BIOL 520 Advanced

Immunology W2009

BIOL 520 Advanced

Immunology W2009

Lecture 2Overview Neuroimmunology

Lecture 2Overview 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)– Plexuses (extensive network of axons +/- neuron cell

bodies outside of CNS)

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

Pituitary Gland• Hypophysis• Production of

various hormones including ACTH– Derived from

proopiomelanocortin

Anterior Pituitary Gland

Cells of the Nervous System

• Neurons• Neuroglia (glial cells)

DendritesNeuron cell body

Axon

Chemical Synapses• Presynaptic terminal

– Neuron

• Synaptic cleft• Postsynaptic

membrane– Neuron– Muscle cell– Gland cell

• Stimulating or inhibitory effects

Neurotransmitters

• Acetylcholine• Monoamines

– Norepinephrine– Dopamine– Serotonine– Histamine

• Amino acids– GABA– Glycine– Glutamate

• Nitric oxide• Neuropeptides

– Endorphines – Enkephaline– Substance P

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

Neurotrophins

• Growthfactors affecting neurons• Prevent neuron apoptosis• Major neurotrophins

– NGF: nerve growth factor– NT3, 4: neurotrophin3,4– BDNF: brain-derived neurotrophic

factor

Glial Cells in the CNS

• Oligodendrocytes– Wrap axons in myelin

• Ependymal cells– Line ventricles– Produce cerebrospinal fluid

• Astrocytes• Microglia

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

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

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

Astrocyte-Microglia Interaction

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

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

Actions of the Autonomic Nerve System

Sympathetic System

Preganglionic neuron

Norepinephrine

Postganglionic neuron

Effector Organ

Nicotinic receptor

Ach

Adrenergic receptor

After Robert Lee Stewart

Preganglionic neuron

Parasympathetic System

Ach

Postganglionic neuron

Effector Organ

Nicotinic receptor

Ach

Muscarinic receptor

After Robert Lee Stewart

Classical Fields of Neuroimmunology

• Immune response to diseases of the nerve system– Infections– Autoimmune– Ischemic– Degenerative– Traumatic– Neoplastic

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

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)

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

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

Nature Reviews Immunology ISSN: 1474-1733 EISSN: 1474-1741

Cytokine HPA Axis

Mix et al. 2007

Cytokine HPA Axis

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

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

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

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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