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H Lassmann

Publications and source records attributed to H Lassmann.

At least 37 records · Page 2Linked to original sources
PubMed2002

The pathology of primary progressive multiple sclerosis.

The present review will focus on the current knowledge of the pathology of primary progressive multiple sclerosis lesions. Multiple sclerosis (MS) is an inflammatory demyelinating disease with a broad clinical variability. The main disease courses are relapsing-remitting, secondary progressive and primary progressive MS. Pathological studies examining the specific underlying pathology of a defined clinical subtype are rare. Here, we focus on the pathological characteristics of the MS lesions and summarize the current findings of the pathology of primary progressive MS with respect to inflammation, oligodendrocyte myelin pathology, axon destruction and immunopathology of the lesions.

Alleles↗
PubMed2001

Enterocolitis induced by autoimmune targeting of enteric glial cells: a possible mechanism in Crohn's disease?

Early pathological manifestations of Crohn's disease (CD) include vascular disruption, T cell infiltration of nerve plexi, neuronal degeneration, and induction of T helper 1 cytokine responses. This study demonstrates that disruption of the enteric glial cell network in CD patients represents another early pathological feature that may be modeled after CD8(+) T cell-mediated autoimmune targeting of enteric glia in double transgenic mice. Mice expressing a viral neoself antigen in astrocytes and enteric glia were crossed with specific T cell receptor transgenic mice, resulting in apoptotic depletion of enteric glia to levels comparable in CD patients. Intestinal and mesenteric T cell infiltration, vasculitis, T helper 1 cytokine production, and fulminant bowel inflammation were characteristic hallmarks of disease progression. Immune-mediated damage to enteric glia therefore may participate in the initiation and/or the progression of human inflammatory bowel disease.

Adolescent↗
PubMed2001

MHC class II-regulated central nervous system autoaggression and T cell responses in peripheral lymphoid tissues are dissociated in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis.

We dissected the requirements for disease induction of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis in MHC (RT1 in rat) congenic rats with overlapping MOG peptides. Immunodominance with regard to peptide-specific T cell responses was purely MHC class II dependent, varied between different MHC haplotypes, and was linked to encephalitogenicity only in RT1.B(a)/D(a) rats. Peptides derived from the MOG sequence 91-114 were able to induce overt clinical signs of disease accompanied by demyelinated CNS lesions in the RT1.B(a)/D(a) and RT1(n) haplotypes. Notably, there was no detectable T cell response against this encephalitogenic MOG sequence in the RT1(n) haplotype in peripheral lymphoid tissue. However, CNS-infiltrating lymphoid cells displayed high IFN-gamma, TNF-alpha, and IL-4 mRNA expression suggesting a localization of peptide-specific reactivated T cells in this compartment. Despite the presence of MOG-specific T and B cell responses, no disease could be induced in resistant RT1(l) and RT1(u) haplotypes. Comparison of the number of different MOG peptides binding to MHC class II molecules from the different RT1 haplotypes suggested that susceptibility to MOG-experimental autoimmune encephalomyelitis correlated with promiscuous peptide binding to RT1.B and RT1.D molecules. This may suggest possibilities for a broader repertoire of peptide-specific T cells to participate in disease induction. We demonstrate a powerful MHC class II regulation of autoaggression in which MHC class II peptide binding and peripheral T cell immunodominance fail to predict autoantigenic peptides relevant for an autoaggressive response. Instead, target organ responses may be decisive and should be further explored.

Alleles↗
PubMed2001

Anti-inflammatory activity of nerve growth factor in experimental autoimmune encephalomyelitis: inhibition of monocyte transendothelial migration.

