Biomedical subjects

S Fredrikson

Publications and source records attributed to S Fredrikson.

At least 91 records · Page 5Linked to original sources

PubMed1994

gamma delta+ T cells are increased in patients with Parkinson's disease.

The etiology of Parkinson's disease is mainly unknown. Immune abnormalities have been reported, including the occurrence of autoantibodies against neuronal structures and abnormal T cell functions. gamma delta+ T cells represent a recently recognized T cell subpopulation which is considered to play a role in immune responses in infections and autoimmunity. We examined by three-colour flow cytometry the proportions of gamma delta+ T cells in blood and cerebrospinal fluid (CSF) from patients with Parkinson's disease. Increased proportions of gamma delta+ T cells were found in CSF in Parkinson's disease compared to other neurological diseases (OND) and tension headache. In peripheral blood, patients with Parkinson's disease had higher numbers of gamma delta+ T cells compared to OND patients. No differences between gamma delta+ T cells in CSF compared to blood were demonstrable in the individual patient groups. CD25 was not expressed on gamma delta+ T cells in blood of the majority of cases, but 50% of patients with Parkinson's disease and 30% with OND and tension headache had CD25+ gamma delta+ T cells in CSF arguing for a preferential activation of gamma delta+ T cells in the CSF compartment. Whether the elevated gamma delta+ T cell population in Parkinson's disease reflects previously unrecognized inflammation or may occur also in non-inflammatory disorders remains to be elucidated.

Aged↗

PubMed1994

Augmented interferon-gamma, interleukin-4 and transforming growth factor-beta mRNA expression in blood mononuclear cells in myasthenia gravis.

The abnormal T lymphocyte-dependent production of antibodies to the nicotinic acetylcholine receptor (AChR) in myasthenia gravis (MG) suggests a role for immunoregulatory cytokines. We examined the T helper type 1 (Th1) cell-associated interferon-gamma (IFN-gamma) that promotes cell-mediated immunity, the Th2 cell-related interleukin-4 (IL-4) that augments B cell immunity, and transforming growth factor-beta (TGF-beta) that downregulates immune responses but enhances isotype switching. Blood mononuclear cells (MNC) expressing cytokine mRNA were enumerated after in situ hybridization with labelled complementary DNA oligonucleotide probes for IFN-gamma, IL-4 and TGF-beta. MG patients had elevated numbers of cells expressing IFN-gamma and IL-4 compared to patients with non-inflammatory neurological diseases and healthy controls, implying that both Th1- and Th2-like cells are involved in MG. TGF-beta-positive cells were also elevated in MG. The levels of cytokine-positive MNC were similar in MG and in control patients with other inflammatory neurological diseases. There were no associations between numbers of cytokine-positive blood MNC and clinical variables of MG, but individual patients need to be studied over the course of MG to clarify a relation between the cytokines under study and clinical or laboratory variables of MG.

Adolescent↗

PubMed1994

V delta 1 gene usage, interleukin-2 receptors and adhesion molecules on gamma delta+ T cells in inflammatory diseases of the nervous system.

This study investigates the expression of T cell receptor V delta 1 chain, interleukin-2 receptor alpha-chain (CD25) and adhesion molecules ICAM-1 (CD54), LFA-1 (CD11a/18) and CD44 on gamma delta+ T cells by three-color flow cytometry on cerebrospinal fluid (CSF) and blood cells in patients with multiple sclerosis (MS), other inflammatory neurological diseases (OIND) and other neurological diseases (OND). Of gamma delta + T cells in CSF and blood, 20-40% belonged to the 'epithelial' V delta 1 subtype. MS patients had the lowest levels in both CSF and blood, but the differences between the patient groups were not significant. The activation markers CD25 and CD54 were expressed by only a small proportion of gamma delta+ T cells and in a minority of patients. Although the occurrence of CD25+ and CD54+ gamma delta+ T cells was somewhat higher in CSF than in blood and in inflammatory diseases than in controls, the small numbers of CD25+ and CD54+ gamma delta+ T cells preclude establishing differences amongst compartments and patient groups. The adhesion molecules CD11a/18 and CD44 were constitutively expressed on all T cells. Therefore, we compared the relative antigen density per cell as measured by the relative fluorescence index (RFI) between CSF and blood, between the patient groups and between gamma delta+ and total T cells. The only difference encountered was a slightly higher expression of adhesion molecules on gamma delta+ compared to total T cells, with preference to MS patients. In conclusion, the V delta 1+ subtype of gamma delta+ T cells does not dominate in the CSF compartment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

The HLA-Dw2 haplotype segregates closely with multiple sclerosis in multiplex families.

