Biomedical subjects

H Link

Publications and source records attributed to H Link.

At least 361 records · Page 20Linked to original sources

PubMed1991

Antibodies to myelin-associated glycoprotein are found in cerebrospinal fluid in polyneuropathy associated with monoclonal serum IgM.

Antibodies to myelin-associated glycoprotein (MAG) have been demonstrated in the serum samples from about half the patients with polyneuropathy associated with serum IgM monoclonal component. We examined cerebrospinal fluid (CSF) and serum samples from 13 patients with this disease by enzyme-linked immunosorbent assay for anti-MAG IgM antibodies. We detected these antibodies in both CSF and serum samples in 10 of the patients; in three of them the antibodies were at higher levels in the CSF. The remaining three patients had anti-MAG IgM antibodies in the CSF only. Intrathecal production of anti-MAG IgM antibodies is thus common in polyneuropathy associated with IgM monoclonal component. In three patients, examined on two occasions from 1 to 7 years, high anti-MAG IgM antibody levels persisted in CSF and serum samples. Among 165 patients with other neurologic diseases, including 60 with multiple sclerosis and 60 control subjects with tension headache, anti-MAG IgM antibodies were detected in the CSF from three patients (two with multiple sclerosis, one with aseptic meningitis), and in the serum sample of one patient with multiple sclerosis. Whether the frequent occurrence of anti-MAG IgM antibodies in CSF and their intrathecal synthesis has pathogenetic relevance for the development of polyneuropathy associated with IgM monoclonal component is unsure.

Aged↗

PubMed1991

Autoreactive T and B cells responding to myelin proteolipid protein in multiple sclerosis and controls.

The pathogenesis of multiple sclerosis (MS) could involve an autoimmune response to proteolipid protein (PLP). Immunization of experimental animals with this major myelin protein can lead to experimental allergic encephalomyelitis. To identify a possible role of PLP as target antigen in MS, we evaluated T cell immunity to PLP in blood and cerebrospinal fluid (CSF) from patients with MS and controls by counting cells which in response to PLP in short-term cultures secreted interferon-gamma. The PLP-specific B cell response was analyzed by counting cells secreting anti-PLP antibodies. PLP-reactive T cells were detected in blood of most MS patients (mean value 1 per 20,408 mononuclear cells), and at 41-fold higher numbers in CSF (mean 1 per 500 CSF cells). Anti-PLP IgG antibody-secreting cells were detected in blood from most MS patients (mean 1 per 30,303 cells), but such cells were 49-fold more frequent in CSF (mean 1 per 625 cells). PLP-reactive T and B cells were also detected in blood and CSF from control patients, but at much lower numbers. A strong and persistent autoimmune response to PLP as well as to other myelin proteins, enriched in CSF, is proposed to be pathogenetically important in MS.

Adolescent↗

PubMed1991

Cells producing antibodies specific for myelin basic protein region 70-89 are predominant in cerebrospinal fluid from patients with multiple sclerosis.

Cells secreting antibodies against guinea pig myelin and synthetic myelin basic protein (MBP) peptides were evaluated in cerebrospinal fluid (CSF) and blood from patients with multiple sclerosis (MS) and a variety of other neurological diseases (OND). The peptides used, reproducing amino acid sequences 1-20, 70-89, 108-126, or 157-166 of MBP, were selected on the basis of their hydrophilic and encephalitogenic properties. Low numbers of cells secreting IgG antibodies against myelin or each of the MBP peptides (about 1 per 50,000) were detected in peripheral blood, with no difference between MS and OND. In CSF, cells secreting IgG antibodies to MBP 70-89 were more frequently (p = 0.007) detected in patients with MS (1/380 IgG-secreting cells on average) than in patients with OND (1/2083 IgG-secreting cells on average). The frequencies of cells secreting antibodies against myelin or the three other MBP peptides were similar in MS and OND. Thus, evaluation of B cell immunity at the cellular level indicates that MBP 70-89 is an immunodominant B cell epitope in MS. It is not clear whether this intrathecal anti-MBP 70-89 IgG antibody response has any pathogenetic relevance in MS or is the result of myelin breakdown.

