biol 520 advanced immunology w2009 lecture 2 overview neuroimmunology lecture 2 overview...
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BIOL 520 Advanced
Immunology W2009
BIOL 520 Advanced
Immunology W2009
Lecture 2Overview Neuroimmunology
Lecture 2Overview Neuroimmunology
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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)
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Hypothalamus• Located in
diencephalon (between brainstem and cerebrum)
• Major control center for maintaining homeostasis and regulating endocrine function
Function
Description
Autonomic Helps control heart rate, urination, digestion
Endocrine Helps regulate pituitary gland
Muscle control Swallowing, shivering
Temperature regulation
Promotes heat loss by sweating and heat increase by shivering
Emotions Stress related and psychosomatic illnesses
Regulation of sleep wake cycle
Coordinates responses to sleep wake cycle with other areas of the brain
Regulation of food and water intake
Hunger and thirst center
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Pituitary Gland• Hypophysis• Production of
various hormones including ACTH– Derived from
proopiomelanocortin
Anterior Pituitary Gland
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Cells of the Nervous System
• Neurons• Neuroglia (glial cells)
DendritesNeuron cell body
Axon
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Chemical Synapses• Presynaptic terminal
– Neuron
• Synaptic cleft• Postsynaptic
membrane– Neuron– Muscle cell– Gland cell
• Stimulating or inhibitory effects
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Neurotransmitters
• Acetylcholine• Monoamines
– Norepinephrine– Dopamine– Serotonine– Histamine
• Amino acids– GABA– Glycine– Glutamate
• Nitric oxide• Neuropeptides
– Endorphines – Enkephaline– Substance P
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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
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Neurotrophins
• Growthfactors affecting neurons• Prevent neuron apoptosis• Major neurotrophins
– NGF: nerve growth factor– NT3, 4: neurotrophin3,4– BDNF: brain-derived neurotrophic
factor
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Glial Cells in the CNS
• Oligodendrocytes– Wrap axons in myelin
• Ependymal cells– Line ventricles– Produce cerebrospinal fluid
• Astrocytes• Microglia
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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
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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
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Microglia: Receptors and Secreted Factors
Molecule Class Examples FunctionScavenger receptors CD36 Uptake of apoptotic
cells
Ig ReceptorsComplement receptors
Fcg RICR3
Uptake of opsonized particles
Growth factor receptor M-CSF R, GM-CSF R Proliferation and survival
TLR TLR1-9 Pathogen and damage associated activation
Antigen presenting molecules
MHC II Presentation of phagocytosed material
Cytokines TNF, IL-6, IL10, M-CSF
Immunostimulation
NeurotransmittersNeurotoxins
GlutamateROS
Cellular toxicity
Neurotrophins BDNF, NGF Neurotrophic signalsFrom Langmann 2007
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Astrocyte-Microglia Interaction
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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
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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
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Actions of the Autonomic Nerve System
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Sympathetic System
Preganglionic neuron
Norepinephrine
Postganglionic neuron
Effector Organ
Nicotinic receptor
Ach
Adrenergic receptor
After Robert Lee Stewart
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Preganglionic neuron
Parasympathetic System
Ach
Postganglionic neuron
Effector Organ
Nicotinic receptor
Ach
Muscarinic receptor
After Robert Lee Stewart
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Classical Fields of Neuroimmunology
• Immune response to diseases of the nerve system– Infections– Autoimmune– Ischemic– Degenerative– Traumatic– Neoplastic
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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 CNSHowever,• Existence of lymph drainage in the CNS• Passage of T and B cells through BBB
(hypothalamus)• Microglia can process and present
antigens
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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)
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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
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Hypothalamic-Pituitary-Adrenal Axis
Cytokine
Hypothalamus
Pituitary gland
Adrenal gland
IL1, IL2, IL6, IL11, IL12, TNF, INF
CRH (Corticotropin Releasing Hormone)
ACTH (Adrenocorticotropic hormone)
Glucocorticoid
Immune system
Cytokine
IL1, IL2, IL6, IL11, IL12, TNF, INF
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Nature Reviews Immunology ISSN: 1474-1733 EISSN: 1474-1741
Cytokine HPA Axis
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Mix et al. 2007
Cytokine HPA Axis
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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
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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
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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
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ReferencesSugama 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,, McGrawHillZiemssen & Kern (2007) Psychoneurology- Cross-talk betweeb the immune and
nervous systems. J. Neurol. 254 [Suppl. 2]: II/8 – II/11
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