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Biomedical subjects

F Heidenreich

Publications and source records attributed to F Heidenreich.

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

A point mutation in PTPRC is associated with the development of multiple sclerosis.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It is widely accepted that a dysregulated immune response against brain resident antigens is central to its yet unknown pathogenesis. Although there is evidence that the development of MS has a genetic component, specific genetic factors are largely unknown. Here we investigated the role of a point mutation in the gene (PTPRC) encoding protein-tyrosine phosphatase, receptor-type C (also known as CD45) in the heterozygous state in the development of MS. The nucleotide transition in exon 4 of the gene locus interferes with mRNA splicing and results in altered expression of CD45 isoforms on immune cells. In three of four independent case-control studies, we demonstrated an association of the mutation with MS. We found the PTPRC mutation to be linked to and associated with the disease in three MS nuclear families. In one additional family, we found the same variant CD45 phenotype, with an as-yet-unknown origin, among the members affected with MS. Our findings suggest an association of the mutation in PTPRC with the development of MS in some families.

Base Sequence↗
PubMed2000

The spectrum of mutations causing end-plate acetylcholinesterase deficiency.

The end-plate species of acetylcholinesterase (AChE) is an asymmetric enzyme consisting of a collagenic tail subunit composed of three collagenic strands (ColQ), each attached to a tetramer of the T isoform of the catalytic subunit (AChE(T)) via a proline-rich attachment domain. The principal function of the tail subunit is to anchor asymmetric AChE in the synaptic basal lamina. Human end-plate AChE deficiency was recently shown to be caused by mutations in COLQ. We here report nine novel COLQ mutations in 7 patients with end-plate AChE deficiency. We examine the effects of the mutations on the assembly of asymmetric AChE by coexpressing each genetically engineered COLQ mutant with ACHE(T) in COS cells. We classify the newly recognized and previously reported COLQ mutations into four classes according to their position in ColQ and their effect on AChE expression. We find that missense mutations in the proline-rich attachment domain abrogate attachment of catalytic subunits, that truncation mutations in the ColQ collagen domain prevent the assembly of asymmetric AChE, that hydrophobic missense residues in the C-terminal domain prevent triple helical assembly of the ColQ collagen domain, and that other mutations in the C-terminal region produce asymmetric species of AChE that are likely insertion incompetent.

Acetylcholinesterase↗
PubMed1999

Expression of matrix metalloproteinase-9 and its inhibitors in mononuclear blood cells of patients with multiple sclerosis.

Inflammatory mononuclear cells invading the nervous system in demyelinating diseases are supposed to be a major source of matrix metalloproteinases which are involved in damaging the blood-brain barrier and facilitating cellular migration through the extracellular matrix. Several studies revealed a crucial role of 92 kDa gelatinase (matrix metalloproteinase-9, MMP-9) in these processes. In this study, we determined MMP-9, TIMP-1 and TIMP-2 (tissue inhibitor of metalloproteinase) mRNA in peripheral blood mononuclear cells of multiple sclerosis (MS) patients by competitive reverse transcription PCR and plasma protein levels by ELISA. In active MS patients, both with relapsing-remitting and chronic progressive disease MMP-9 mRNA and plasma protein levels were significantly increased compared to healthy controls. No significant changes in mRNA expression were found for TIMP-1 and TIMP-2. However, unbound TIMP-2 in plasma was significantly higher in MS patients compared to healthy controls. MMP-9 and TIMP-1 expression was significantly correlated in MS with a significantly higher MMP-9/TIMP-1 ratio in active MS than in healthy controls. These results are in support of an important pathogenic role of MMP-9 activity in MS.

Adult↗
PubMed1999

Costimulatory molecules B7-1 and B7-2 on CSF cells in multiple sclerosis and optic neuritis.

The aberrant expression of B7 costimulatory molecules is involved in the pathogenesis of autoimmune diseases and overexpression of B7-1 was found in inflammatory multiple sclerosis (MS) lesions. We here report that costimulatory molecules B7-1 and B7-2 are expressed on cerebrospinal fluid (CSF) monocytes and B-lymphocytes from patients with MS, optic neuritis (ON) and other inflammatory central nervous system (CNS) diseases. In patients with ON but not MS, increased expression of B7-2 was detected as compared to non-inflammatory controls. The expression of B7-1 in MS and ON patients correlates with disease duration but not with relapses in patients with MS indicating a role in early disease but not as a reliable marker of disease activity at later stages of MS.

Antigens, CD↗
PubMed1999

Analysis of cerebrospinal fluid cells by flow cytometry and immunocytochemistry in inflammatory central nervous system diseases: comparison of low- and high-density cell surface antigen expression.