Adult↗

PubMed1991

High-dose ara-C and etoposide in refractory or relapsing acute leukemia.

A total of 32 patients (15 men and 17 women) presenting with relapsing or refractory acute leukemia were treated with a 3-h infusion of 3 g/m2 cytosine arabinoside (ara-C) twice daily on days 1-6 and a 1-h infusion of 100 mg/m2 etoposide on days 1-5. In all, 6 subjects had acute lymphocytic leukemia (ALL); 25 had acute myeloid leukemia (AML) of types M1 (n = 6), M2 (n = 10), M4 (n = 5), and M5 (n = 4); and 1 had mixed-type leukemia. The median age was 35 years (ranges, 16-62 years). Of the patients presenting with AML, 11 were primarily refractory and 3 became refractory after their first relapse. Six subjects had an early first relapse following a complete remission (CR) that lasted less than 6 months and five, a second relapse. Another patient underwent a primary relapse after greater than 6 months but had been heavily pretreated. In all, 5 subjects with refractory AML achieved a CR (36%; 95% confidence interval (CI), 10%-62%) as did 7 patients exhibiting relapsing AML (58%; CI, 30%-86%). Three patients who had relapsing or resistant ALL achieved a CR. Side effects consisted of severe hematotoxicity associated with granulocytopenia of less than 500/mm3 that lasted for a mean of 23.6 days and thrombocytopenia of less than 20,000/mm3 whose mean duration was 20.8 days. Marked gastrointestinal toxicity and infections were also prevalent. Cutaneous and ocular toxicity as well as allergic, pulmonary and cerebellar side effects were observed in a few cases. We conclude that the combination of high-dose ara-C and etoposide is a powerful but toxic induction regimen for refractory or relapsed acute leukemia.

Acute Disease↗

PubMed1991

Five-day 4'-(9-acridinylamino)methanesulphon-m-anisidide and intermediate-dose cytosine arabinoside in high-risk relapsing or refractory acute myeloid leukemia.

Twenty-two patients with acute myeloid leukemia (AML), having a median age of 48.3 years (range 26-70; 10 male, 12 female), were treated with 4'-(9-acridinylamino) methanesulphon-m-anisidide (m-AMSA) 100 mg/m2 and cytosine arabinoside (AraC) 2 x 1000 mg/m2i.v. on days 1-5. There were 2M1,8 M2, 9 M4, 2M4 Eo, and 1 M5a. Of these, 12 achieved a complete remission, 3 a partial remission and 6 did not respond. The median remission duration was 9.0 months and the median overall survival 8.1 months. Side-effects of induction consisted mainly of haematological toxicity and infections with a median duration of WHO-grade-4 granulopenia and thrombopenia of 20 and 28 days respectively. Organ toxicity was mild with mucositis and cutaneous and liver toxicity being experienced by only a few patients. There was one treatment-related death. Five-day m-AMSA and intermediate-dose AraC is an easy-to-handle condensed treatment schedule with tolerable toxicity. Its effectiveness in relapsed and refractory AML is comparable to combinations of high-dose AraC with m-AMSA, anthracyclines or etoposide.

Acute Disease↗

PubMed1991

Anti-presynaptic membrane receptor antibodies in myasthenia gravis.