Multiple sclerosis (MS) is associated with the HLA class II specificity Dw2, but the importance of its influence has been questioned, since sib-pair analysis has failed to show linkage with this haplotype. However, the use of 'identity by descent' (IBD) analysis may not be ideal, since it does not make use of the facts that (i) the Dw2-haplotype is the only haplotype with a confirmed role in MS, and (ii) it performs its influence in a dominant manner. We have investigated nine Swedish multiplex MS families. In eight of the families, the Dw2 haplotype occurred in MS patients. Within these families, Dw2 was shared by all 17 individuals with MS. In a compilation of 48 published multiplex MS families in which at least one patient carried Dw2, only three of 107 individuals with MS did not carry the Dw2 haplotype. This indicates that the Dw2 haplotype, when present in familial MS, may confer a stronger influence in MS susceptibility than generally recognized.

Genes, MHC Class II↗

PubMed1994

Multiple sclerosis: occurrence of myelin basic protein peptide-reactive T cells in healthy family members.

Genetic factors influence the susceptibility to multiple sclerosis (MS). This disease is accompanied by augmented T cell responses to CNS myelin components such as myelin basic protein. To evaluate the familial occurrence of such T cell autoreactivity, we have studied 12 MS families including 37 healthy first-degree relatives for occurrence of numbers of interferon-gamma (IFN-gamma) secreting cells among blood mononuclear after culture in presence of myelin basic protein (MBP), eight synthetic MBP peptides and the control antigen acetylcholine receptor (AChR). There were no differences between MS patients and healthy family members regarding frequencies of autoreactive T cells recognizing MBP, the eight different MBP peptides or AChR. None of the MBP peptides predominated as T cell antigen among the MS patients or their unaffected family members. In some families the highest number of MBP peptide reactive T cells were found among unaffected family members. No correlation was observed between numbers of MBP or MBP peptide reactive T cells in various subjects and their HLA-DR-DQ phenotypes. In conclusion, this study has revealed the presence of MBP and MBP peptide reactive T cells of similar frequencies in MS patients and their healthy family members.

Adult↗

PubMed1994

Optic neuritis and multiple sclerosis: the T cell repertoires to myelin proteins and MBP peptides change with time.

Autoreactive T cells recognizing myelin basic protein (MBP), proteolipid protein (PLP) and MBP peptides have been described in multiple sclerosis (MS) and optic neuritis (ON), but their role in disease pathogenesis, if any, is unknown. A consistency of the T cell repertoire over the course of MS and ON should facilitate the development of specific immunotherapies. We have examined the T cell responses to autoantigens in two consecutive blood specimens taken from patients with ON and MS, and in two consecutive CSF specimens obtained from ON patients. As read-out numbers of T cells responding to antigen stimulation by the secretion of interferon-gamma were estimated. Pronounced differences in occurrence and numbers of T cells recognizing MBP, MBP peptides with the amino acid sequences 63-88, 110-128 and 148-165, and PLP were noticed in individual ON and MS patients over the course of disease. The MBP peptide among those three included, that was predominantly recognized by T cells in the individual patient, also varied over the course. The quantitative and qualitative changes of the myelin antigen-specific T cell response in MS and in ON, the latter to a certain extent reflecting the situation in early MS, do not favor the future useful development of specific immunotherapies in these diseases.

Adult↗

PubMed1994

Parkinson's disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood.

