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Bernd C Kieseier

Publications and source records attributed to Bernd C Kieseier.

At least 19 recordsLinked to original sources
PubMed2007

The cell-specific expression of metalloproteinase-disintegrins (ADAMs) in inflammatory myopathies.

Inflammatory cell invasion and cytokine activation are important steps in the pathogenesis of immune-mediated diseases of muscle. Metalloproteinase-disintegrins (ADAMs) are considered to play a critical role in leukocyte migration by promoting cellular adhesion, cleavage of molecules of the extracellular matrix and shedding of membrane bound cytokines. Here, we report the expression patterns of ADAM8, ADAM9, ADAM10, ADAM12, ADAM17 and ADAM19 in cultured human myoblasts and peripheral blood mononuclear cells (PBMCs) in vitro, as well as in biopsies from patients suffering from polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM) and non-inflammatory controls. We observed an in vitro downregulation of the RNAs of ADAM10, ADAM17 and ADAM19 in myoblasts after stimulation with various pro- and anti-inflammatory mediators, whereas in PBMCs an RNA upregulation of ADAM9, ADAM10, ADAM17 and ADAM19 was detectable under identical conditions. In human muscle biopsies, invading CD3+ T lymphocytes expressed ADAM17 and ADAM19, whereas macrophages co-localized to ADAM8, as detected by immunohistochemistry. Transfection of PBMCs with ADAM19 single interfering RNA and incubation with a metalloproteinase inhibitor suggest proteolytic activity of ADAM19 and involvement in the shedding of tumor necrosis factor-alpha. No differences in the cellular expression profiles between PM, DM and IBM were found, whereas the sections from non-inflammatory controls did not reveal any positive immunoreactivity for ADAMs, except for ADAM10, which is localized exclusively to muscle fibres. Our results suggest that certain ADAMs are expressed by specific cell populations during the genesis of immune-mediated diseases of human muscle.

ADAM Proteins↗
PubMed2007

Passive immunization with anti-ganglioside antibodies directly inhibits axon regeneration in an animal model.

Recent studies have proposed that neurite outgrowth is influenced by specific nerve cell surface gangliosides, which are sialic acid-containing glycosphingolipids highly enriched in the mammalian nervous system. For example, the endogenous lectin, myelin-associated glycoprotein (MAG), is reported to bind to axonal gangliosides (GD1a and GT1b) to inhibit neurite outgrowth. Clustering of gangliosides in the absence of inhibitors such as MAG is also shown to inhibit neurite outgrowth in culture. In some human autoimmune PNS and CNS disorders, autoantibodies against GD1a or other gangliosides are implicated in pathophysiology. Because of neurobiological and clinical relevance, we asked whether anti-GD1a antibodies inhibit regeneration of injured axons in vivo. Passive transfer of anti-GD1a antibody severely inhibited axon regeneration after PNS injury in mice. In mutant mice with altered ganglioside or complement expression, inhibition by antibodies was mediated directly through GD1a and was independent of complement-induced cytolytic injury. The impaired regenerative responses and ultrastructure of injured peripheral axons mimicked the abortive regeneration typically seen after CNS injury. These data demonstrate that inhibition of axon regeneration is induced directly by engaging cell surface gangliosides in vivo and imply that circulating autoimmune antibodies can inhibit axon regeneration through neuronal gangliosides independent of endogenous regeneration inhibitors such as MAG.

Animals↗
PubMed2006

Phagocytosis of apoptotic inflammatory cells downregulates microglial chemoattractive function and migration of encephalitogenic T cells.

Apoptosis of autoaggressive T cells in the central nervous system (CNS) and subsequent phagocytosis by microglia is probably crucial in the rapid resolution of the inflammatory infiltrate in T cell mediated neuroinflammatory diseases. In addition to mere clearance, phagocytosis of apoptotic leukocytes results in the downregulation of different microglial immune functions. Chemoattractive functions of Lewis rat microglia and secretion of chemokines and matrix-metalloproteinases (MMPs) were investigated after phagocytosis of apoptotic T cells in vitro. In a modified Boyden chamber assay migration of encephalitogenic T cells toward LPS-stimulated microglial supernatants after phagocytosis of apoptotic thymocytes was reduced by 24.9% in comparison to interaction with viable target cells (P < 0.001). Phagocytosis of apoptotic cells downregulated CC-chemokine ligand (CCL)-5-secretion by LPS-stimulated microglia by 66.2% (P < 0.001), whereas there was only a trend toward decreased CCL2-secretion. As determined by gelatinase-zymography, secretion of MMP-9 by microglia was decreased after phagocytosis of apoptotic cells, whereas MMP-2 secretion was not altered. These mechanisms may reduce further recruitment of pathogenic inflammatory cells into the CNS-lesion and thus contribute to the active resolution of the inflammatory infiltrate and termination of the autoimmune attack.