In order to analyze a putative immunomodulatory effect of NGF in experimental autoimmune encephalomyelitis (EAE) of the Lewis rat, we transduced myelin basic protein (MBP)-specific CD4(+) T cells with a recombinant retrovirus encoding NGF. These T(MBP)NGF cells secreted high levels of NGF, along with an unaltered Th1-like cytokine pattern. Transfer studies showed that T(MBP)NGF cells were unable to mediate clinical EAE, when transferred alone, and, more important, they efficiently suppressed induction of clinical EAE by non-transduced MBP-specific T cells (T(MBP )cells). In contrast, NGF transduced ovalbumin-specific T cells, which secreted high NGF levels, did not affect EAE induction. Suppression of clinical EAE by T(MBP)NGF cells was associated with a general reduction of inflammatory CNS infiltrates, with a most pronounced decrease of the monocyte/macrophage component. Using a culture model of the endothelial blood-brain barrier (BBB), we found that NGF directly acts on blood-derived monocytes via the p75 NGF receptor, thus interfering with monocyte migration through the activated BBB endothelium. Our data establish NGF as an anti-inflammatory mediator interfering with T cell mediated autoimmune disease in the CNS. They further point to monocyte migration through blood vascular endothelium as one possible mechanism of NGF action.

Animals↗
PubMed2001

Superantigen overcomes resistance of IL-6-deficient mice towards MOG-induced EAE by a TNFR1 controlled pathway.

Experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein peptide 35-55 (MOG) leads to a chronic form of disease characterized by demyelination, inflammation and gliosis in the central nervous system (CNS). Recently IL-6 and LT alpha were found to be required for induction of the disease. The main features associated with EAE resistance of IL-6(-/-) and LT alpha(-/-) mice were reduced T cell proliferation and endothelial activation. As shown here treatment of MOG-immunized IL-6(-/-) mice with staphylococcal enterotoxin B (SEB)reversed their resistance to MOG-induced EAE. SEB failed to restore susceptibility to EAE in LT alpha(-/-) mice. The effect of SEB to induce EAE in IL-6(-/-) mice depends on TNF receptor type 1 (TNFR1) signaling because IL-6/TNF/LT alpha(-/-) and IL-6/TNFR1(-/-) are refractory to SEB. TNFR1 is involved in SEB induced trafficking of T cells into the CNS as evidenced by the failure to up-regulate VCAM-1 on CNS endothelium and lack of accumulation of V beta 8(+) T cells in the CNS of IL-6/TNFR1(-/-) mice upon immunization with MOG and treatment with SEB. The course of SEB triggered EAE in MOG immunized IL-6(-/-) mice was characterized by reduced severity and duration of clinical manifestations, which were associated with a significant drop of CNS infiltrating neutrophils and MIP-2 expression after peak disease. Taken collectively the effect of SEB to overcome EAE resistance points to a transient IL-6 independent but TNFR1 dependent proinflamatory pathway in EAE pathogenesis and suggests a crucial function for IL-6 in disease perpetuation.

Animals↗
PubMed2001

A longitudinal MRI study of histopathologically defined hypointense multiple sclerosis lesions.

Severe tissue destruction is the presumed histopathological correlate of hypointense multiple sclerosis (MS) lesions. In this study we correlated changes of lesion hypointensity over time with initial histopathological features in 14 biopsied MS lesions. The extent of hypointensity increased in initially demyelinated plaques and decreased in remyelinating lesions. The initial axonal loss determined the increase of hypointensity over time. In conclusion, both axonal loss and demyelinating activity determine the evolution of hypointensity over time.

Adult↗
PubMed2001

Inflammation in the nervous system: the human perspective.

Many basic aspects of brain inflammation, recently disclosed in experimental models, are reflected in the pathology of human inflammatory brain diseases. Examples include the key role of T lymphocytes in immune surveillance and in the regulation of the inflammatory response, the essential contributions of adhesion molecules, proinflammatory cytokines, chemokines, and proteases in the recruitment of inflammatory cells into the nervous tissue, the modulating effect of glia cells on the inflammatory process and the termination of T-cell-mediated inflammation by apoptotic cell death. Despite this progress in our understanding of the pathogenesis of brain inflammation, there are still major unresolved questions. Because of technical constraints, most of our knowledge on central nervous system inflammation so far relates to the role of a specific T-cell subset, the so-called T-helper-1 cells. Other T-cell subsets, in particular cytotoxic class I MHC-restricted T lymphocytes, however, appear to be of major importance in human disease. Furthermore, the detailed mechanisms, which are responsible for the profound differences in the patterns of tissue damage in different human inflammatory brain diseases, such as multiple sclerosis or various forms of virus encephalitis, are largely unresolved. We discuss the open questions to be addressed in the future, which, when answered, may help to design novel therapeutic strategies.