Myasthenia gravis (MG) is considered as an autoimmune disease of neuromuscular junction resulting from antibodies directed to acetylcholine receptors (AChR). We describe the use of beta-bungarotoxin (beta-BuTx) and alpha-bungarotoxin (alpha-BuTx) to capture their corresponding proteins from preparation of crude human muscle receptor. beta-BuTx binds to presynaptic membrane receptor (PsmR) of the whole receptor fraction, while alpha-BuTx binds to AchR. The captured proteins were used as antigen in ELISA to detect antibodies to PsmR and to AchR in sera from 82 Chinese patients with MG and in controls. In MG, antibodies to PsmR only were detected in 13%, to AchR only in 11% and both to PsmR and AchR in 54%. Only 3 of 50 patients with other neurological diseases and none of 50 healthy subjects had these antibodies. Specificity tests for antibodies showed that the detection systems which we used are specific and confident. No correlation was found between antibody levels and clinical status. The significance of the PsmR antibodies in the pathogenesis of MG is unknown. We suggest that myasthenia gravis is not only due to damage of the postsynaptic membrane, but of presynaptic structures as well.

Adult↗

PubMed1991

Immunological specificity and cross-reactivity of anti-acetylcholine receptor and anti-presynaptic membrane receptor antibodies in myasthenia gravis.

Antibodies against acetylcholine receptor (AChR), a protein that binds to alpha-bungarotoxin (alpha-BuTx), are characteristic for myasthenia gravis (MG) and are considered to be of importance in the pathogenesis of the disease. Antibodies against a beta-BuTx binding protein, presynaptic membrane receptor (PsmR), have also been reported in most MG patients. We have analysed the specificity and cross-reactivity of antibodies to bovine AChR and PsmR in sera from 11 patients with MG. More than 90% of antibodies to PsmR were adsorbed specifically by PsmR conjugated affinity chromatography. Similarly, more than 90% of anti-AChR antibodies were absorbed by AChR conjugated affinity chromatography. Specificities of antibodies from affinity chromatography were also confirmed by ELISA and agarose isoelectric focusing. However, the antibodies to PsmR and AChR from MG patients' sera showed about 45-55% cross-reactivity, and there was a high correlation between serum levels of both antibodies. The demonstration of anti-PsmR antibodies could be important in documenting presynaptic damage and understanding the pathogenetic process in MG.

Autoantibodies↗

PubMed1991

CD5+ B cells and CD4-8-T cells in neuroimmunological diseases.

Using 2- and 3-colour FACS analysis we found increased levels of fetal-type CD5+ B cells and CD4-8- T cells in cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) and aseptic meningitis (AM) compared to control probands with muscular tension headache (TH). Similar differences were found for CD5+ B cells in peripheral blood, but at lower levels. CD4-8- T cells in blood exceeded those in CSF in all patient groups, with the exception of relapsing remitting MS, revealing the highest values in AM. There was a positive correlation between CD4-8- T cells and T cell receptor (TCR) gamma delta bearing T cells in blood and CSF. The double-negative T cells exceeded the TCR gamma delta T cells by about 1%. A positive correlation between CD5+ B cells and CD4-8- T cell level in CSF was found in MS and AM, but not in TH, nor in blood of any patient group. HLA-DR expression was lower in CD5+ B cells than in CD5- B cells. We conclude that fetal-type lymphocytes are enriched in CSF compartment of patients with inflammatory diseases of the central nervous system, irrespective of autoimmune mechanisms involved, but the function of CD5+ B cells is mainly to produce the autoantibodies.

Adolescent↗

PubMed1991

Antibodies to myelin-oligodendrocyte glycoprotein in cerebrospinal fluid from patients with multiple sclerosis and controls.

Myelin-oligodendrocyte glycoprotein (MOG) has been implicated as a target for antibody-mediated immune attack in experimental autoimmune encephalomyelitis (EAE) which has been used extensively as an experimental model of multiple sclerosis (MS). We have screened cerebrospinal fluid (CSF) and plasma from 30 patients with MS, 30 with other neurological diseases (OND) and 30 with tension headache for anti-MOG antibodies of IgG isotype by enzyme-linked immunosorbent assay (ELISA). Such antibodies were detected in CSF from seven of the patients with MS, compared to two with OND and one with tension headache. No anti-MOG IgG antibodies were demonstrable in plasma. Antibody specificity was confirmed by Western blot immunostaining. Antibody levels were higher in MS compared to OND and tension headache. No correlation was observed between anti-MOG IgG antibodies and total IgG levels in CSF. The significance of anti-MOG antibodies demonstrated in MS CSF remains to be defined.