Animals↗
PubMed2006

Inhibition by mitoxantrone of in vitro migration of immunocompetent cells: a possible mechanism for therapeutic efficacy in the treatment of multiple sclerosis.

BACKGROUND: Damage of the blood-brain barrier and invasion of immunocompetent cells into the central nervous system represent key events in the immunopathogenesis of multiple sclerosis. Mitoxantrone hydrochloride reduces progression of disability and clinical exacerbations in patients with multiple sclerosis. Its precise mode of action is unclear. OBJECTIVE: To investigate the effects of mitoxantrone on the migratory capacity of immunocompetent cells ex vivo and in vitro. DESIGN: Case-control study. SETTING: Department of Neurology, Heinrich Heine University, Düsseldorf, Germany. PARTICIPANTS: Peripheral blood mononuclear cells (PBMCs) were obtained from 11 patients with multiple sclerosis before and after intravenous mitoxantrone treatment; PBMCs from 5 healthy control donors were treated with mitoxantrone in vitro. MAIN OUTCOME MEASURES: The migratory capacity was studied in an in vitro Boyden chamber assay; cells and their rates of migration were analyzed by light microscopy and flow cytometry. To determine the specificity of our findings, PBMCs were treated with perfosfamide in vitro. RESULTS: Mitoxantrone decreased the migratory capacity of CD14(+) monocytes and (to a lesser degree) of CD4(+) and CD8(+) T lymphocytes. These observations were confirmed when control PBMCs were treated with an equivalent dose of mitoxantrone in vitro. Similar effects were seen when PBMCs were preincubated with perfosfamide. The inhibitory effects of mitoxantrone on the migratory capacity of PBMCs were mediated by reduced matrix metalloproteinase 9 activity, as demonstrated by zymography, polymerase chain reaction, and inhibitory studies. CONCLUSION: Mitoxantrone may inhibit the migration of inflammatory cells into and within the central nervous system.

Adult↗
PubMed2006

Interleukin 23 in acute inflammatory demyelination of the peripheral nerve.

BACKGROUND: Interleukin (IL) 23, a newly identified heterodimeric proinflammatory cytokine and a novel IL-12 family member comprising the p40 subunit of IL-12 but a different p19 subunit, has been reported to preferentially act on memory T cells and play an important role during cellular immune responses. Recent evidence suggests that IL-23 rather than IL-12 is critically involved in the pathogenesis of various immune-mediated disorders. OBJECTIVE: To determine the role of IL-23p19 during the course of acute immune-mediated demyelinating diseases of the peripheral nervous system. DESIGN: The sequential RNA expression of IL-23p19 in sciatic nerves from rats with experimental autoimmune neuritis, an animal model of the human Guillain-Barré syndrome (GBS), was analyzed by semiquantitative reverse transcriptase-polymerase chain reaction. Expression and distribution patterns of IL-23p19 protein were studied in sural nerve biopsies and cerebrospinal fluid samples from 5 patients with classical Guillain-Barré syndrome and 5 controls with noninflammatory neuropathies using immunohistochemistry and immunoblotting, respectively. RESULTS: We found IL-23p19 RNA to be up-regulated prior to the onset of first clinical symptoms with peak expression levels preceding maximum disease severity during experimental autoimmune neuritis. In patients, IL-23p19 protein was detectable in cerebrospinal fluid samples from patients with Guillain-Barré syndrome, and endoneurial macrophages were identified as the cellular source of IL-23p19 in sural nerve biopsies. CONCLUSION: Our present data indicate that IL-23 may play an important role during the early effector phase in immune-mediated demyelination of the peripheral nerve.

Animals↗
PubMed2006

Plasma exchange in neuroimmunological disorders: Part 1: Rationale and treatment of inflammatory central nervous system disorders.

Plasma exchange is a well-established therapeutic procedure commonly used in many neurological disorders of autoimmune etiology. It is thought that the beneficial effects of plasma exchange occur through the elimination of pathognomonic inflammatory mediators, including autoantibodies, complement components, and cytokines. In various neurological disorders, randomized controlled studies have demonstrated the efficacy of plasma exchange (eg, in Guillain-Barré syndrome and other forms of immune neuropathies). Although widely used, the potential benefit of plasma exchange in the treatment of multiple sclerosis, myasthenia gravis, and Lambert-Eaton syndrome is less clear.

Central Nervous System Diseases↗
PubMed2006

Plasma exchange in neuroimmunological disorders: part 2. Treatment of neuromuscular disorders.

