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BIOL 520 Advanced Immunology W2009

BIOL 520 Advanced Immunology W2009. Lecture 2 Overview Neuroimmunology. Nervous System. Central nervous system (CNS) Brain Hypothalamus Pituitary gland Spinal cord Peripheral nervous system Sensory receptors Nerves Ganglia (collection of neuronal cell bodies located outside of CNS)

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BIOL 520 Advanced Immunology W2009

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  1. BIOL 520 Advanced Immunology W2009 Lecture 2 Overview Neuroimmunology

  2. Nervous System • Central nervous system (CNS) • Brain • Hypothalamus • Pituitary gland • Spinal cord • Peripheral nervous system • Sensory receptors • Nerves • Ganglia (collection of neuronal cell bodies located outside of CNS) • Plexuses (extensive network of axons +/- neuron cell bodies outside of CNS)

  3. Hypothalamus • Located in diencephalon (between brainstem and cerebrum) • Major control center for maintaining homeostasis and regulating endocrine function

  4. Pituitary Gland Anterior Pituitary Gland • Hypophysis • Production of various hormones including ACTH • Derived from proopiomelanocortin

  5. Cells of the Nervous System • Neurons • Neuroglia (glial cells) Axon Neuron cell body Dendrites

  6. Chemical Synapses • Presynaptic terminal • Neuron • Synaptic cleft • Postsynaptic membrane • Neuron • Muscle cell • Gland cell • Stimulating or inhibitory effects

  7. Acetylcholine Monoamines Norepinephrine Dopamine Serotonine Histamine Amino acids GABA Glycine Glutamate Nitric oxide Neuropeptides Endorphines Enkephaline Substance P Neurotransmitters

  8. Substance P • Derived from protachykinin • Belongs to tachykinin family • Peptides with broad activities • gut peristalsis • vascular permeability • transmission of pain • Include neurokinin A, neurokinin B • Excitatory neurotransmitter • Neurokinin receptors expressed by leukocytes

  9. Neurotrophins • Growthfactors affecting neurons • Prevent neuron apoptosis • Major neurotrophins • NGF: nerve growth factor • NT3, 4: neurotrophin3,4 • BDNF: brain-derived neurotrophic factor

  10. Glial Cells in the CNS • Oligodendrocytes • Wrap axons in myelin • Ependymal cells • Line ventricles • Produce cerebrospinal fluid • Astrocytes • Microglia

  11. Astrocytes • Star shaped • Structural frame work • Participate in blood brain barrier • Regulate what substances from the blood reach neurons • Survey neurons • Recent evidence that astrocytes also regulate synaptic communication among neurons

  12. Microglia • Part of mononuclear phagocyte system • Express typical monocyte markers like CD11b, CD45, MHC II • Unique is ability to proliferate • Differentiate upon activation • Long survival (over 6 months) • Friend of neurons • Phagocytose apoptotic neurons • Secrete neuroprotective factors • BDNF, Neurotrophin 3 • Resting microglia secrete IL10 • Foe of neurons • Secrete neurotoxic molecules • TNF and IL1, glutamate, free radical species • Can induce apoptosis • Interact with astrocytes

  13. Microglia: Receptors and Secreted Factors From Langmann 2007

  14. Astrocyte-Microglia Interaction

  15. The Peripheral Nerve System • Sensory or afferent division • Motor or efferent division • Somatic nervous system • Innervates skeletal muscles • Autonomic nerve system • Innervates smooth muscles, cardiac muscles and glands

  16. The Autonomic Nerve System • Two major systems • Sympathetic • Prepares body for physical activity • Parasympathetic • Prepares body for resting activity including digestion and urination • Enteric nervous system • Plexuses within the walls of digestive tract

  17. Actions of the Autonomic Nerve System

  18. Sympathetic System Postganglionic neuron Preganglionic neuron Ach Nicotinic receptor Adrenergic receptor Norepinephrine Effector Organ After Robert Lee Stewart

  19. Parasympathetic System Postganglionic neuron Ach Preganglionic neuron Nicotinic receptor Muscarinic receptor Ach Effector Organ After Robert Lee Stewart