The etiology of Parkinson's disease is mainly unknown. Immune abnormalities have been described, but the cause of such abnormalities has not been resolved. We examined by two-colour flow cytometry HLA-DR antigen expression on monocytes from cerebrospinal fluid (CSF) and blood and, moreover, lymphocyte subpopulations (CD4+ CD45RO+, CD4+ CD45RA+, CD8+ CD11b+high) in peripheral blood from patients with Parkinson's disease compared with age-matched patients with other neurological diseases (OND) and tension headache. We found higher HLA-DR expression on CSF monocytes compared with blood monocytes. This difference was restricted to Parkinson's disease patients. T helper cell analysis revealed a decreased percentage of CD45RA+ "naive" and an increased percentage of CD45RO+ "memory" T cell subset from CD4+ T cells in peripheral blood of patients with Parkinson's disease compared with patients with tension headache. The proportions of CD8+ CD11b+high "suppressor" T cells remained unchanged, among the three patient groups compared. A selective loss of CD4+ CD45RA+ cells, previously observed in diseases like multiple sclerosis and Down's syndrome as compared with healthy controls suggests a common immunological abnormality in neurological disorders.

Adult↗

PubMed1994

Familial clustering of multiple sclerosis in a northern Swedish rural district.

A small rural district in the most northerly province of Sweden was found to have a very high occurrence of multiple sclerosis. A total of 12 patients with multiple sclerosis among 4744 inhabitants were identified (five females, seven males), corresponding to a prevalence of 253/100,000. Many of the patients were related and a further 21 cases with multiple sclerosis (14 females, seven males), mostly living in the neighbouring area, have family ties to the district. A genealogical investigation showed that 22 of the 33 patients identified had ties of kinship and thus, to our knowledge, the largest aggregation of multiple sclerosis in a family is presented.

Adolescent↗

PubMed1994

Autoimmune T cell repertoire in optic neuritis and multiple sclerosis: T cells recognising multiple myelin proteins are accumulated in cerebrospinal fluid.

Monosymptomatic unilateral optic neuritis is a common first manifestation of multiple sclerosis. Abnormal T cell responses to myelin components including myelin basic protein (MBP), proteolipid protein (PLP), and myelin-associated glycoprotein (MAG) have been implicated in the pathogenesis of multiple sclerosis. Antigen-reactive T helper type 1 (Th1)-like cells that responded by interferon gamma (IFN-gamma) secretion on antigen stimulation in vitro were counted. Untreated patients with optic neuritis and multiple sclerosis had similarly raised levels of T cells recognising MBP, PLP, and MAG in peripheral blood. Such T cells were strongly enriched in CSF. None of these myelin antigens functioned as immunodominant T cell antigen characteristic for optic neuritis or multiple sclerosis. The autoimmune T cell repertoire was not more restricted in optic neuritis (as an example of early multiple sclerosis). The autoreactive T cell repertoires differed in blood compared with CSF in individual patients with optic neuritis and multiple sclerosis. No relations were found between specificity or quantity of autoreactive T cells in blood or CSF, and clinical variables of optic neuritis or multiple sclerosis, or occurrence of oligoclonal IgG bands in CSF. The role of raised MBP, PLP, and MAG reactive Th1-like cells found in optic neuritis and multiple sclerosis remains unexplained.

Adolescent↗

PubMed1994

Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report.

The Committee of the European Concerted Action for Multiple Sclerosis (Charcot Foundation) organised five workshops to discuss CSF analytical standards in the diagnosis of multiple sclerosis. This consensus report from 12 European countries summarises the results of those workshops. It is hoped that neurologists will confer with their colleagues in clinical chemistry to arrange the best possible local practice. The most sensitive method for the detection of oligoclonal immunoglobulin bands is isoelectric focusing. The same amounts of IgG in parallel CSF and serum samples are used and oligoclonal bands are revealed with IgG specific antibody staining. All laboratories performing isoelectric focusing should check their technique at least annually using "blind" standards for the five different CSF and serum patterns. Quantitative measurements of IgG production in the CNS are less sensitive than isoelectric focusing. The preferred method for detection of blood-CSF barrier dysfunction is the albumin quotient. The CSF albumin or total protein concentrations are less satisfactory. These results must be interpreted with reference to the age of the patient and the local method of determination. Cells should be counted. The normal value is no more than 4 cells/microliters. Among evolving optional tests, measurement of the combined local synthesis of antibodies against measles, rubella, and/or varicella zoster could represent a significant advance if it offers higher specificity (not sensitivity) for identifying chronic rather than acute inflammation. Other tests that may have useful correlations with clinical indices include those for oligoclonal free light chains, IgM, IgA, or myelin basic protein concentrations.

