Immune response in central nervous system
Immune Response in the Central Nervous System
In addition to the protection conferred by bone, meninges, and CSF, the Central Nervous System, comprised of the brain and spinal cord, is protected by the blood-brain barrier (BBB). The blood brain barrier provides neurons with a relatively constant metabolic environment, protection against toxins and infectious agents, and other humoral agents such as antibodies and large proteins. The BBB is not perfectly impermeable, however, and does allow communication through circumventricular organs such as the pituitary gland, pineal gland, and area postrema. These areas present potential paths for the spreading of infection into brain tissue and triggering of inflammation and immune response-like processes mediated principally by microglia, the resident macrophages of the CNS. Microglias, the key immune mediators of the brain, are in charge of the phagocytosis of cellular debris and secretion of neurotrophic factors and cytokines upon damage or infection.
Although the brain is considered an immune privileged site, extensive research has demonstrated that bi-directional communication takes place between the nervous and the immune system in both healthy and diseased individuals. Immune cells cross the BBB by means of diapedesis. The binding and internalization phases of this process are initiated by interactions between glycoproteins on the endothelial surface with glycoproteins on the immune cell surface. Activation of the immune system results in the elaboration of cytokines and inflammatory mediators that induce hypothalamic CRF, which stimulates the release of the same immunosuppressive molecules that mediate the response to stress
The immune system and the central nervous system interact with each other by way of cell signaling. Cytokines, growth factors and chemokines produced by macrophages and lymphocytes can modulate brain functions. Pro-inflammatory cytokines, such as interleukin-1, interleukin-6, interferons, and tumor necrosis factor alpha induce weakness, malaise, listlessness, inability to concentrate, feelings of depression, lethargy, anhedonia and loss of appetite (sickness behavior). Studies in animals and humans have shown that infusion of systemic or central cytokines induces sickness behavior symptoms. Cytokines and chemokines are capable of regulating neurotrophins and other molecules critical to neurodevelopmental and other neural processes (i.e. synaptic plasticity). TNF-alpha plays a facilitatory role in glutamate excitotoxicity by inhibiting glial glutamate transporters on astrocytes, increasing expression of AMPA receptors on synapses and can inhibit long-term potentiation. IFN-γ is capable of inhibiting remyelination in demyelinated lesions of the CNS. Elevated levels of IL-6 in the CNS primes developing neurons to NMDA neurotoxicity by affecting intracellular Ca2+ homeostasis. Lymphocytes can synthesize neurotransmitters like substance P, norepinephrine
Central Nervous System can modulate immune response directly the release of neurotransmitters and other molecules. Reported evidence shows that lesions of the left cortex produced pronounced immune deficits in spleen cell number, lymphocyte proliferation, and natural killer cell activity. Lymphocytes express neurotransmitter receptors on their cell surface. Somatostatin, neuropeptide Y, dopamine and substance P can directly induce cytokine secretion of T CD4+ cells in vitro. Neuropeptides can activate immune cells (for example, Substance P signaling via NK1R enhances NK cell response against Herpes Simplex Virus type2). Substance P has the ability to inhibit T cell adhesion by closing T cell voltage-gated K+ channels
Clinical Application 1: Clinical Application 1: Multiple Schlerosis
Multiple Sclerosis is an inflammatory and debilitating autoimmune disease. It is named such because it produces sclerotic lesions in the central nervous system. In Multiple Sclerosis T- cell’s of the thymus and their effector population attack “ self “ nerve cells causing their de-myelination. The cause is unknown but there have been some discussions that it can be due to exposure to virus or in some instances lack of vitamin D, there has also been some evidence of its hereditary component. Some of the symptoms include shaky movement, difficulty walking and involuntary contraction of muscles. Many patients have diminished eyesight and double vision. Needless to say, they also suffer from depression, inability to control mood and inappropriate elation or giddiness. There is no cure currently for Multiple Sclerosis and some of the treatment involves the use of corticosteroids, interferon and most recently stem cell placement, in order to reduce the body’s immune response to self nerves.
Clinical Application 2: Acute Demyelinating Encephalomyelinitis
Acute Demyelinating Encephalomyelitis is an immune mediated disease of the brain. This disease usually occurs in children following viral infection, sometimes after bacterial infection or vaccination. This disease is similar to Multiple Schlerosis because it involves autoimmune demyelination of neurons in the central nervous system. ADEM produces lesions in the brain stem and spinal cord. The transformation of the viral infection to onset of ADEM requires participation of other genetic or immuno-experiential factor. These factor are genetically or experientially determined aspects of immunoregulation, particularly T-helper cell function. Symptoms of ADEM include: Alterations in personality, abnormal consciousness, ataxia, cranial nerve palsies, hallucinations, headache, nystagmus, Seizures and visual field defects. In the earliest stages of inflammation, ADEM are mediated by stimulated clones of T-helper cells sensitized to autoantigens such as myelin proteins. This immune response involves action of cytokines, chemokine, lymphokine-induced chemotaxis of other cellular mediators of inflammation (eg, other T cell lines, B cells, microglia, phagocytes). The pattern of cytokine elevation suggests that ADEM involves activation of macrophages, microglial cells, and various Th (T helper)–1 and Th2 cells 8.
Clinical Application 3: Lupus
Systemic Lupus Erythomatous is a multisystem rheumatic disorder that produces autoantibodies against almost every organ and tissue in the body. The cause of SLE is unknown but a defect in the regulation of the immune system has been considered important in its pathogenesis. The antibodies formed in SLE target host antigens and form immune complexes that deposit in the microvasculature of various target organs. The immune complexes initiate inflammation and complement activation which results in cell-mediated tissue injury. The antibodies against nuclear antigens (ANA’s) are the main antibody found in all SLE patients and the presence of antibodies to double stranded DNA (dsDNA) is used to diagnose it. SLE symptoms are varied and differ from one patient to another but the most common include: Red rashes (butterfly or malar rash), Arthritis, Purple fingers and toes (Raynaud’s Syndrome), Difficulty breathing, Edema in legs and around eyes, Anemia, Depression, Seizures. The involvement of the Central Nervous System is considered the most serious form of Systemic Lupus Erythematous and has been attributed to the damage that SLE related Vasculitis causes in the blood vessels that supply the CNS. Clinical findings have shown ischemias caused by narrowing and occlusion of these vessels as a result of vasculitis. The interrupted blood flow to the CNS damages the tissue and nerve cells and results in symptoms such as fevers, seizures and psychosis with rapid progression to stupor and coma if the condition is not treated properly.
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