Animals↗
PubMed2001

Congenic mapping confirms a locus on rat chromosome 10 conferring strong protection against myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis.

Myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in rats closely mimics the human disease multiple sclerosis (MS). As in MS, genetic predisposition to MOG-EAE is regulated by both MHC and non-MHC genes. Based on disease regulatory influences on MOG-EAE on chromosome 10 in an F2 cross between susceptible DA and resistant ACI rats, we have now isolated this locus in a congenic rat strain to enable further dissection of disease mechanisms. This region is of particular interest, since it is homologous to human 17q for which human whole-genome scans have indicated harbors genes regulating susceptibility to MS. Phenotypic comparison between DA and the congenic DA.ACI-D10Rat2-D10Rat29 strain confirms that the chromosomal segment harbors gene(s) conferring strong protection against MOG-EAE. Furthermore, resistance to EAE in this congenic strain is associated with absence or a low level of inflammation and demyelination in the central nervous system. Levels of anti-MOG antibody isotypes did not differ between parental and congenic rats, thus an action on Th1/Th2 differentiation is unlikely. In conclusion, this is the first example of an EAE-regulating locus isolated in a congenic rat strain with retained phenotype. The mechanism by which gene(s) in the region act is still unclear and will require further studies with this congenic rat strain as a tool.

Animals↗
PubMed2001

CCR1+/CCR5+ mononuclear phagocytes accumulate in the central nervous system of patients with multiple sclerosis.

Mononuclear phagocytes (monocytes, macrophages, and microglia) are considered central to multiple sclerosis (MS) pathogenesis. Molecular cues that mediate mononuclear phagocyte accumulation and activation in the central nervous system (CNS) of MS patients may include chemokines RANTES/CCL5 and macrophage inflammatory protein-1alpha/CCL3. We analyzed expression of CCR1 and CCR5, the monocyte receptors for these chemokines, on circulating and cerebrospinal fluid CD14+ cells, and in MS brain lesions. Approximately 70% of cerebrospinal fluid monocytes were CCR1+/CCR5+, regardless of the presence of CNS pathology, compared to less than 20% of circulating monocytes. In active MS lesions CCR1+/CCR5+ monocytes were found in perivascular cell cuffs and at the demyelinating edges of evolving lesions. Mononuclear phagocytes in early demyelinating stages comprised CCR1+/CCR5+ hematogenous monocytes and CCR1-/CCR5- resident microglial cells. In later stages, phagocytic macrophages were uniformly CCR1-/CCR5+. Cultured in vitro, adherent monocytes/macrophages up-regulated CCR5 and down-regulated CCR1 expression, compared to freshly-isolated monocytes. Taken together, these findings suggest that monocytes competent to enter the CNS compartment derive from a minority CCR1+/CCR5+ population in the circulating pool. In the presence of ligand, these cells will be retained in the CNS. During further activation in lesions, infiltrating monocytes down-regulate CCR1 but not CCR5, whereas microglia up-regulate CCR5.

Adult↗
PubMed2001

Migratory activity and functional changes of green fluorescent effector cells before and during experimental autoimmune encephalomyelitis.

Homing behavior and function of autoimmune CD4+ T cells in vivo was analyzed before and during EAE, using MBP-specific T cells retrovirally engineered to express the gene of green fluorescent protein. The cells migrate from parathymic lymph nodes to blood and to the spleen. Preceding disease onset, large numbers of effector cells invade the CNS, with only negligible numbers left in the periphery. In early EAE, most (>90%) infiltrating CD4+ cells were effector cells. Migratory effector cells downregulate activation markers (CD25, OX-40) but upregulate several chemokine receptors and adsorb MHC class II on their membranes. Within the CNS, the effector cells are reactivated, with upregulated proinflammatory cytokines and downmodulated T cell receptor-associated structures, presumably reflecting autoantigen recognition in situ.