Adult↗

PubMed1991

Interleukin-6 is elevated in plasma in multiple sclerosis.

Levels of interleukin-6 (IL-6)--a cytokine which induces immunoglobulin production of activated B cells--were measured in cerebrospinal fluid (CSF) and plasma of patients with multiple sclerosis (MS), acute meningo-encephalitis (AM) and muscular tension headache (TH). MS patients had in repeated samples higher levels of IL-6 in plasma compared to patients with AM and TH. IL-6 concentrations in MS plasma were about 17 times higher than MS CSF, while in AM 20-fold higher levels were found in CSF compared to plasma during the acute stage. IL-6 in AM CSF decreased rapidly during clinical recovery. No correlation was found between IL-6 in MS patients' plasma or CSF and disease activity. The functional significance of elevated IL-6 concentrations in MS plasma is unknown, although the findings support the hypothesis of a systemic B cell response in MS.

Acute Disease↗

PubMed1991

Sulfasalazine aggravates experimental autoimmune encephalomyelitis and causes an increase in the number of autoreactive T cells.

Sulfasalazine (SASP; 5-(p-(2-pyridylsulfamoyl)phenylazo)salicyclic acid) has beneficial effects on certain inflammatory diseases and has been proposed for clinical trials in multiple sclerosis (MS). We have explored the effects of SASP on actively induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats. SASP was given orally at three different doses from the day of immunization to day 40 post-immunization (p.i.). All doses led to a clinically more protracted disease, increased numbers of T cells infiltrating into the central nervous system (CNS) and to increased numbers of interferon-gamma-secreting cells (IFN-gamma-sc) in the CNS. The effects of SASP treatment on T cell-mediated autoimmunity against CNS myelin and peptides of myelin basic protein (MBP) were measured by IFN-gamma secretion and proliferation by lymph node mononuclear cells in response to these antigens. In SASP-treated rats, increased numbers of IFN-gamma-sc appeared in response to myelin antigens, while the proliferative responses were decreased. We suggest that monitoring cell-mediated immunity with the IFN-gamma-sc method may be relevant for the evaluation of new immunotherapeutic strategies in inflammatory demyelinating diseases. Furthermore, our results demand caution as to clinical trials with SASP in MS.

Animals↗

PubMed1991

Cells secreting anti-MAG antibody occur in cerebrospinal fluid and bone marrow in patients with polyneuropathy associated with M component.

Occurrence and distribution of cells secreting antibodies against myelin associated glycoprotein (MAG) were studied in 9 patients with polyneuropathy associated with the monoclonal (M) component in serum. Utilizing an immunospot assay, we found that 4 of 7 patients with polyneuropathy associated with an IgM M component had cells secreting anti-MAG IgM antibody in cerebrospinal fluid (CSF) numbering between 1 per 212 and 1 per 3333 mononuclear cells. All 7 patients had cells secreting anti-MAG IgM antibody in bone marrow (median value 1 per 2000 cells). In contrast, peripheral blood from only 2 of these patients contained low numbers of such cells. One patient with polyneuropathy associated with an IgA M component had cells secreting anti-MAG IgA antibody in CSF, and 1 with an IgG M component had cells secreting anti-MAG IgG antibody in CSF; both patients also had anti-MAG IgM antibodies detectable in CSF only by ELISA. These 2 patients may thus have concurrent intrathecal production of antibodies of 2 different isotypes which are directed against the same or different epitopes of MAG. The production of antibodies directed against a component of myelin occurring in the immediate vicinity of the peripheral nervous system might be involved in the pathogenesis of the polyneuropathy.