The examination of cerebrospinal fluid (CSF) continues to play an important role in the diagnosis of inflammatory diseases of the central nervous system (CNS). Immunocytochemistry and flow cytometry are the most commonly used methods for analysis of surface markers on CSF cells. We here compared these methods in the examination of CSF cells from a total of 68 patients with acute and chronic inflammatory CNS diseases. Expression of costimulatory molecules CD80 (B7-1) and CD86 (B7-2) as activation markers that are present at low density on the cell surface was analyzed in comparison to CD22 (B-cells) and CD4 (T-cell subset), that show high staining intensities. For CD22 and CD4, the results obtained with both methods were similar and reliable. Using flow cytometry, CD80 expression was detected in 6% of CSF cells in patients with chronic inflammatory CNS disease, as compared to 2% using immunocytochemistry, where the reliability of the data was found to be higher. We conclude that for examination of low-density surface markers on CSF cells, particularly with low cell counts, immunocytochemistry may be more reliable.

Antigens, CD↗
PubMed1999

Human polymorphonuclear neutrophils express a B7-1-like molecule.

Polymorphonuclear neutrophils (PMN) are part of the innate immune system and are first-line effector cells in acute inflammatory responses. On activation PMNs secrete cytokines and oxygen metabolites that might be involved in the regulation of the acquired immune response. We show here that peripheral blood PMNs constitutively express a B7-1-like molecule as detected by immunostaining with several B7-1 antibodies. Reverse transcriptase-polymerase chain reaction using three sets of primers spanning different regions of B7-1 indicate dissimilarities at the mRNA level. B7-1 mRNA is expressed in bone marrow cells and lipopolysaccharide (LPS)-stimulated but not in unstimulated PMNs. The B7-1-like molecule is localized to the cytoplasmic granules and translocated to the cell surface after stimulation with LPS or interleukin-12 in some donors. Binding of CTLA4-Ig suggests that the B7-1-like molecule can interact with functional B7 ligand and might be important in the immunobiology of PMNs.

Antibodies, Monoclonal↗
PubMed1999

Early and late results after thymectomy in myasthenia gravis: a retrospective study [correction of analysis].

BACKGROUND: This study aims to evaluate the early and late outcome of patients treated by surgery for myasthenia gravis and the diagnostic value of the Besinger Score, which is based on a correlation of severity of symptoms with specific antibodies to acetylcholine receptors, in the follow-up investigation after surgical therapy. METHODS: Between June 1984 and April 1992 thoracotomy was performed in 51 myasthenia gravis cases at our department. The retrospective analysis considered patients with (n = 13) or without thymoma (n = 38). The Besinger score was used to describe the severity of disease preoperatively and up to 5 years postoperatively. RESULTS: The Besinger score fell continually post surgery. Changes in relative serum concentrations of antibodies were similar to the Besinger score. Five years after thymectomy complete remission was diagnosed in 40% of the patients. The required dosage of pyridostigmine had fallen by two thirds after 5 years. Patients with follicular hyperplasia had significantly higher remission rates than those with thymoma. CONCLUSIONS: Surgery for myasthenia gravis is successful. The Besinger score well quantifies the severity of the disease.

Adolescent↗
PubMed1998

Antibodies to ion-channel proteins in thymoma with myasthenia, neuromyotonia, and peripheral neuropathy.

A patient presented with anti-acetylcholine receptor antibody-positive myasthenia gravis. After removal of a thymoma and use of cytotoxic therapy, there was worsening of myasthenia, onset of muscle stiffness and hyperexcitability, and electrophysiologic signs of peripheral neuropathy. Elevated serum titers of antibodies to neuronal voltage-gated K+ channels were present, consistent with neuromyotonia (Isaacs' syndrome). A beneficial response to treatment paralleled changes in antibody titers.

Antibodies, Neoplasm↗
PubMed1996

Synthesis of anti-acetylcholine receptor antibodies by CD5- B cells from peripheral blood of myasthenia gravis patients.

An increased frequency of CD5+ B cells (or, according to a new nomenclature, B1 cells) has been detected in the peripheral blood of a proportion of patients with myasthenia gravis (MG), as in some other autoimmune diseases. To elucidate the pathogenic significance of this B-cell subset in myasthenia gravis, mononuclear cells from the peripheral blood of six MG patients were separated into T and B lymphocytes by a magnetic cell separation procedure employing superparamagnetic microbeads (MACS). Subsequently, the B-cell fraction was depleted of CD5+ B cells in a second separation. The resulting purified CD5- B-cell fraction was cultured alone or with the addition of autologous T cells. Anti-acetylcholine receptor (AChR) synthesis by CD5- B cells in cultures with T cells was significantly increased by pokeweed mitogen (176 +/- 130 fmol/ml per week/2 x 10(5) B cells) compared with unfractionated cells (75 +/- 101) or CD5- B cells alone (19 +/- 4). These results demonstrate that in MG anti-AChR are synthesized, at least in part, by CD5- B cells which are dependent on T cells. Although this does not exclude the existence of AChR-specific CD5+ B cells, it provides evidence against a pivotal role of this B-cell subset in anti-AChR synthesis.

