Download immune system

Homeostasis 3
Árpád Dobolyi
Laboratory of Molecular and Systems Neurobiology,
Department of Physiology and Neurobiology, Eötvös
Loránd University
Outline of the lecture
1. Internal environment of living organisms
2. Homeostatic regulations – the endocrine system
3. Examples of homeostatic regulations not
requiring the nervous system
4. Homeostatic regulations – nervous system
5. Examples of regulations involving the brain
– Water balance
– Body temperature regulation
6. Homeostatic regulations – immune system
7. The role of the nervous system in immune
regulations
Heat produced by basal metabolism
Energy produced by basal metablism leaves the body in the form of
heat. It depends on the size of the animals:
- Heat produced by bigger animals is larger
- Heat produced per body weight decreases with the size of the
animal
Rubner’s surface area law: heat produced by the basal metabolism
of animals is proportional with their surface area rather than their
body weight.
More precisely: Heat produced by basal metabolism is proportional
to W0.75 , where W is the body weight. Thus, heat production is 290
KJ/W0.75, and does not depend on the individual or the species.
Factors determining heat balance of animals
Animals with
constant body
temperature thrive for
heat balance:
Heat loss =
heat taken from the
environment + heat
produced by the body
Red color:
controlability
Body temperature control 1.
1. In response to small alterations from set point body temperature,
animals first change the circulation of the skin:
• If ambient temperature decreases, skin arterioles contract thereby
decreasing heat dissipation
• If ambient temperature increases, skin arterioles dilatate thereby
increasing heat dissipation
Body temperature control 2.
In response to larger alterations from set point body
temperature:
A. In cold environment
• Heat production by the brown adipose tissue is activated
• Muscle contraction can further increase heat production
(shivering)
• Activation of thyroid hormone production increases metabolism
by enhancing cellular oxidation
• Appropriate behavioral changes
B. In warm environment
• Enhanced ventillation of the lung
• Sweating starts, water evaporates from the skin
• Appropriate behavioral changes
Mechanism of heat production in brown adipose tissue
If the inner membrane of mitochondrium leaks H-ions then heat is produced instead of ATP
Body temperature control 3.
If previous measures were insufficient and body
temperature alteration is life-threatening:
A. In cold environment
• Due to the activation of stress axis, cellular metabolism is
further increased
B. In hot environment
• Heart frequency and blood circulation increases
Body temperature control 4.
Slower adaptations to changes of long-time
alterations of ambient temperature:
1. Alterations of thermal insulation:
- adiposity depos build up
- Changes of outer integument
(e.g. seasonal changes of hair, feather)
2. Appropriate behavioral changes
Temperature receptors: transients receptor potential (TRP) channels
Etain A. Tansey, and Christopher D. Johnson Advan in Physiol Edu 2015;39:139-148.
Temperature receptors (TRP channels) are located
on free (or bare) nerve terminals in the skin
Thin myelinated (Aδ) or
unmyelinated axons (C)
A
Termination of heatsensitive primary
afferents in the
spinal cord
A termosensitive (cold) fibers
termination:
lamina I
lamina IIa
lamina V
C termosensitive (warm) fibers
termination :
lamina IIb
A
A
C
Neuronal pathways carrying temperature
information
Pathways of heat sensation and heat
localization (only ascending)
- spinothalamic tract
- trigeminothalamic tract
Thermoregulatory pathways
- ascending and descending
Pathways of thermal stress (only descending)
The ventral
posterolateral
nucleus of the
thalamus (VPL)
relays sensory
inputs from the
body to the
cerebral cortex
Thermoregulatory
pathways
DH: dorsal horn of spinal cord
LPB: lateral parabrachial nucleus
POA: preoptikus terület
MnPO: median preoptic nucleus
MPA: medial preoptic area
CVC: cutaneous vasoconstrictor
W-S: warm-sensitive
DMH: dorsomedial hypothalamic nucleus
rRPA: rostral raphe pallidus
VH: ventral horn of spinal cord
IML: intermediolateral cell column
BAT: brown adipose tissue
Lateral parabrachial nucleus (LPBN)
scp: superior cerebellar peduncle = brachium superior
Heat-sensitive neurons in the preoptic region of
the hypothalamus
•: Cells reacting to central and peripheral change of temperature
Summation of peripheral and central input on heatsensitive neurons of the medial preoptic area
a, b: activation of peripheral warm-sensitive receptors
c-d: activation of central warm-sensitive receptors
e: activation of central cold-sensitive receptors
Thermoregulatory
patyways
DH: dorsal horn of spinal cord
LPB: lateral parabrachial nucleus
POA: preoptikus terület
MnPO: median preoptic nucleus
MPA: medial preoptic area
CVC: cutaneous vasoconstrictor
W-S: warm-sensitive
DMH: dorsomedial hypothalamic nucleus
rRPA: rostral raphe pallidus
VH: ventral horn of spinal cord
IML: intermediolateral cell column
BAT: brown adipose tissue
Location of the dorsomedial nucleus in the
hypothalamus and the raphe pallidus in the medulla
Body temperature control 2.