Acute Disease↗

PubMed1994

Organ-specific autoantigens induce interferon-gamma and interleukin-4 mRNA expression in mononuclear cells in multiple sclerosis and myasthenia gravis.

T cells recognizing the myelin components myelin basic protein (MBP) and proteolipid protein (PLP) are increased in multiple sclerosis (MS), and there are elevated numbers of T cells recognizing the nicotinic acetylcholine receptor (AChR) in myasthenia gravis (MG). However, the cytokine repertoires in these diseases are largely unknown. We adopted in situ hybridization with radiolabeled complementary DNA oligonucleotide probes to enumerate mononuclear cells that expressed the T-helper type 1 (Th1) cell-related interferon-gamma (IFN-gamma) and Th2-associated interleukin-4 (IL-4) after short-term culture in the presence of autoantigen. High numbers of IFN-gamma and IL-4 mRNA-expressing cells in response to MBP and PLP were detected in patients with untreated MS, and to AChR in MG. The levels of IFN-gamma and IL-4 mRNA-positive cells in MS after culture in the presence of AChR, and in MG after culture in the presence of MBP or PLP, did not differ from those detected after culture without antigen. The CSF of MS patients contained four- to eightfold more myelin protein-reactive IFN-gamma and IL-4 expressing cells. The findings imply that MS and MG are associated with mixed Th1- and Th2-like cell responses directed to organ-specific target antigens.

Adult↗

PubMed1993

Interleukin-2 secreting cells in multiple sclerosis and controls.

To evaluate systemic T cell activation and reactivity against putative autoantigens in multiple sclerosis (MS), numbers of interleukin-2 (IL-2) secreting cells were determined in peripheral blood of 32 patients with MS, 7 patients with acute aseptic meningitis (AM) and 12 patients with tension headache (TH). Numbers of IL-2 secreting cells were higher in MS patients compared to patients with AM + TH after stimulation with myelin proteolipid protein (PLP), myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG), but not after stimulation with myelin basic protein (MBP). In response to MAG, MOG and acetylcholine receptor (AChR) the frequencies of IL-2 secreting cells were higher in patients with MS than TH, while there were no differences between AM and TH to any of the tested antigens. Between patients with MS and AM there was no difference regarding frequency of IL-2 secreting cells in response to any of the tested antigens except MAG to which the response was higher in MS patients. Six of 10 MS patients had IL-2 secreting cells in response to all four myelin antigens (MBP + PLP + MAG + MOG) or to three antigens, while this broad reactivity was not found in any control patient. There was no correlation between numbers of IL-2 secreting cells in MS patients and clinical variables, including exacerbation versus remission, disability and duration of disease. The results suggest that the systemic T cell response in patients with MS is directed to several antigens.

Adult↗

PubMed1993

Cord blood contains high numbers of autoimmune T cells recognizing multiple myelin proteins and acetylcholine receptor.

To analyze Ag-specific T cell autoimmunity in the newborn, umbilical cord blood cells of newborns were investigated by an immunospot assay for occurrence and numbers of cells secreting IFN-gamma after short-term culture in presence of myelin basic protein (MBP), proteolipid protein, myelin associated glycoprotein, nicotinic acetylcholine receptor and the synthetic MBP amino acid sequences 1-20, 63-88, and 110-128. These Ag were chosen because they represent putative targets for autoimmune attack in multiple sclerosis and myasthenia gravis. Surprisingly, numbers of T cells recognizing MBP, proteolipid protein, MBP peptides, and acetylcholine receptor were high in cord blood of newborns compared to peripheral blood of patients with neurologic diseases. No immunodominant T cell epitope could be discerned among the Ag included. The responses to purified protein derivate and PHA were lower among cord blood cells than peripheral blood cells of adults. Parallel enumeration of autoimmune T cells in cord blood and peripheral blood obtained from corresponding mothers at delivery, revealed that the high cell numbers in newborns were not a result of contamination from the mothers blood. The high numbers of T cells recognizing nervous system myelin proteins and acetylcholine receptor in cord blood could have importance for the mechanism and timing of tolerance induction, and also reflect excessive myelination and receptor maturation at birth.

