Astrocytes as potential targets to suppress inflammatory demyelinating lesions in multiple sclerosis. 2010

Jacques De Keyser, and Guy Laureys, and Frauke Demol, and Nadine Wilczak, and Jop Mostert, and Ralph Clinckers
Department of Neurology, University Hospital Brussel, Vrije Universiteit Brussel, Brussels, Belgium. Jacques.DeKeyser@uzbrussel.be

A hallmark of multiple sclerosis (MS) is the occurrence of focal inflammatory demyelinating lesions in the central nervous system. The prevailing view that activated anti-myelin T cells inherently mediate these lesions has been challenged after observations that these T cells, which are part of the normal immune repertoire, can also intermittently become activated in healthy people and subjects with other diseases. Astrocytes in the white matter of subjects with MS are deficient in beta(2) adrenergic receptors. Stimulation of beta(2) adrenergic receptors increases cAMP, leading to activation of protein kinase A (PKA). beta(2) adrenergic receptor deficiency will reduce the suppressive action of PKA on coactivator class II transactivator (CIITA), which is a key regulator of interferon gamma-induced major histocompatibility (MHC) class II molecule transcription. The expression of MHC class II may deviate astrocytes to function as facultative antigen presenting cells, which can then initiate the inflammatory cascade. In a proof of concept study in MS subjects it was shown that fluoxetine, which activates PKA in astrocytes, reduced the development of focal inflammatory lesions. If confirmed and extended by additional studies, suppressing the antigen presenting capacity of astrocytes could be a novel therapeutic option for the treatment of MS.

UI MeSH Term Description Entries
D007108 Immune Tolerance The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc. Immunosuppression (Physiology),Immunosuppressions (Physiology),Tolerance, Immune
D007249 Inflammation A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. Innate Inflammatory Response,Inflammations,Inflammatory Response, Innate,Innate Inflammatory Responses
D009103 Multiple Sclerosis An autoimmune disorder mainly affecting young adults and characterized by destruction of myelin in the central nervous system. Pathologic findings include multiple sharply demarcated areas of demyelination throughout the white matter of the central nervous system. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia, and bladder dysfunction. The usual pattern is one of recurrent attacks followed by partial recovery (see MULTIPLE SCLEROSIS, RELAPSING-REMITTING), but acute fulminating and chronic progressive forms (see MULTIPLE SCLEROSIS, CHRONIC PROGRESSIVE) also occur. (Adams et al., Principles of Neurology, 6th ed, p903) MS (Multiple Sclerosis),Multiple Sclerosis, Acute Fulminating,Sclerosis, Disseminated,Disseminated Sclerosis,Sclerosis, Multiple
D003711 Demyelinating Diseases Diseases characterized by loss or dysfunction of myelin in the central or peripheral nervous system. Clinically Isolated CNS Demyelinating Syndrome,Clinically Isolated Syndrome, CNS Demyelinating,Demyelinating Disorders,Demyelination,Demyelinating Disease,Demyelinating Disorder,Demyelinations
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001253 Astrocytes A class of large neuroglial (macroglial) cells in the central nervous system - the largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the BLOOD-BRAIN BARRIER. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with MICROGLIA) respond to injury. Astroglia,Astroglia Cells,Astroglial Cells,Astrocyte,Astroglia Cell,Astroglial Cell,Astroglias,Cell, Astroglia,Cell, Astroglial
D018340 Receptors, Adrenergic, alpha-1 A subclass of alpha-adrenergic receptors that mediate contraction of SMOOTH MUSCLE in a variety of tissues such as ARTERIOLES; VEINS; and the UTERUS. They are usually found on postsynaptic membranes and signal through GQ-G11 G-PROTEINS. Adrenergic alpha-1 Receptors,Receptors, alpha-1 Adrenergic,alpha-1 Adrenergic Receptors,Adrenergic Receptor, alpha-1,Adrenergic alpha-1A Receptors,Adrenergic alpha-1B Receptors,Adrenergic alpha-1D Receptors,Receptor, Adrenergic, alpha-1,Receptor, Adrenergic, alpha-1A,Receptor, Adrenergic, alpha-1B,Receptor, Adrenergic, alpha-1D,Receptors, Adrenergic, alpha-1A,Receptors, Adrenergic, alpha-1B,Receptors, Adrenergic, alpha-1D,alpha 1 Adrenergic Receptor,alpha-1A Adrenergic Receptor,alpha-1B Adrenergic Receptor,alpha-1C Adrenergic Receptor,alpha-1D Adrenergic Receptor,Adrenergic Receptor, alpha 1,Adrenergic Receptor, alpha-1A,Adrenergic Receptor, alpha-1B,Adrenergic Receptor, alpha-1C,Adrenergic Receptor, alpha-1D,Adrenergic Receptors, alpha-1,Adrenergic alpha 1 Receptors,Adrenergic alpha 1A Receptors,Adrenergic alpha 1B Receptors,Adrenergic alpha 1D Receptors,Receptor, alpha-1 Adrenergic,Receptor, alpha-1A Adrenergic,Receptor, alpha-1B Adrenergic,Receptor, alpha-1C Adrenergic,Receptor, alpha-1D Adrenergic,Receptors, Adrenergic alpha-1,Receptors, Adrenergic alpha-1A,Receptors, Adrenergic alpha-1B,Receptors, Adrenergic alpha-1D,Receptors, alpha 1 Adrenergic,alpha 1 Adrenergic Receptors,alpha 1A Adrenergic Receptor,alpha 1B Adrenergic Receptor,alpha 1C Adrenergic Receptor,alpha 1D Adrenergic Receptor,alpha-1 Adrenergic Receptor,alpha-1 Receptors, Adrenergic,alpha-1A Receptors, Adrenergic,alpha-1B Receptors, Adrenergic,alpha-1D Receptors, Adrenergic

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