In response to larger alterations from set point body
temperature:
A. In cold environment
• Heat production by the brown adipose tissue is activated
• Muscle contraction can further increase heat production
(shivering)
• Activation of thyroid hormone production increases metabolism
by enhancing cellular oxidation
• Appropriate behavioral changes
B. In warm environment – neuronal pathways are not known
• Enhanced ventillation of the lung
• Sweating starts, water evaporates from the skin
• Appropriate behavioral changes
Neuroendocrine and
descending
thermoregulatoy
pathways controlling
the secretion of
thyroid hormones
Body temperature control 3.
If previous measures were insufficient and body
temperature alteration is life-threatening:
A. In cold environment
• Due to the activation of stress axis, cellular metabolism is
further increased
B. In hot environment
• Heart frequency and blood circulation increases
Pathways of heat
stress
When the set point of body temperature
regulation in increased: fever
• The effects of fever:
– Proliferation of bacteria and viruses
decreases
– T–cell proliferation increases
– Lymphocyte transformation is enhanced
– Gamma-interferon production is elevated
Pyrogenes
• Any substance that leads to fever
• Endogenous pyrogenes:
- Some cytokines produced by macrophages:
Interleukin 1 (α és β), interleukin 6 (IL-6) and tumor
necrosis factor-alpha (TNFα)
• Exogenous pyrogenes:
- Any inflammatory reaction that activates
macrophages. Bacterial lipopolysaccharide (LPS) is
particularly effective in inducing fever
Mechanism of action: Pyrogenes result in the production of
prostaglandin E2-t (PGE2). PGE2 acts on the hypothalamus
to increase the set point. Consequently, the body produces
heat and decreases its dissipation.
pirogene
citokynes
Humoral and neuronal
hypothesis of fever
IL-1
TNF-
IL-6
Endothel /
microglia
PGE2
Prosztaglandin E receptor 3
in preoptic neuros
C5a
Thermogenesis 
Het loss
(vasokonstriction
a bőrben)
Dorsomedial
hypothalamus
(DMH)
Synthesis of Prostaglandin E2 (PGE2)
• From arachidonic acid
• Using the following enzymes:
– phospholipase A2 (PLA2),
– cyclooxygenase-2 (COX-2),
– prostaglandin E2 synthase
• Pyrogenes stimulate the
enzymes thereby inducing
PGE2 synthesis
Anti-fever drugs inhibit these
enzymes
Location of the
action of PGE2
within the
thermoregulatory
pathway
Tr. spinothalamicus
Outline of the lecture
1. Internal environment of living organisms
2. Homeostatic regulations – the endocrine system
3. Examples of homeostatic regulations not
requiring the nervous system
4. Homeostatic regulations – nervous system
5. Examples of regulations involving the brain
– Water balance
– Body temperature regulation
6. Homeostatic regulations – immune system
7. The role of the nervous system in immune
regulations
Immune system
Function
– Defense against tissue damage:
•
•
•
•
Bacterial or viral infection, other pathogens
Ischemic, traumatic damage
Bleeding
Tumor cells
Components
– Barriers: skin, mucose, lung, blood-brain barrier
– Innate (or natural) immune system
– Adaptive immune system
Comparison of innate and adaptive
immune systems
Innate immune system:
inflammatory processes
Adaptive immune system:
Not antigen-specific
Antigen-specific
Does not have a threshold
Does have a threshold
Works immediately
Works with a latency
Has no memory
Does have a memory
Linearly amplified