Animals↗
PubMed2001

Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy.

Multiple sclerosis is a chronic inflammatory disease of the nervous system in which a T-cell-mediated inflammatory process is associated with destruction of myelin sheaths. Although demyelination is the primary event, axons are also destroyed in the lesions, and the loss of axons correlates with permanent functional deficit. Here, we discuss evidence that demyelination and axonal destruction follow different pathogenetic pathways in subgroups of patients. This might, at least in part, explain the heterogeneity in genetic susceptibility, clinical presentation and response to treatment observed between individuals.

Genetic Heterogeneity↗
PubMed2001

Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis.

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are immune-mediated diseases of the CNS. They are characterized by widespread inflammation, demyelination and a variable degree of axonal loss. Recent magnetic resonance spectroscopy studies have indicated that axonal damage and loss are a reliable correlate of permanent clinical disability. Accordingly, neuropathological studies have confirmed the presence and timing of axonal injury in multiple sclerosis lesions. The mechanisms of axonal degeneration, however, are unclear. Since calcium influx may mediate axonal damage, we have studied the distribution of the pore-forming subunit of neuronal (N)-type voltage-gated calcium channels in the lesions of multiple sclerosis and EAE. We found that alpha(1B), the pore-forming subunit of N-type calcium channels, was accumulated within axons and axonal spheroids of actively demyelinating lesions. The axonal staining pattern of alpha(1B) was comparable with that of beta-amyloid precursor protein, which is an early and sensitive marker for disturbance of axonal transport. Importantly, within these injured axons, alpha(1B) was not only accumulated, but also integrated in the axoplasmic membrane, as shown by immune electron microscopy on the EAE material. This ectopic distribution of calcium channels in the axonal membrane may result in increased calcium influx, contributing to axonal degeneration, possibly via the activation of neutral proteases. Our data suggest that calcium influx through voltage-dependent calcium channels is one possible candidate mechanism for axonal degeneration in inflammatory demyelinating disorders.

Adult↗
PubMed2001

Classification of demyelinating diseases at the interface between etiology and pathogenesis.

The classical demyelinating diseases include the 'autoimmune' inflammatory demyelinating diseases, the inflammatory demyelinating diseases of infectious aetiology, and the demyelinating or dysmyelinating diseases of genetic/hereditary background. In addition, primary demyelination is present in other conditions, such as brain ischaemia and intoxication. Irrespective of the primary aetiology, selective demyelination can be mediated through various pathogenetic pathways: the immune-mediated inflammatory pathway; the metabolic pathway; and the ischaemic/excitotoxic pathway. These pathways are only partly segregated with distinct aetiologies of demyelinating diseases, but they also reflect the way in which the patient copes with the disease-inciting event in relation to their particular genetic background. For future therapeutic strategies it will be important to interfere with the specific pathogenetic pathways of demyelination, which may be common to various demyelinating diseases, but may differ in subgroups of patients who suffer from a particular clinical demyelinating disease entity.

Animals↗
PubMed2001

Expression of cell death-associated proteins in neuronal apoptosis associated with pontosubicular neuron necrosis.

Expression of apoptosis-associated proteins p53, bcl-2, bax, and caspase-3/CPP32, activation of caspase-3, and modification of proteins via poly(ADP-ribosyl)ation was studied in pontosubicular neuron necrosis (PSN), a form of perinatal brain damage revealing the morphological hallmarks of neuronal apoptosis. Immunoreactivity for p53 was completely absent. The majority of cells stained with the bax and procaspase-3 antibodies did not show morphological signs of apoptosis. In contrast, an antibody against activated caspase-3 almost exclusively stained cells with apoptotic morphology. Poly(ADP-ribosyl)ated proteins were only rarely detected in cells with apoptotic morphology. The expression patterns of bax, procaspase-3, bcl-2, and p53 in PSN were similar to that found in age-matched control brains. However, activated caspase-3 and poly-ADP-ribosylated proteins were exclusively found in apoptotic cells. These data indicate that detection of active caspase-3 is a reliable marker for apoptosis in formalin-fixed human tissue, and that neuronal apoptosis in pontosubicular neuron necrosis is accompanied by a pronounced activation of caspase-3.