Adult↗

PubMed1993

T cells recognizing multiple peptides of myelin basic protein are found in blood and enriched in cerebrospinal fluid in optic neuritis and multiple sclerosis.

The cause of multiple sclerosis (MS) is unknown. Recently reported abnormal T-cell responses to several myelin proteins and myelin basic protein (MBP) peptides in peripheral blood constitute one line of evidence that autoimmune mechanisms could be involved in the pathogenesis of the disease. Monosymptomatic unilateral optic neuritis (ON) is a common first manifestation of MS and important to examine for a possible restriction of the T-cell repertoire early in the disease. T-cell activities to MBP and the MBP amino acid sequences 63-88, 110-128 and 148-165 were examined by short-term cultures of mononuclear cells from cerebrospinal fluid (CSF) and blood in the presence of these antigens, and subsequent detection and counting of antigen-specific T cells that responded by interferon-gamma (IFN-gamma) secretion. Most patients with MS and ON had MBP and MBP peptide-reactive T cells in CSF, amounting to mean values of between about 1 per 2000 and 1 per 7000 CSF cells and without immunodominance for any of the peptides. Numbers were 10-fold to 100-fold lower in the patients' blood. Values were similar in ON and MS, and no evidence was obtained for a more restricted T-cell repertoire in ON. The MBP peptide-recognizing T-cell repertoire was different in CSF than in blood in individual patients with ON and MS, thereby giving further evidence for an autonomy of the autoimmune T-cell response in the CSF compartment. No relations were observed between numbers of autoreactive T cells and presence of oligoclonal IgG bands in CSF or abnormalities on magnetic resonance imaging of the brain in ON or clinical variables of MS. The high numbers of MBP and MBP peptide-reactive T cells could play a role in the pathogenesis of ON via secretion of effector molecules, one of them being IFN-gamma, as well as in the transfer of ON to MS.

Adult↗

PubMed1992

T cell responses to human recombinant acetylcholine receptor-alpha subunit in myasthenia gravis and controls.

Antibodies against the nicotinic acetylcholine receptor (AChR) of the neuromuscular junction are detectable in most patients with myasthenia gravis (MG) and assumed to participate in the destruction of the AChR, thereby, causing the characteristics signs and symptoms of the disease. The extent and importance of T cell responses to AChR and its subunits in MG are still unsettled. We have now examined T cell reactivities using human recombinant AChR-alpha subunit as antigen. Upon recognition of appropriate antigen in an MHC-class II-restricted fashion, memory T cells secrete interferon-gamma (IFN-gamma). Adopting this principle in an immunospot assay we found that 73% of MG patients had recombinant human AChR-alpha subunit-reactive T cells at a median value of 1 per 56,000 blood mononuclear cells, while only 27% of the MG patients responded to the alpha subunit in a conventional lymphocyte proliferation assay. This compares with even lower numbers of AChR-reactive T cells and 14% positivity in the proliferation assay among control subjects. The T cell responses to the control antigens purified protein derivative and myelin basic protein did not differ between MG and controls, underlining the specificity of an augmented T cell reactivity to AChR-alpha subunit in MG. Alpha Subunit-specific T cell lines and clones propagated from patients with MG and healthy controls yielded a high proportion of alpha subunit-reactive T cells in the IFN-gamma immunospot assay. Their appearance was inhibited by the addition of monoclonal anti-MHC class II antibodies, demonstrating that an MHC-restricted T cell response was measured. Our data underline that the AChR-alpha subunit is a major T cell autoantigen in MG.

Adolescent↗

PubMed1992

Myasthenia gravis: T and B cell reactivities to the beta-bungarotoxin binding protein presynaptic membrane receptor.