Exponentially amplified
AFR
33
Inflammatory processes can be divided
into 2 steps
Step 1: inflammation
Step 2: acute phase
reaction (APR)
Immediate
Starts with a latency
Local
Systemal
Without threshold
Above threshold
Goal: separation and
elimination of damages
tissue, regeneration
Goal: maintain inflammation
but also prevent its
spreading
Initiation (0-6 hours)
Bleeding
Bacteria
Necrosis
Thrombocyte
activation
Complement
activation
Phagocyte
activation
C5a C3a
ROI
TNF-, IL-1
lipids
IL-1
Virus-infected
cell
IL: interleukin; ROI: reaktíve oxygen intermedier, TNF: tumor nekrosis factor
Machanisms how bacteria can activate phagocytes
Receptors on the surface of phagocytes::
1. Pattern recognition receptors
E.g. Lipopolysaccharid (LPS; a bacterial
endotoxin) receptor: CD14(+TLR4)
2. Receptors of the complement system
3. IgG receptors
Phagocytes are resident macrophages
and arriving granulocytes.
Their response to activation:
1. Phagocyte bacteria
2. Production of cytokines
Cytokines produced by macrophages and their functions
©Fülöp AK 2010
37
Mast cell activation
results in:
1. degranulation
2. lipid mediators
3. cytokine production
Consequences:
-
Vasodilatation
Increase of tissue
permeability
Pain
Activation of
additional cells
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©Fülöp AK 2010
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38
Vasodilatory effect of histamine
Leukocyte infiltration to the site of inflammation
Resting
State
Inflammatory
Stimulus
Leukocyte
Vessel Lumen
Activated
Integrin
Inactive
Integrin
Selectin
Counter-receptor
Rolling
Adhesion
Firm
Adhesion
Selectin
Selectin
Expression
Endothelial Cell
Subendothelial Matrix
VCAM
Transendothelial
Migration
Cytokine receptors
Signal transduction of IL-1
Progression (6-12 hours)
Inflammation
Acute phase reaction (APR)
Early mediators
Targets:
Phagocytes,
endothel,
fibroblast,
mast cell,
keratinocyte,
TH2
Systemic
cytokines:
TNF,
IL-1,
IL-6
INFg
Adaptive response
Liver
Production of
proteins
Bone
marrow
Leukocytosis
Adipose
tissue
Lipid
mobilisation
CNS
Antiinflammation
Outline of the lecture
1. Internal environment of living organisms
2. Homeostatic regulations – the endocrine system
3. Examples of homeostatic regulations not
requiring the nervous system
4. Homeostatic regulations – nervous system
5. Examples of regulations involving the brain
– Water balance
– Body temperature regulation
6. Homeostatic regulations – immune system
7. The role of the nervous system in immune
regulations
Acute phase reaction of the central
nervous system
Systemic cytokines activate the hypothalamus
– Systemic inhibition of the
immune system
• HPA axis
• Vegetative nervous system
– Fever
– Behavioral effects:
• No appetite
• Drowsiness
• Lack of exploratory and
sexual behaviors
Relationship of the immune system with the
HPA (Hypothalamic-Pituitary-Adrenal) axis
Cytokine
IL1, IL6, TNF, INFg
Hypothalamus
CRH (Corticotropin Releasing
Hormone)
Pituitary gland
ACTH (Adrenocorticotropic
Hormone)
Adrenal gland
Glucocorticoid
Immune system
Paraventricular nucleus in the anterior hypothalamic region
Paraventricular hypothalamic nucleus
Corticotropin-releasing hormon (CRH)-expressing
neurons in the PVN
Initiation of CNS acute phase reaction: activation of
PVN neurons by IL-1 as compared to other stressors
Paraventricular nucleus (PVN) – c-Fos immunolabeling