Adult↗
PubMed1995

Circulating adhesion molecules and tumor necrosis factor receptor in multiple sclerosis: correlation with magnetic resonance imaging.

Adhesion molecules are important in T-cell trafficking to sites of inflammation. We determined levels of circulating vascular cell adhesion molecule-1 (VCAM-1), L-selectin, and E-selectin in the serum of 147 patients with definite multiple sclerosis of the remitting-relapsing or secondary progressive type. Soluble VCAM-1 and L-selectin concentrations were increased compared to levels in a large group of control subjects. Levels were highest in patients with gadolinium-enhancing lesions on magnetic resonance imaging (VCAM-1: 1,011 +/- 276 vs 626 +/- 87 ng/ml; L-selectin: 1,130 +/- 272 vs 793 +/- 207 ng/ml [mean +/- standard deviation]; p < 0.0001 vs patients without enhancing lesions). Serum levels of soluble tumor necrosis factor receptor (60 kd) were also raised (2.64 +/- 1.23 vs 2.17 +/- 0.69 ng/ml in subjects with other neurological diseases and 2.1 +/- 0.77 ng/ml in healthy control subjects; p < 0.05). Soluble VCAM-1 and L-selectin levels were correlated to concentrations of soluble tumor necrosis factor receptor. In 13 patients with viral encephalitis, similar observations were made. Raised levels of soluble VCAM-1 and L-selectin probably reflect cytokine-induced endothelial cell and T-lymphocyte/monocyte activation occurring in the process of T-cell migration into the central nervous system. Tumor necrosis factor-alpha may be critically involved.

Cell Adhesion Molecules↗
PubMed1995

Multiple paraneoplastic syndromes in a patient with antibodies to neuronal nucleoproteins (anti-Hu).

We report the clinical and autopsy studies of a patient with an unusual combination of multiple paraneoplastic neurological syndromes in association with antibodies to a 35-40 kDa neuronal nucleo-protein (anti-Hu). Neurological disease preceded the detection of a small cell carcinoma of the lung. The patient had combined sensory and motor neuronopathy or neuropathy, cerebellar degeneration, brain-stem and limbic encephalitis, and clinical evidence of the Lambert-Eaton myasthenic syndrome and gastrointestinal pseudo-obstruction of paraneoplastic origin.

Autoantibodies↗
PubMed1994

Serum and cerebrospinal fluid levels of soluble intercellular adhesion molecule 1 (sICAM-1) in patients with HIV-1 associated neurological diseases.

We measured levels of soluble intercellular adhesion molecule 1 (sICAM-1) in paired serum and CSF samples of 110 HIV-1-positive patients with and without neurological symptoms and 40 HIV-negative non-immune neurological controls, and in sera of 26 asymptomatic HIV-1-positive patients. Serum sICAM-1 levels in asymptomatic HIV-1-positive patients were significantly increased in comparison to HIV-negative controls. Moreover, they were significantly higher in HIV-1-positive patients with AIDS-defining diseases than in the asymptomatic HIV-1-positive group. In subgroups of patients with neurological disease, the highest serum values were found in HIV encephalopathy. CSF levels of sICAM-1 were elevated only in HIV-1-positive patients with neurological disease mainly due to passive diffusion through a defective blood-brain barrier. An sICAM-1 index was calculated as a measure for intrathecal production of sICAM-1 but showed no significant differences between patients with and without neurological involvement. However, increased levels of the sICAM-1 index were found in some patients with opportunistic CNS infection of bacterial or fungal origin. Serum and CSF levels of sICAM-1 correlated with neopterin levels, a marker of interferon-gamma-mediated macrophage activation and CSF sICAM-1 levels were inversely correlated to numbers of CD4+ T cells. Elevated serum sICAM-1 levels already in asymptomatic HIV-1-positive individuals add to the evidence for an early immune activation in HIV infection. With the further increase of serum and CSF s-ICAM-1 in patients with AIDS-defining diseases sICAM-1 could serve as a new surrogate marker similar to neopterin.

