients with peripheral atherosclerotic disease.

OBJECTIVES: To investigate the prevalence of anticardiolipin and antiendothelial cell antibodies in patients operated on for atherosclerotic peripheral vascular disease before 50 years of age. The hypothesis to be tested was whether antibodies associated with an immune/inflammatory damage to the vascular wall were associated also with early atherosclerosis. DESIGN: A case-control study. SETTING: Departments of surgery and an immunological research laboratory, and routine laboratories of two tertiary referral hospitals. SUBJECTS: All patients operated for atherosclerotic peripheral vascular disease before 50 years of age. Sixty-two patients (33 males, 29 females), and 67 age- and sex-matched controls participated. The diagnosis of atherosclerosis was made on the basis of the clinical presentation and angiographic visualization of the diseased vasculature. MAIN OUTCOME MEASURES: Subjects were compared for the prevalence of anticardiolipin and antiendothelial cell antibodies, altered serum lipoprotein levels, smoking, diabetes, hypertension, and signs of inflammation. RESULTS: Antibodies against endothelial cells and cardiolipin were found in 12.9 and 14.5% of the patients, respectively, which was higher than observed in the control group (P < 0.05). Sixty per cent of patients with antibodies were females. Conventional risk factors were more often noted in the patient group. However, patients with antibodies against endothelial cell and/or cardiolipin had a lower prevalence of hyperlipidaemia/dyslipidaemia when compared to patients without these antibodies (P < 0.05). CONCLUSIONS: Antibodies against endothelial cells and cardiolipin are present in a subset of patients with clinical and angiographic diagnosis of severe premature atherosclerotic peripheral vascular disease. The lower occurrence of hyperlipidaemia/dyslipidaemia in patients with autoantibodies, in comparison to patients without the antibodies, suggests that these antibodies have a role in vascular damage.

Adult↗

PubMed1995

C4 null alleles in a Swedish population.

The distribution of C4 null alleles (C4Q0) was studied in a Swedish population comprising 410 male individuals from Stockholm County and Uppsala City. The prevalances of homozygous C4A*Q0 and C4B*Q0 determined by analysing the gene products in serum were 5.0 and 5.6%, respectively, in the Stockholm population and 4.0% each in the Uppsala population. These values are higher than those previously reported from other Caucasian populations. The finding reflects a different genetic composition of the Swedish population and may have relevance to the disease spectrum in this population as compared to other Caucasian populations.

Adult↗

PubMed1995

Patients with early-onset peripheral vascular disease have increased levels of autoantibodies against oxidized LDL.

Oxidative modification of LDL has been proposed as an early and crucial step in the development of atherosclerosis, and antibodies against such modified LDL are found in both healthy individuals and patients with atherosclerosis. In this study, 62 patients who were surgically treated for peripheral arterial occlusive disease below the age of 50 were investigated and compared with age- and sex-matched healthy individuals in a case-control study. Autoantibodies against oxidized LDL were measured with an enzyme-linked immunosorbent assay method. Risk factors such as smoking, hypertension, family history of premature cardiovascular events, and lipoprotein levels were also determined. The patients had significantly higher levels of autoantibodies against oxidized LDL; significantly higher levels of total cholesterol, LDL cholesterol, triglycerides, and apo A-I; and significantly lower levels of HDL cholesterol than did control subjects. In multivariate analyses autoantibodies against oxidized LDL discriminated better between patients and control subjects than did any of the different lipoprotein analyses. Among patients, the presence of hypertension and a family history of cardiovascular events were the only factors significantly associated with increased levels of autoantibodies against oxidized LDL.

Adult↗

PubMed1995

Association between circulating immune complexes, complement C4 null alleles, and myocardial infarction before age 45 years.

One hundred patients who had survived a myocardial infarction before the age of 45 years and 90 age- and sex-matched healthy individuals were investigated for circulating immune complexes (CICs) and the presence of complement C4 null alleles (C4Q0). CICs were found in increased concentrations in 20% of patients and 6.7% of control subjects. Patients and control subjects had the same prevalence of C4Q0. CICs were present in all patients and in 36% of the control subjects homozygous for C4Q0. Patients and control subjects heterozygous for C4Q0 had CICs in 71% and 0%, respectively. The high prevalence and a high concentration of CICs were particularly associated with C4A*Q0. Patients homozygous for C4A*Q0 had concentrations of LDL that were lower than found in other patients. The increased concentration of CICs associated with genetic deficiencies of the complement factor C4 might thus be an additional etiological factor for the development of chronic vascular damage and premature myocardial infarction.

