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B C Kieseier

Publications and source records attributed to B C Kieseier.

At least 37 records · Page 2Linked to original sources
PubMed2001

Expression of specific matrix metalloproteinases in inflammatory myopathies.

The family of matrix metalloproteinases (MMPs) comprises endopeptidases that are capable of degrading all extracellular matrix components. Given these actions, it is conceivable that MMPs may play a pathogenic role in inflammatory myopathies. These immune-mediated disorders are characterized by the invasion of mononuclear phagocytes and T lymphocytes and the loss of muscle fibres. We examined whether specific MMPs and their natural inhibitors (tissue inhibitors of metalloproteinases; TIMPs) are expressed in muscle during acute inflammatory attacks by studying muscle biopsies obtained from patients diagnosed as having polymyositis, dermatomyositis, sporadic inclusion body myositis and, for comparison, from cases of various muscular dystrophies. Quantitative polymerase chain reaction analysis revealed significantly elevated mRNA expression of interstitial collagenase (MMP-1) and gelatinase B (MMP-9) in polymyositis and dermatomyositis and to a lesser extent in inclusion body myositis, whereas the level of expression of TIMPs remained unchanged in comparison with controls. Increased mRNA levels were associated with enhanced enzyme expression, as determined by immunoblotting, gelatin zymography and in situ zymography. Immunohistochemically, MMP-1 could be localized around the sarcolemma of diseased muscle fibres and to cells resembling fibroblasts, whereas MMP-9 seemed to be expressed primarily by invading T lymphocytes. Raised levels of MMPs could not be detected in the sera of affected patients, emphasizing the crucial action of MMPs in the inflamed muscle. Our results imply a pathogenic role for specific MMPs in the genesis of inflammatory myopathies, and open new strategies for therapeutic intervention.

Adult↗
PubMed2001

Progress in Guillain-Barré syndrome.

This editorial review summarizes and critically analyses reports published in the preceding 18 months on the pathogenesis of Guillain-Barré syndrome, with particular emphasis on the role of ganglioside antibodies, antecedent infections, and the concept of molecular mimicry. It concludes with an appraisal of currently available and proposed therapies.

Autoantibodies↗
PubMed2000

Sequential expression of chemokines in experimental autoimmune neuritis.

Recruitment of inflammatory cells is of critical importance in the pathogenesis of immune-mediated demyelinating diseases in the peripheral nervous system (PNS). Evidence is increasing that chemokines might play a key role in this process, since they promote leukocyte entry into the nervous system during immune-mediated inflammation. In the present study we report the expression pattern of the chemokines interferon-gamma-inducible protein (IP)-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and regulated upon activation normal T cell expressed and secreted (RANTES) in sciatic nerves from animals with myelin-induced experimental autoimmune neuritis, using a semiquantitative reverse transcriptase-PCR dot-blot hybridization assay. The mRNAs for MIP-1alpha and MIP-1beta were found to be upregulated with peak values at day 13 post-immunization (p.i.), preceding maximum disease severity. In contrast, mRNAs for MCP-1, RANTES, and IP-10 exhibited peak levels coincident with peak of the disease at day 15 p.i. Increased mRNA expression was associated with enhanced protein levels, as demonstrated by immunoblotting for each chemokine investigated. Immunohistochemistry for IP-10 protein revealed immunoreactivity associated with perineurial endothelial cells. RANTES protein was localized immunohistologically to invading T lymphocytes. Our findings suggest that chemokines, which act towards T cells and mononuclear phagocytes, are sequentially upregulated during the clinical course of EAN and thus may contribute to the pathogenesis of inflammatory demyelinating diseases of the PNS.

Animals↗
PubMed2000

The role of matrix metalloproteinases in autoimmune damage to the central and peripheral nervous system.

Members of the family of matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of inflammatory demyelination. MMPs apparently mediate important steps in the genesis of inflammatory demyelination, such as cell migration, blood-brain/nerve barrier breakdown, demyelination, and cytokine activation. This review will highlight in vitro as well as in vivo findings, which support the importance of this group of proteases in the pathogenesis of inflammatory demyelinating disorders of the central and peripheral nervous system.