Adult↗

PubMed1991

Cord blood contains cells secreting antibodies to nervous system components.

Umbilical cord blood of newborns and peripheral blood of healthy adults were investigated by an immunospot assay for cells secreting IgG, IgA and IgM antibodies against myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG) which represent putative antigens for an autoimmune attack in multiple sclerosis (MS) and against acetylcholine receptor (AChR) which is considered an important autoantigen in myasthenia gravis. Cells secreting antibodies against one or more of these autoantigens were detected in 18 out of 24 newborns, and in eight out of 20 adults. Eight of the cord blood samples contained cells secreting antibodies of IgG, IgA and/or IgM isotypes to one antigen, five to two antigens, two to three antigens, two to four antigens, and one to five antigens. Most prominent were anti-MBP IgG antibody secreting cells which were detected in 13 newborns at a mean number of 1/20,000 cord blood cells, and in six adults at a mean number of 1/10(5) peripheral blood cells. Anti-AChR IgG antibody secreting cells were detected in four out of 12 newborns versus four out of 14 peripheral blood specimens, at mean values of 1/10(5) cells in both instances. Cells secreting autoantibodies of IgA and IgM isotypes were less frequent both in cord blood and peripheral blood. The occurrence of nervous tissue autoantibody secreting cells in newborns must be related to a possible primary role of such autoantibodies in MS and myasthenia gravis.

Adult↗

PubMed1991

Lyme arthritis: oligoclonal anti-Borrelia burgdorferi IgG antibodies occur in joint fluid and serum.

The antibody response to Borrelia (B.) burgdorferi, and to measles virus as control antigen, was analysed by agarose isoelectric focusing (AIF) and immunoblot of joint fluid and serum from 10 patients with Lyme arthritis and 10 controls with rheumatoid arthritis. Among the Lyme arthritis patients, six had oligoclonal anti-B. burgdorferi IgG antibody bands in joint fluid and corresponding serum, one patient had oligoclonal antibody bands in joint fluid only and also an elevated B. burgdorferi-specific joint fluid to serum antibody ratio as evidence of intra-joint production of specific antibodies, and the remaining three patients were negative for oligoclonal-specific antibody bands. Absorption with B. burgdorferi antigen confirmed the specificity of the oligoclonal antibody bands. They comigrated only partially on AIF with oligoclonal bands of total IgG, and the specificity of most oligoclonal IgG in joint fluid and serum in Lyme arthritis remains undefined. Among the controls, no anti-B, burgdorferi IgG antibodies were detected by AIF and immunoblot. Instead, 9 of the 10 rheumatoid arthritis patients had oligoclonal anti-measles IgG antibody bands which were restricted to the joint fluid in three of them, indicating local production. We conclude that Lyme arthritis is often accompanied by an oligoclonal specific antibody response in joint fluid and serum simultaneously, and occasionally by intrasynovial synthesis of oligoclonal-specific antibodies.

Adolescent↗

PubMed1991

Multiple sclerosis: cells secreting antibodies against myelin-associated glycoprotein are present in cerebrospinal fluid.

We evaluated the B-cell response in cerebrospinal fluid (CSF) and blood by enumerating cells secreting antibodies to myelin-associated glycoprotein (MAG) and, for reference, to myelin basic protein (MBP), two myelin components which may constitute targets for autoimmune attack in multiple sclerosis (MS). Among 25 untreated MS patients, 12 had cells in CSF secreting anti-MAG IgG antibodies (mean value 1 per 1429 CSF cells) and three also had cells secreting anti-MAG antibodies of the IgM isotype but at lower levels. In CSF from 2 out of 10 MS patients examined, anti-MAG and anti-MBP IgG antibody-secreting cells were present concurrently. Antibody-secreting cells were less frequent in blood and bone marrow, reflecting compartmentalization to CSF. Anti-MAG antibody-secreting cells were found in CSF from only 1 out of 27 control patients. The intrathecal production of anti-MAG and anti-MBP antibodies may be important in the pathogenesis of MS.