Adult↗

PubMed1995

Neonatal myasthenia gravis and the role of agalactosyl IgG.

Neonatal autoimmune diseases are thought to be due to the transfer of maternal autoantibodies. However, there is a puzzling lack of correlation between maternal autoantibody titres and disease in the neonate. So far, no factor reliably predictive of neonatal disease has been found. Agalactosyl IgG is a variable feature of normal IgG. Preliminary studies indicated that the percentage of agalactosyl IgG is lower in the serum of normal neonates, than in the serum of the mother at delivery. Since raised % agalactosyl IgG is often associated with autoimmune disease we sought to determine whether this relationship holds true in a neonatal autoimmune disease. We measured the % agalactosyl IgG in paired maternal-cord sera from patients with myasthenia gravis, some of whom had offspring with neonatal myasthenia gravis. We found that the percentage of agalactosyl IgG was significantly higher in affected than in unaffected neonates. Moreover % agalactosyl IgG was higher in sera of affected neonates than in serum from their mothers, while unaffected infants of mothers with myasthenia had %Gal(0) lower than their mothers, mimicking the normal situation. This suggests that in affected neonates a high proportion of the IgG is synthesised by the baby itself rather than derived from the mother. This agrees with previous evidence based on the presence of idiotypes not found in the mother which implied that the neonates with neonatal myasthenia gravis produce their own autoantibodies.

Age Factors↗

PubMed1995

Different HLA-DQ are positively and negatively associated in Swedish patients with myasthenia gravis.

The aim of this study was to determine the association between HLA-DQ and myasthenia gravis (MG) in 79 Swedish patients and 155 unrelated population based controls. HLA genotyping was done using polymerase chain reaction combined with sequence specific oligonucleotide probes. The DQB allele, DQB1*0201 was positively associated with MG, 39/79 (49%) patients and 43/152 (28%) controls (OR 2.47, Pc = 0.037). DQB1*0201 was observed more frequently in patients with an early onset of disease, below 30 years (Pc = 0.033). A negative association was found for DQA1*0103, 7/78 (9%) patients and 38/154 (25%) controls (OR 0.30, Pc = 0.037). DQA1*0501-DQB1*0201 and DQA1*0201-DQB1*0201 together was significantly increased in patients when compared to controls (OR 2.68; Pc = 0.019). In conclusion, two different DQ2 haplotypes (DQA1*0501-DQB1*0201 and DQA1*0201-DQB1*0201) were positively and the DQA1*0103 allele was negatively associated with MG. Susceptibility and resistance to MG in Swedish patients is mediated by HLA-DQ.

Adolescent↗

PubMed1995

Agalactosyl IgG and antibody specificity in rheumatoid arthritis, tuberculosis, systemic lupus erythematosus and myasthenia gravis.

Agalactosyl IgG (Gal(0) is a glycoform lacking terminal galactose from the oligosaccharides situated on the Fc. The percentage of circulating IgG that is Gal(0) is increased in a a number of autoimmune diseases, and in certain chronic infections associated with autoantibody production. However it is not known whether this represents decreased galactosylation of all IgG, or an increase in the relative concentration of a subset of agalactosyl antibodies of specificity relevant to the disease process. Since there is currently no way to separate agalactosyl from galactosylated IgG, we devised an assay for the relative degree of galactosylation of antibody to tetanus toxoid (TT), an antigen irrelevant to the diseases studied, and compared this value with the %Gal(0) of the whole circulating IgG. In rheumatoid arthritis (RA) and tuberculosis (TB), a raised %Gal(0) in serum IgG was reflected in a parallel rise in the extent to which antibody to TT was agalactosyl. In SLE a rise in %Gal(0) was seen in the presence of very little rise in agalactosyl anti-TT, and in myasthenia gravis (MG), where serum %Gal(0) is normal, an abnormally low percentage of the anti-TT was agalactosyl. These results imply that in RA and TB a systemic influence is downregulating the galactosylation even of irrelevant IgG. However in SLE and MG antibodies of specificities not studied here must be responsible for the %Gal(0) found in serum. It remains to be seen whether these are the autoantibodies involved in the disease process.

Antibody Specificity↗