  20. Classical Fields of Neuroimmunology • Immune response to diseases of the nerve system • Infections • Autoimmune • Ischemic • Degenerative • Traumatic • Neoplastic

  21. The Central Nervous System was Considered an Immunological Privileged Site • Blood brain barrier (BBB) • Proapoptotic molecules at BBB • No MHC molecules on nerve cells • No classical dendritic cells in the CNS However, • Existence of lymph drainage in the CNS • Passage of T and B cells through BBB (hypothalamus) • Microglia can process and present antigens

  22. Recent Advances in Neuroimmunology • Interactions between the immune and the nerve system • Neural influences on the immune system • Neurotransmitters: acetylcholine, norepinephrine, serotonin, etc. • Neuropeptides: Substance P, endorphin, etc • Neurotrophic growth factors: Nerve growth factor, etc • Hormonal influences on the immune system • Epinephrine, glucocorticoids • Modulation of nerve cell function by immune and inflammatory mediators • Cytokines • Reactive oxygen and nitrogen species • Similarities between nerve cells and immune cells • Synapses • K+ channels in immune cells (electroimmunology)

  23. Communication Between Nerve System and Immune System • Hard wired synapses • Neutrotransmitters and neuropeptides • Innervation of lymph nodes • Cytokine-hypothalamic-pituitary-adrenal axis • Neuroimmunoendocrine • TLR expression in neurons and endocrine cells of the HPA axis

  24. Hypothalamic-Pituitary-Adrenal Axis Cytokine IL1, IL2, IL6, IL11, IL12, TNFa, INFg Hypothalamus CRH (Corticotropin Releasing Hormone) Pituitary gland ACTH (Adrenocorticotropic hormone) Adrenal gland Glucocorticoid Immune system IL1, IL2, IL6, IL11, IL12, TNFa, INFg Cytokine

  25. Nature Reviews Immunology ISSN: 1474-1733 EISSN: 1474-1741 Cytokine HPA Axis

  26. Cytokine HPA Axis Mix et al. 2007

  27. Inflammation: Pain Pathways and the Immune System • Sensory nerves are stimulated by mast cell derived tryptase and release substance P which in turn triggers edema and inflammation

  28. Stress: Cross-Talk between CNS and Immune System • Macrophages and circulating immune cells express catecholamin receptors • IL18 secreted by neurons, microglia, ependymal cells, and gland cells of HPA

  29. Similarities Between Neural and Immunological Synapses Mix et al. 2007 Agrin: heparan sulphate proteoglycan, induces clustering of Ach receptor, stabilizes synapsis; rapsyn: ; Ephrin B: transmembrane protein; receprtor tyrosine kinase; NMDAR: N-methyl-D-aspartate receptor, glutamate receptor; PSD95: post synaptic density protein 95 required for synaptic plasticity; CD2AP: CD2 adaptor protein, adapter protein between membrane proteins and the actin cytoskeleton

  30. References Sugama S, Conti B. (2008) Interleukin-18 and stress. Brain Res Rev. 58(1):85-95. Kanczkowski W, Ziegler CG, Zacharowski K, Bornstein SR (2008) Toll-like receptors in endocrine disease and diabetes. Neuroimmunomodulation. 2008;15(1):54-60. Seeley, Stephens, and Tate (2003) Anatomy & Physiology. 6th edition,, McGrawHill Ziemssen & Kern (2007) Psychoneurology- Cross-talk betweeb the immune and nervous systems. J. Neurol. 254 [Suppl. 2]: II/8 – II/11 http://www.uniprot.org http://www.web-books.com/MoBio/Free/images/Synapse.jpg http://www.biosci.utexas.edu/images/upload/DirectoryID_1899/49_shigeocell1.jpghttp://cercor.oxfordjournals.org/content/vol13/issue8/images/medium/coverfig.gif http://www.duiattorneydirectory.com/DUI-attorney-brain.gif http://www.biology.uiowa.edu/daileylab/images/microglial-activation-sequence.gif http://neuromedia.neurobio.ucla.edu/campbell/nervous/wp_images%5C199_brain_ependyma.gif http://www.nature.com/ng/journal/v39/n8/images/ng0807-936-F1.jpg http://www.nature.com/nm/journal/v12/n8/images/nm0806-885-F1.jpg

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