Guillain-Barre Syndrome↗
PubMed2000

Toxic effector molecules in the pathogenesis of immune-mediated disorders of the central nervous system.

A growing body of evidence supports the notion that inflammatory reactions in the central nervous system (CNS) are not only restricted to established immune mediated disorders, such as multiple sclerosis, but also contribute to the pathogenesis of Alzheimer's disease and other types of neurodegenerative disorders. The biological roles of toxic mediators, such as nitric oxide, reactive oxygen species, as well as complement and proteases in the genesis of inflammatory reactions in the CNS are reviewed within the context of demyelination and neuronal damage.

Animals↗
PubMed1999

The immunopathogenesis of multiple sclerosis. A survey of recent advances and implications for future therapy.

The etiology of multiple sclerosis (MS) still remains elusive. However, the association of the disease with relevant genes, the characteristic white matter infiltrates, similarities with animal models, and the fact that MS can be treated with immunomodulatory and immunosuppressive therapies support the notion that this disorder is autoimmune in nature. During the last few years the knowledge about the mechanisms involved in the pathogenesis of MS increased rapidly. In this review, recent advances in our understanding about relevant pathomechanisms in inflammatory demyelinating diseases of the central nervous system will be discussed and the rational of some novel immunotherapies is explained in context of the current understanding of immunological principles.

Autoimmunity↗
PubMed1999

Matrix metalloproteinases in inflammatory demyelination: targets for treatment.

Matrix metalloproteinases (MMPs) degrade all protein components of the extracellular matrix. Functionally, they contribute to several different physiologic conditions, such as angiogenesis or bone remodeling, as well as pathologic conditions in humans, such as rheumatoid arthritis and tumor growth. MMPs seem to be important in the pathogenesis of inflammatory demyelinating diseases of the central and peripheral nervous system, especially in MS and in Guillain-Barré syndrome (GBS). Key mechanisms in the genesis of inflammatory demyelination, such as leukocyte recruitment, blood-brain barrier or blood-nerve barrier breakdown, myelin destruction, and release of disease-promoting cytokines, are considered to be MMP-dependent processes. In experimental autoimmune encephalomyelitis, an animal model of MS, and experimental autoimmune neuritis, an animal model of GBS, different synthetic inhibitors targeting MMP activity are able to suppress and even reverse ongoing disease. This evidence points to MMPs as new targets for treatment in inflammatory demyelination.

Animals↗
PubMed1999

[Matrix metalloproteinases. Potential targets for new treatments in inflammatory demyelinating diseases of the nervous system].

Inflammatory demyelinating diseases of the nervous system, such as multiple sclerosis or the Guillain-Barré syndrome represent severely disabling disorders, often seen by the neurologist, with still only limited means for therapeutical intervention. The underlying pathomechanisms remain in large part elusive, however mounting evidence suggests that enzymes of the family of matrix metalloproteinases are of relevance in the pathogenesis of these disorders. Experimental in vivo data as well as results from other medical fields emphasize that the selective inhibition of these proteases could be a promising therapeutical approach. The following review summarizes the role of matrix metalloproteinases in inflammatory demyelinating diseases of the central as well as peripheral nervous system and discusses the therapeutical application of synthetic inhibitors in these disorders.

Autoimmune Diseases↗
PubMed1999

Differential expression of matrix metalloproteinases in bacterial meningitis.

Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of various inflammatory diseases of the central nervous system. Evidence is accumulating that gelatinase B (MMP-9) might be involved in the pathogenesis of meningitis, but the spectrum of different MMPs involved in the inflammatory reaction of this disease has not been determined. We investigated the temporal and spatial mRNA expression pattern of gelatinase B in experimental meningococcal meningitis in rats. In contrast to controls, increased mRNA levels with peak values 6 h after injection with menigococci were found in brain specimens of the animals. Elevated MMP-9 mRNA expression was accompanied by enhanced proteolytic activity, as demonstrated by gelatin zymography, and positive immunoreactivity. The mRNA expression pattern of six other MMPs was investigated. Collagenase-3 and stromelysin-1 mRNAs were also found to be upregulated. In contrast, mRNA levels for gelatinase A, matrilysin, stromelysin-2 and stromelysin-3 remained unchanged. As evidenced by significantly increased intracranial pressure and by leakage of intravenously injected Evans blue through the blood vessel walls into the brain parenchyma, the animals injected with meningococci revealed signs of blood-brain barrier disruption. Augmented proteolytic activity of MMP-9 could also be demonstrated in CSF samples obtained from patients with bacterial meningitis, underlining the clinical relevance of our experimental findings. Our data indicate that gelatinase B, collagenase-3 and stromelysin-1 are selectively upregulated in bacterial meningitis and thus may contribute to the pathogenesis of this infectious disease of the central nervous system.

Animals↗
PubMed1999

Effector pathways in immune mediated central nervous system demyelination.

Multiple sclerosis is generally regarded to be a primarily T-cell driven disease. Recent evidence has refocused interest on antibodies. Adhesion molecules, matrix metalloproteinases, chemokines and cytokines, and nitric oxide and oxygen metabolites all participate in the amplification and effector stages of the disease.

Animals↗
PubMed1998

Matrix metalloproteinases MMP-9 and MMP-7 are expressed in experimental autoimmune neuritis and the Guillain-Barré syndrome.

Matrix metalloproteinases (MMPs) are a family of enzymes that may be implicated in the pathogenesis of inflammatory demyelinating disorders such as multiple sclerosis. The present study investigated the expression of 92-kd gelatinase (MMP-9) and five other MMPs in sciatic nerve from Lewis rats with autoimmune experimental neuritis (EAN), an experimental model of the Guillain-Barré syndrome (GBS). Quantitative polymerase chain reaction analysis revealed an up-regulation of MMP-9 mRNA with peak levels concurrent with maximal disease severity. Increased mRNA expression was associated with enhanced enzyme activity, as detected by gelatin zymography. Immunohistochemically, MMP-9 could be localized primarily around blood vessels within the epineurium and endoneurium in diseased but not normal sciatic nerve. Among all other MMPs investigated, mRNA levels of matrilysin (MMP-7) were found to be up-regulated at the peak of the disorder, remaining at high levels throughout the clinical recovery phase of the disease. To apply these findings to human disease, sural nerve biopsies from GBS patients were examined. By using immunohistochemistry, positive immunoreactivity against MMP-9 and MMP-7 was noted and corroborated by demonstrating augmented mRNA expression in comparison with noninflammatory neuropathies. Furthermore, increased MMP-9 activity was detected by zymography. These findings indicate that 92-kd gelatinase and matrilysin are selectively up-regulated during EAN and expressed in nerves of GBS patients and thus may contribute to the pathogenesis of inflammatory demyelination of the peripheral nervous system.

Animals↗
PubMed1998

Matrix metalloproteinase-9 and -7 are regulated in experimental autoimmune encephalomyelitis.

Matrix metalloproteinases (MMPs) comprise a group of proteolytic enzymes that are implicated in the pathogenesis of inflammatory diseases of the nervous system such as multiple sclerosis. However, the exact function and expression pattern of MMPs in the inflamed nervous system are not known. In the present study we investigated the expression of 92-kDa gelatinase (MMP-9) in spinal cord from animals with adoptive transfer experimental autoimmune encephalomyelitis (AT-EAE), using a semiquantitative competitive reverse transcriptase-polymerase chain reaction assay. Increased levels of MMP-9 mRNA were found with peak values at times of maximum disease severity. Increased mRNA expression was associated with enhanced proteolytic activity of this enzyme, as demonstrated by gelatin zymography. Immunohistochemistry revealed immunoreactivity along the meninges, around blood vessels and within the parenchyma, in diseased but not in normal spinal cord. Furthermore, the expression pattern of five other MMPs was investigated. Matrilysin (MMP-7) was also found to be upregulated with maximum mRNA levels at the peak of the disease. In contrast, mRNAs for collagenase-3, 72-kDa gelatinase, and stromelysin-1 and -3 were not changed. Our findings indicate that 92-kDa gelatinase and matrilysin are selectively upregulated during AT-EAE and thus may contribute to the pathogenesis of inflammatory diseases of the CNS.