AIDS Dementia Complex↗
PubMed1994

T cell-dependent activity of ganglioside GM1-specific B cells in Guillain-Barré syndrome and multifocal motor neuropathy in vitro.

Synthesis of anti-ganglioside GM1 antibodies of the IgM class by peripheral blood mononuclear cells (PBMNC) from patients with immune-mediated neuropathies and motor neuron diseases and from normal controls was stimulated by Pokeweed mitogen (PWM) in vitro. In patients with acute Guillain-Barré syndrome or multifocal motor neuropathy and high serum titers of IgM anti-ganglioside GM1 antibodies this culture response was greatly enhanced as compared to controls and already detectable in unstimulated cultures. Limiting dilution analysis demonstrated high frequencies of GM1-specific B cells in these patients. Anti-ganglioside GM1 antibodies of the IgG and IgA class were only produced by PBMNC from patients with Guillain-Barré syndrome corresponding to serum titers. In cultures taken at intervals over 6 months in vitro B cell activity for IgM, IgG and IgA anti-ganglioside GM1 antibodies in two Guillain-Barré syndrome patients declined accompanied by clinical improvement and falling serum titers. We conclude that GM1-specific PWM-responsive B cells pre-exist in peripheral blood and respond to T cell-dependent stimulation in Guillain-Barré syndrome and multifocal motor neuropathy.

Adult↗
PubMed1994

Serum levels of soluble E-selectin (ELAM-1) in immune-mediated neuropathies.

Adhesion molecules are critically involved in inflammatory responses. We studied serum concentrations of the soluble form of E-selectin (endothelial-leukocyte adhesion molecule-1, ELAM-1) in 187 patients with neuropathies of diverse etiology, 54 patients with other noninflammatory, nondemyelinating neurologic disorders, and 15 healthy controls. Serum E-selectin levels, quantitated by a two-site enzyme-linked immunosorbent assay, were significantly increased in 126 patients with Guillain-Barré syndrome (GBS) (mean +/- SD, 45.1 +/- 16.3 ng/ml) and 13 patients with vasculitic neuropathies (47.1 +/- 19.1ng/ml) compared with patients with other neurologic diseases (19.8 +/- 7.4 ng/ml) and healthy controls (21.9 +/- 8.1 ng/ml). In GBS, E-selectin levels were temporally related to disease activity. Cytokine-mediated upregulation of E-selectin may be important in homing and attachment of leukocytes to endoneurial endothelial cells. Raised E-selectin concentrations probably reflect endothelial cell activation occurring early in the sequence of immunopathologic events culminating in peripheral nerve damage.

Cell Adhesion Molecules↗
PubMed1993

Serum and CSF levels of soluble intercellular adhesion molecule-1 (ICAM-1) in inflammatory neurologic diseases.

Intercellular adhesion molecule-1 (ICAM-1), a cell surface receptor important for cellular interactions in immune responses, especially leukocyte trafficking into inflamed tissue, is released in a soluble form (sICAM-1) into the extracellular space. In this study, we measured sICAM-1 in paired serum and CSF samples from patients with inflammatory diseases of the nervous system (IND) and calculated a sICAM-1 index as a measure of the intrathecal release of ICAM-1. In comparison with noninflammatory neurologic disease (NIND) controls, we found increased sICAM-1 index levels in viral meningoencephalitis, bacterial meningitis and, to a lesser degree, multiple sclerosis but not in Guillain-Barré syndrome. Serial examination of viral meningoencephalitis patients in most cases showed a decrease of sICAM-1 index in parallel with falling cell counts and clinical improvement. Except for those in bacterial meningitis, sICAM-1 serum levels of IND patients were not significantly different from those of NIND controls. The increased intrathecal release of sICAM-1 in viral meningoencephalitis and bacterial meningitis most likely reflects activation of macrophages and lymphocytes and provides evidence for a strong local immune response that itself, in addition to the infectious agent, may damage nervous tissue.

Cell Adhesion Molecules↗
PubMed1991

Electrophysiological characterization of the X-linked recessive bulbospinal neuronopathy (XRBSN).

Detailed electrophysiological analyses including nerve conduction velocity measurements of motor and sensory nerves, EMG recordings of a variety of muscles, evoked potentials, magnetic brain stimulation, electrophysiological testing of autonomic functions, tremor measurements and testing of voluntary movements were applied to three patients with X-linked recessive bulbospinal neuronopathy (XRBSN). All three patients presented with a slowly progressive anterior horn impairment, involvement of sensory nerves and posterior columns, but intact central descending motor pathways and an essential tremor responding to propranolol treatment. The spectrum of electrophysiological findings helps to diagnose XRBSN reliably even in sporadic cases.

Adult↗