Antibodies against acetylcholine receptor (AChR) can be detected in most patients with myasthenia gravis (MG) and are considered to be involved in the immunopathogenesis of this disease. AChR are isolated from crude receptor preparations by binding to alpha-bungarotoxin (alpha-BuTx). Patients with MG have also antibodies against a second protein tentatively named presynaptic membrane receptor (PsmR), which has been isolated from crude receptor utilizing beta-bungarotoxin (beta-BuTx). PsmR could represent another antigen besides AChR relevant for the development of MG. We have now evaluated the T cell reactivity to PsmR in MG and controls by analysing the frequencies of cells which in response to PsmR in short-term cultures secreted interferon-gamma (IFN-gamma). The B cell response to PsmR was analysed in parallel by counting cells secreting anti-PsmR antibodies. Most patients with MG had PsmR reactive T cell in blood with a median number of about 1 per 44,000 mononuclear cells. Cells secreting anti-PsmR antibodies belonging to the IgG and IgA isotypes, less frequently of the IgM isotype were detected in most MG patients. A positive correlation was found between T cells reactive with PsmR and anti-PsmR IgG antibody secreting cells. PsmR reactive T and B cells were also detected in control patients, but at much lower numbers. Our results indicate that MG is accompanied by T as well as B cell responses to PsmR, in addition to the previously recognized responses to AChR. It remains to be shown whether these PsmR reactivities are of pathogenetic importance in MG.

Adult↗

PubMed1992

Virus-reactive and autoreactive T cells are accumulated in cerebrospinal fluid in multiple sclerosis.

Elevated numbers of B cells--plasma cells secreting antibodies to measles and mumps virus, and to myelin associated glycoprotein (MAG), one of several putative myelin autoantigens--have previously been reported in cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS), while it is unknown if corresponding T cell reactivities occur. We have defined the T cell reactivities to measles and mumps virus and to MAG in an immunospot assay which is based on the detection of secretion of interferon-gamma (IFN-gamma) by single cells upon stimulation with specific antigen in short term cultures. Patients with MS had higher numbers of MAG-reactive T cells in blood compared to controls, while no differences were observed for measles or mumps virus-reactive T cells. In CSF, elevated numbers of MAG-reactive T cells and also of measles- and mumps-reactive T cells were found in patients with MS compared to other neurological diseases. A strong accumulation of antigen-reactive T cells was observed in the MS patients' CSF compared to blood. The magnitude of these T cell reactivities did not correlate with clinical MS variables. The T cell repertoire in MS thus includes, besides myelin basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein, also MAG and, in addition, measles and mumps virus. It is not clear whether these T cell reactivities accumulated in the CSF have importance for the pathogenesis of MS or reflect phenomena secondary to myelin damage, or result from both these alternatives.

Adolescent↗

PubMed1992

The T-cell repertoire in myasthenia gravis involves multiple cholinergic receptor epitopes.

Antibodies against the alpha-subunit of the acetylcholine receptor (AChR) are found in most patients with myasthenia gravis and are considered to contribute to the receptor damage which leads to the characteristic signs and symptoms of the disease. This B-cell response is T-cell driven. Elevated T-cell reactivities to AChR and its alpha-subunit have been described in myasthenia gravis, and AChR alpha-subunit peptide reactive T-cell lines and clones preferentially recognizing certain defined sequence segments have been reported, thereby disclosing the possibility of specific immunotherapy. We have defined the T-cell repertoire to AChR, its alpha-subunit and the synthetic peptide sequences 100-117, 113-130, 143-163, 161-179, 207-225, 221-240, and 235-255 of the alpha-subunit in an immunospot assay which is based on secretion of interferon-gamma (IFN-gamma) by individual memory T cells upon stimulation with specific antigen in short-term cultures. Most patients with myasthenia gravis displayed T-cell reactivities to 1 to 6 different peptides. The mean numbers of T cells recognizing individual peptides varied in the myasthenia gravis patients between 1 per 77,000 and 1 per 167,000 peripheral blood mononuclear cells. None of the seven peptides evaluated could be identified as an immunodominant T-cell epitope, and any of them was found to dominate in individual patients. The numbers of T cells reacting with AChR and recombinant human AChR alpha-subunit were slightly higher (mean numbers 1 per 26,000 and 1 per 50,000 mononuclear cells, respectively). Such cells, as well as AChR alpha-subunit peptide reactive T cells, were also found in patients with other neurological diseases and in healthy subjects, but at lower frequencies and numbers. In myasthenia gravis, the elevated numbers of memory T cells recognizing multiple AChR alpha-subunit peptides may be crucial for the development of the disease, and the IFN-gamma released by such T cells might be important for its perpetuation.

Adolescent↗