Adult↗

PubMed1991

Anti-Borrelia burgdorferi antibody response over the course of Lyme neuroborreliosis.

Characteristic findings on examination of cerebrospinal fluid (CSF) in Lyme neuroborreliosis include mononuclear pleocytosis, oligoclonal immunoglobulin G (IgG) bands, and evidence for local production of specific antibodies. We utilized an immunospot assay to detect cells secreting anti-Borrelia burgdorferi antibodies of different isotypes over the course of disease. Such cells were detected in CSF from 13 consecutive patients with neuroborreliosis examined before treatment. IgG antibody-secreting cells were present in high numbers (mean, 32 cells per 10(4) CSF cells), whereas IgA and IgM antibody-secreting cells were found less frequently and at lower numbers (mean, 5 and 6 cells per 10(4) CSF cells, respectively). Clinical improvement after penicillin treatment was paralleled by a rapid decline of antibody-secreting cells in CSF, but they were still detected, although at lower numbers, in 5 of 10 patients examined more than 6 months after treatment. This specific B-cell response persisted despite clinical improvement. Whether it reflects persistence of antigen is unsettled.

Adult↗

PubMed1991

Immunoglobulin producing cells in bone marrow and blood of patients with multiple sclerosis and controls.

Multiple sclerosis (MS) is characterised by intrathecal synthesis of IgG, less frequently of IgA and IgM. Local production of antibodies to myelin basic protein (MBP) and other myelin components has also been reported, and autoimmune pathogenesis has been postulated. Whether MS is accompanied by a systemic B cell response is less clear. To elucidate this question, we examined bone marrow and peripheral blood from patients with MS and controls for cells secreting IgG, IgA and IgM, as well as anti-MBP antibodies of these three isotypes. Patients with MS without any signs of concurrent infections had higher numbers of IgG + IgA + IgM secreting cells both in bone marrow and peripheral blood compared with healthy controls. The same abnormalities were observed in patients with other inflammatory neurological diseases (OIND). When analysing individual isotypes, patients with MS and OIND had higher numbers of IgA secreting cells both in bone marrow and blood compared with healthy controls. Only one of 13 MS patients examined had anti-MBP antibody secreting cells in bone marrow and blood. The systemic B cell response registered in MS is also present in other inflammatory neurological diseases and its specificity and possible role in the pathogenesis of MS remains unknown.

Adult↗

PubMed1991

Acetylcholine receptor-reactive T and B cells in myasthenia gravis and controls.

Myasthenia gravis (MG) is strongly associated with antibodies to acetylcholine receptor (AChR), whereas the extent of T cell involvement is not settled. The number of cells secreting interferon-gamma (IFN-gamma) in response to AChR during 48 h culture of blood mononuclear cells (PBL) may reflect AChR-reactive T cells. Using an immunospot assay, we detected such cells in 23 of 30 patients with MG at a mean number of 1 per 33.333 PBL. AChR-reactive T cells were also found in patients with other neurological diseases (OND) and in healthy subjects but at lower frequencies and numbers. The T cell response to purified protein derivative and to PHA, and also to two major myelin proteins (basic protein and proteolipid protein) did not differ between MG and the two control groups, underlining the specificity of an augmented T cell reactivity to AChR in MG. Evaluation of the B cell response by enumerating anti-AChR IgG antibody secreting cells revealed such cells in 27 of 28 patients with MG at a mean value of 1 per 14,085 PBL. Cells secreting anti-AChR antibodies of the IgA and IgM isotypes were also detected in MG, but less frequently, at lower numbers, and only in conjunction with IgG antibody secreting cells. Anti-AChR antibody secreting cells were also found among patient with OND and in healthy controls, but at lower frequencies and numbers. These data confirm that AChR is a major target for autoimmune response in MG.

B-Lymphocytes↗