Animals↗
PubMed1998

Macrophage differentiation antigens in acute and chronic autoimmune polyneuropathies.

The pathological differential diagnosis between potentially treatable autoimmune neuropathies and degenerative neuropathies is often difficult if major T-cell infiltrates are absent in sural nerve biopsies. Since it is suggested that macrophages play a central pathogenetic role in inflammatory neuropathies, we investigated the expression of macrophage differentiation antigens associated with acute (MRP14 and 27E10 antigens) and more chronic inflammation (MRP8 and 25F9 antigens) in 76 sural nerve biopsies from patients with Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, other inflammatory neuropathies, hereditary neuropathies and normal sural nerves. Macrophage differentiation antigens were immunocytochemically detected in a majority of inflammatory biopsies but rarely in non-inflammatory disease controls and normal-looking nerves. Quantification of labelled endoneurial cells revealed significantly elevated cell counts compared with controls. In individual biopsies, elevated levels of one differentiation antigen were not necessarily associated with high expression of the other antigens, pointing to functional heterogeneity of endoneurial macrophages. Endoneurial cell counts for at least one of the differentiation markers that were greater than in any of the non-inflammatory control nerves were found in two-thirds of all inflammatory biopsies, whereas T-cell counts and in particular total macrophage counts were less sensitive in picking up biopsies from patients with inflammatory neuropathies. Antibodies to macrophage differentiation antigens are additional simple and helpful diagnostic tools in differentiating autoimmune from non-inflammatory neuropathies in sural nerve biopsies.

Acute Disease↗
PubMed1997

The monocyte-macrophage system is affected in lysosomal storage diseases: an immunoelectron microscopic study.

Studying peripheral blood mononuclear cells (PBMCs) has become an important diagnostic tool in lysosomal storage diseases. Previous studies revealed that B and subclasses of T lymphocytes participate in the storage process, whereas the role of circulating monocytes was not clear. In this study, the involvement of CD14+ monocytes in lysosomal diseases was investigated. Blood samples from six patients with different lysosomal storage disorders were studied, including one with late--infantile and three with juvenile neuronal ceroid--lipofuscinoses, and two with mucopolysaccharidosis type VI. CD14+ cells were separated immunomagnetically from PBMCs and studied by light and electron microscopy. In all investigated disorders, disease-specific lysosomal storage material could be found in monocytes. The ratio of affected to non-affected cells did not differ from previously reported data on lymphocytes and their subforms in these diseases. Our data were obtained by studying a small number of different lysosomal storage disorders. Nevertheless, they suggest that lysosomal storage in the monocyte-macrophage system might also be found in other forms of lysosomal diseases.

Humans↗
PubMed1997

Leukocytes in neuronal ceroid-lipofuscinoses: function and apoptosis.

The neuronal ceroid-lipofuscinoses (NCL) are a group of progressive encephalopathies with a fatal course that are mostly of autosomal recessive inheritance. The pathophysiological mechanisms causing the diseases are not known. The characteristic histomorphological feature of the NCL is an abnormal lysosomal accumulation of lipopigments in neural and extraneural cells, including peripheral blood leukocytes. We studied the function of peripheral venous blood immunocompetent cells in ten patients with NCL and in age- and sex-matched controls to determine how, if at all, the accumulation of intracytoplasmic storage material influences the functional capacity of affected tissue. Our results did not reveal any functional impairment of affected cells, but rather suggested a higher turnover rate in NCL. Apoptosis was increased, suggesting that abnormally controlled programmed cell death might play an important role in the pathogenesis of NCL.

Adolescent↗