Anti-inflammatory actions of corticosteroids
Activity
Effect
IL-1, TNF, GM-CSF,
IL-3, IL-4. IL-5, IL-8
Inflammation
(mediated
by cytokines)
NOS
NO
Foszfolipase A2
Ciklooxygenase2
Prostaglandins,
leukotriens
Adhesion molecules
Reduced migration
Induction of
endonucleases
Apoptosis
(limfocytes, leukocytes)
The effect of glucocorticoids on the
number of leukocytes
10,000-
Sejt/mm3
4,000-
Neutrophil granulocytes
2,000-
Lymphocytes
400-
Eozinophils
300-
Monocytes
100-
Basophils
6h
12 h
24 h
Immunosuppression therapy
To eliminate unwanted immune response:
- Allergy
- Autoimmune diseases
- Organ transplant
a, Antigene-specific immune suppression – selective tolerance
b, Not-antigene- specific
• Corticosteroids (in supraphysiological, pharmacological doses)
• CY-A, FK 506, Rapamycin (T cell proliferation inhibitor)
• Radiation therapy
• Cytostatics
Natural and artificial glococorticoids
Synthetic products:
CH2OH
CH2OH
OH
Cortisol
C=O
C=O
OH
O
O
Cortizon
O
CH2OH
CH2OH
C=O
Prednizolon
OH
O
OH
C=O
OH
Prednizon
(4x more effective
O
O
than Cortizon)
Anti-inflammatory mechanism of glucocorticoids
GRE: glucocorticoid receptor element
Sites of action of cytokines in the CNS
- Through circumventricular organs and also through viscerosensory nerves
- It may depend on the type of mediator and its concentration
Circumventricular organs – humoral inputs
The effect of
IL-1 on
neuronal
activation
(c-fos
expression)
in different
brain areas
Activity of the vagal nerve in response to IL-1
injection
IL-1
The role of nociceptive sensory
system in inflammation
• Tryptase released by mast cells stimulates
nociceptive sensory terminals, which contributes to
the activation of HPA axis.
In additon:
• Substance P is released from the sensory terminals
upon inflammation
• G-protein coupled receptor of substance P is
present in macrophages, through which substance P
increases inflammation
Innervation of the immune system
Hypothalamo-spinal
tract and other
descending pathways
regulating vegetative
functions
The effect of the sympathetic
nervous system on the
immune system
Preganglionic
neuron
Postganglionic
neuron
Ach
Nikotinic
receptor
Adrenerg
receptor
Target
organ
Noradrenaline
Macrophages and lymphocytes
possess beta 2 adrenerg receptors,
which inhibit their actions
Additional effects of the sympathetic nervous
system on inflammation
- In additon to noradrenaline, dopamine and neuropeptide Y are also released from
sympathetic terminals
- Immune cells have receptors for these modulators as well, through which they
inhibit their migration, activation and proliferation, which all contribute to the
localization of inflammation
Neuromodulation of
inflammation
1. sensory
terminal
(stimulatory)
2. sympath.
(inhibitory)
3. parasymp.
(inhibitory)
©Fülöp AK 2010
Acute phase reaction of the central
nervous system
Systemic cytokines activate the hypothalamus
– Systemic inhibition of the
immune system
• HPA axis
• Vegetative nervous system
– Fever
– Behavioral effects:
• No appetite
• Drowsiness
• Lack of exploratory and
sexual behaviors
Systemic inflammatory mediators reduce appetite by
acting on hypothalamic food intake regulatory neurons
Additional effect of inflammatory hormones on energy
homeostasis
LPL: Lipoprotein lipase, NF: nuclear factor
Immune activation produces sickness behaviors,
symptomes that resemble to depression
Thank you for your
attention!