Plasma exchange is a well-established therapeutic procedure commonly used in many neurological disorders of autoimmune etiology. In this second part of our review, we assess the role of plasma exchange in the treatment of neuromuscular disorders. In Guillain-Barré syndrome and other immune-mediated neuropathic disorders, randomized controlled trials have demonstrated the therapeutic efficacy of plasma exchange. Myasthenia gravis and Lambert-Eaton syndrome represent neuromuscular disorders where plasmapheresis might be of potential efficacy.

Autoimmune Diseases of the Nervous System↗
PubMed2006

Therapy of immune neuropathies with intravenous immunoglobulins.

Autoimmune-mediated disorders belong to the main causes of neuropathies worldwide. During recent years much progress has been achieved in the understanding of the underlying pathomechanisms, associated with implications for therapeutic approaches. Here we will briefly review the pathogenesis and discuss treatment options of the Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and neuropathies associated with paraproteinemias. In most of these disease entities intravenous immunoglobulins play a major role as effective and safe treatment options.

Guillain-Barre Syndrome↗
PubMed2006

Immune circuitry in the peripheral nervous system.

PURPOSE OF REVIEW: The aim of this review is to describe the local immune circuitry in the peripheral nervous system and its dialogue with systemic immunity under pathological conditions. Specifically, interactions of the immune system with cellular and extracellular components within peripheral nerve and immune functions of tissue-resident endoneurial macrophages and Schwann cells will be discussed. RECENT FINDINGS: New insights into the elements involved in the pathogenesis of immune-mediated disorders of the peripheral nervous system provide a better understanding of the complex interplay of these cellular and molecular components in the immunology of the peripheral nervous system. SUMMARY: The application of innovative and cutting-edge technologies to the study of immunoinflammatory disorders of the peripheral nervous system provides a better understanding of underlying principles of the organization of the immune network present in the peripheral nerve and its dialogue with the systemic immune system. This may foster the development of specific and highly effective therapies for immune-mediated disorders of the peripheral nerve.

Animals↗
PubMed2005

Expression of the immune-tolerogenic major histocompatibility molecule HLA-G in multiple sclerosis: implications for CNS immunity.

HLA-G is a non-classical major histocompatibility complex (MHC) class I antigen with highly limited tissue distribution under non-pathological conditions. Although capable of acting as a peptide-presenting molecule, its strong immune-inhibitory properties identify HLA-G as a mediator of immune tolerance with specific relevance at immune-privileged sites such as trophoblast or thymus. To assess the role of HLA-G in CNS immunity, we investigated its expression in brain specimens from patients with multiple sclerosis (n = 11), meningitis (n = 2) and Alzheimer's disease (n = 2) and non-pathological CNS controls (n = 6). Furthermore, cultured human microglial cells and CSF of patients with multiple sclerosis and controls were assessed. Furthermore, CSF from MS patients and controls, as well as cultured human microglial cells were assessed. Using several HLA-G specific mAb and immunohistochemistry, HLA-G protein was found strongly expressed in brain specimens from patients with multiple sclerosis while it was rarely detectable in the non-pathological control specimens. In multiple sclerosis brain specimens, HLA-G immunoreactivity was observed in acute plaques, in chronic active plaques, in perilesional areas as well as in normal appearing white matter. In all areas microglial cells, macrophages, and in part endothelial cells were identified as the primary cellular source of expression. HLA-G was also found in other disease entities (meningitis, Alzheimer's specimens) where expression correlated to activation and MHC class II expression on microglial cells. Importantly, ILT2, a receptor for HLA-G, was also found in multiple sclerosis brain specimens thus emphasizing the relevance of this inhibitory pathway in vivo. HLA-G mRNA and protein expression and regulation could also be corroborated on cultured human microglial cells in vitro. Further, expression of HLA-G in the CSF of multiple sclerosis patients and controls was analysed by flow cytometry and ELISA. Monocytes represented the main source of cellular HLA-G expression in the CSF. Corresponding to the observations with the tissue specimens, CSF mean levels of soluble HLA-G were significantly higher in multiple sclerosis than in non-inflammatory controls (171 +/- 31 versus 39 +/- 10 U/ml; P = 0.0001). The demonstration of HLA-G and its receptor ILT2 on CNS cells and in areas of microglia activation implicate HLA-G as a contributor to the fundamental mechanisms regulating immune reactivity in the CNS. This pathway may act as an inhibitory feedback aimed to downregulate the deleterious effects of T-cell infiltration in neuroinflammation.

Adult↗
PubMed2005

Therapeutic role of mitoxantrone in multiple sclerosis.

Mitoxantrone is approved by several health authorities for treatment of active forms of relapsing-remitting or secondary progressive multiple sclerosis (SPMS). This review provides an outline on relevant preclinical as well as clinical studies, places mitoxantrone in the context of other therapeutic approaches against multiple sclerosis (MS), and discusses relevant side effects. The current knowledge of the putative mechanisms of action of the compound is discussed.

Humans↗