Apoptosis↗
PubMed2001

Expression of death-related proteins in dentate granule cells in human bacterial meningitis.

Neuronal apoptosis in the dentate gyrus has been observed in animal models of bacterial meningitis and in humans dying in the course of the disease. To evaluate the mechanisms of neuronal cell death, hippocampal sections of 20 patients dying from bacterial meningitis were investigated by immunohistochemistry using antibodies against the proform of caspase-3 and the active enzyme, bcl-2, bax and p53. In the dentate granule cell layer, the median density of neurons with an apoptotic morphology was 7.6/mm2 (0-15.6/mm2). The median density of immunoreactive neurons was 2.3/mm2 (procaspase-3), 0.9/mm2 (activated caspase-3), 1.8/mm2 (bcl-2), 1.1/mm2 (bax) and 0.4/mm2 (p53). 80% of neurons immunoreactive for active caspase-3 had an apoptotic morphology, whereas only 10% of all procaspase-3 stained neurons showed signs of apoptosis. Apoptotic cell death is present in humans dying in the course of bacterial meningitis in the dentate gyrus of the Formatio hippocampi. Neuronal expression of caspase-3, bcl-2 and bax suggests an involvement of these proteins in neuronal death.

Adolescent↗
PubMed2001

Disease progression in chronic relapsing experimental allergic encephalomyelitis is associated with reduced inflammation-driven production of corticosterone.

In this study, we demonstrate that disruption of neuroendocrine signaling is a major factor driving disease progression in myelin oligodendrocyte glycoprotein-induced chronic relapsing experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Although the initial episode of chronic relapsing experimental autoimmune encephalomyelitis is associated with a robust hypothalamic-pituitary-adrenocortical axis response, we show that subsequent disease progression is associated with a selective desensitization of hypothalamic-pituitary-adrenocortical responsiveness to inflammatory mediators. Inflammatory activity in the central nervous system during relapse is therefore unable to produce an endogenous immunosuppressive corticosterone response, and disease progresses into an ultimately lethal phase. However, disease progression is inhibited if the circulating corticosterone level is maintained at levels seen during the initial phase of disease. The effect of hypothalamic-pituitary-adrenocortical axis desensitization on the clinical course of experimental autoimmune encephalomyelitis is aggravated by a marked reduction in proinflammatory cytokine synthesis in the central nervous system in the later stages of disease, reflecting an increasing involvement of antibody, rather than T cell-dependent effector mechanisms, in disease pathogenesis, with time. Thus, our data indicate that distinct immune-endocrine effects play a decisive role in determining disease progression in multiple sclerosis, a concept supported by reports that a subpopulation of multiple sclerosis patients shows evidence of hypothalamic-pituitary-adrenocortical axis desensitization.

Animals↗
PubMed2000

MAP1B is required for axon guidance and Is involved in the development of the central and peripheral nervous system.

Microtubule-associated proteins such as MAP1B have long been suspected to play an important role in neuronal differentiation, but proof has been lacking. Previous MAP1B gene targeting studies yielded contradictory and inconclusive results and did not reveal MAP1B function. In contrast to two earlier efforts, we now describe generation of a complete MAP1B null allele. Mice heterozygous for this MAP1B deletion were not affected. Homozygous mutants were viable but displayed a striking developmental defect in the brain, the selective absence of the corpus callosum, and the concomitant formation of myelinated fiber bundles consisting of misguided cortical axons. In addition, peripheral nerves of MAP1B-deficient mice had a reduced number of large myelinated axons. The myelin sheaths of the remaining axons were of reduced thickness, resulting in a decrease of nerve conduction velocity in the adult sciatic nerve. On the other hand, the anticipated involvement of MAP1B in retinal development and gamma-aminobutyric acid C receptor clustering was not substantiated. Our results demonstrate an essential role of MAP1B in development and function of the nervous system and resolve a previous controversy over its importance.

Animals↗