Kondo T, Cortese I, Markovic-Plese S, Wandinger KP, Carter C, Brown M, Leitman S, Martin R
Nat Immunol 2001 Sep 17
National Institutes of Health, National Institute of Neurological Disorders and Stroke, NeuroImmunology Branch, Cellular Immunology Section, Bethesda, MD 20892-1400, USA
Interactions with self-Major Histocompatibility Complex molecules on Dendritic Cells (DCs) are important for the survival of mature CD4+ T-Cells.
We have followed the DC-mediated signal from the T-Cell surface to the nucleus and identified a pattern of activation that correlates with increased in vitro survival.
This response is induced exclusively by DCs and is likely associated with a modulation of the T-Cell activation threshold.
We have also found that DC-mediated activation results in Antigen-independent Cytokine Gene expression, which points to a new role for DCs in shaping the Chemokine milieu.
Such Antigen-independent activation of T-Cells may play a role in protective Immunity, but may also induce and perpetuate AutoImmune states such as Multiple Sclerosis.
Inflammation In The Nervous System: The Human Perspective
Bauer J, Rauschka H, Lassmann H
Glia 2001 Nov;36(2):235-43
Univ of Vienna, Division of NeuroImmunology, Brain Research Institute, Austria
PMID# 11596131; UI# 21479418
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.
Copyright 2001 Wiley-Liss, Inc.
Glia 2001 Nov;36(2):191-9
Max-Planck Institute of NeuroBiology, NeuroImmunology, Martinsried; European NeuroScience Institute Gottingen, Gottingen, Germany
PMID# 11596127; UI# 21479414
The Immune status of the Central Nervous System (CNS) is strictly regulated. In the healthy Brain, Immune responses are kept to a minimum.
In contrast, in a variety of Inflammatory and NeuroDegenerative Diseases, including Multiple Sclerosis, Infections, Trauma, Stroke, Neoplasia, and Alzheimer's Disease, Glial Cells such as Microglia gain Antigen-Presenting capacity through the expression of Major Histocompatibility Complex (MHC) molecules.
Further, ProInflammatory Cytokines, such as Tumor Necrosis Factor-alpha (TNF-), InterLeukin-1beta (IL-1ß), and Interferon-gamma (IFN-γ), as well as Chemokines, are synthesized by resident Brain cells and T-Lymphocytes invade the affected Brain tissue.
The proinflammatory Cytokines stimulate Microglial MHC expression in the lesioned CNS areas only. However, the induction of Brain Immunity is strongly CounterRegulated in intact CNS areas.
For instance, recent work demonstrated that Microglia are kept in a quiescent state in the intact CNS by local interactions between the Microglia Receptor CD200 and its Ligand, which is expressed on Neurons.
Work done in our laboratory showed that Neurons suppressed MHC expression in surrounding Glial Cells, in particular Microglia and Astrocytes.
This control of MHC expression by Neurons was dependent on their electrical activity.
In Brain tissue with intact Neurons, the MHC Class II inducibility of Microglia and Astrocytes by the ProInflammatory Cytokine IFN-γ was reduced.
Paralysis of Neuronal electric activity by NeuroToxins restored the induction of MHC molecules on Microglia and Astrocytes.
Loss of Neurons or their physiological activity would render the impaired CNS areas recognizable by invading T-Lymphocytes.
Thus, Immunity in the CNS is inhibited by the local MicroEnvironment, in particular by physiologically active Neurons, to prevent unwanted Immune mediated damage of Neurons.
Copyright 2001 Wiley-Liss, Inc.
Pathogenesis Of Virus-Induced Immune-Mediated DeMyelination
Kim BS, Lyman MA, Kang BS, Kang HK, Lee HG, Mohindru M, Palma JP
Immunol Res 2001;24(2):121-30
Northwestern Univ Medical School, Dept of Microbiology-Immunology, Chicago, IL 60611, USA
PMID# 11594451; UI# 21477644
Theiler's Murine EncephaloMyelitis Virus-induced DeMyelinating Disease has been extensively studied as an attractive infectious model for human Multiple Sclerosis.
Virus-specific inflammatory Th1 cell responses followed by AutoImmune responses to Myelin Antigens play a crucial role in the pathogenic processes leading to DeMyelination.
AntiBody and CytoToxic T-Cells (CTL) responses to Virus appears to be primarily protective from DeMyelinating Disease.
Although the role of Th1 and CTL responses in the induction of DeMyelinating Disease is controversial, assessment of Cytokines produced locally in the Central Nervous System (CNS) during the course of disease.
And the effects of altered inflammatory Cytokine levels strongly support the importance of Th1 responses in this Virus-induced DeMyelinating disease.
Induction of various Chemokines and Cytokines in different Glial and Antigen Presenting Cells upon Viral infection appears to be an important initiation mechanism for inflammatory Th1 responses in the CNS.
Coupled with the initial inflammatory responses, Viral persistence in the CNS may be a critical factor for sustaining inflammatory responses and consequent Immune-mediated DeMyelinating Disease.