the brain and the immune system mind over matter ד " ר יוסי רימר
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History Tenkoff 1899 – nerves enter lymph nodes Loper & Crouzon 1904 – leukocytosis after adrenalin injection Ishigami 1919 – stress and infection Metalnikov 1920 – immune sys and pavlov Euler 1946 – NE isolated from spleen 70-80’s – cytokines and hormones are cross-
talking . Sterenberg 1989 - Stress system and autoimmune
dis.
Thymic anatomy
Thymus is inervated along blood vessels
by postgang. sympath. Fibers to the cortex
but spar the medula Outer cortex has the dancest inervation
(immature thymocyte) Vasculature in the corticomedullary parts
are richly inervated (migration)
Spleen innervation anatomy
Most innervation to spleen is sympathetic Innervation to white pulp Sympathetic innervation to periarterial
lymphatic sheath Almost no innervation to B cells follicles
and red pulp
Lymph node anatomy
Noradrenergic fibers to cortical and paracortical regions (T cells).
No innervation to medulla or germinal centers (B cells)
Bone marrow anatomy
Not enough information Nerves end in parenchyma Nerves mature before immune cells dev. Maturation of immune cells nerve
dependent ?
Nonsynaptic NE release
Lymphoid organs as thymus or spleen can store NE and release it .
DA from circulation can also be stored. NPY is also released from nerves but only
during high frequency stimulation, NE is released with slow frequency stimulation.
Nonsynaptic NE release
Nonsynaptic connection differ from synaptic one
Diffusion distance is larger Communication is one to many Action is long and tonic Receptors are high affinity α2-ARs as receptors Most innervation in lymphoid tissue nonsy.
The NPY connection
NPY acts as neurotransmitter and modulator
in the CNS and periphery. NPY fibers supply mostly vasculature May affect lymphocyte traffic In vitro NPY suppresses NK activity
Cytokines and SNS
1970 Besedovsky : immune system signals
CNS IL-1 induced increase in plasma steroids IL-1 altered hypothalamic NE activity IL-1 lowers NE in spleen
SNS and immune sys. development
At bitrh almost no innervation of lymphoid tissues by the SNS.
Density of neurons increase with age. Even when thymus involution is
pronounced no decrease in innervation. Neonatally sympathectomized rats show
alteration in T B and NK activity and decrease in IgM production.
Hematopoiesis and the SNS
In mice NE and DA exhibit daily rhythm NE has positive correlation with G2/M and
S phases . When exposed to pritoneal Pseudomonas
mice respondes in 130% increase of NE turnover in bone marrow.
Hematopoiesis and SNS
α1-AR antagonists increase blood granulocytes.
They also decrease spleen T and B cells.
Myelopoiesis is under sympathetic inhibition whereas lymphocyte production needs NE
stimulation.
The cytokine way
IL-1& INF-α produce increase in sympath. Activity in spleen
IL-1 IL-6 & TNF- α activates CRH and trigger activation of SNS and HPA
ICV infusion of IL-1 and INF- α decrease peripheral and splenic NK cell activity and
suppress mitogen response. Evidence to specific functional pathways in
ANS controlled by distinct reflexes.
TNF- α and IL-1systemic Vs. local effects
Systematically - NE increase ME - TNF decrease NE innervation in ME
causing elevation of ACTH ME -IL-1 elevates NE
Adrenoreceptors and lymphocytes beta receptors
All lymphoid cells express beta receptors
except T help. Type 2. Receptors density : NK>mono>Tc=B>Th1 Other cells also have beta AR:
eosin. Baso. Neutrop. Thymoc. cAMP response difference in the cells
Physiologic control of β-adrenergic receptors
A very complex multi-layer control mechanism with feed-backs between the CNS/SNS and the immune system.
IL-1 TNF-α increase receptors density Steroids augment this effect further more G-proteins also play a major role in β-AR
regulation in immune cells
SNS and lymphocyte traffic
CA administration causes a quick lymphocyte mobilization.
Followed by granulocyte increase and relative neutropenia
CA mainly affect NK cells and granulocyte
not T or B cells. Acute psychological stress or physical
exercise cause transient lymphocytosis mainly NK cells
SNS and lymphocyte traffic
Terbutaline is a β2 -AR agonist.
7 days of treatment cause Tc and NK reduction.
CA modulated NK circulation mainly via spleen-dependent β2 -AR
Different lymphocyte subpopulation have different sensitivity to CA
To be (Th2) or not to be (Th1)
β2 -AR are found on Th1 only
β2 -AR agonist inhibit INF-γ production by Th1 cells
No effect on IL-4 production by Th2
In vivo – deralin causes increase in LPS induced TNF-α production and β2 -AR agonists inhibits.
Catacholamines and signal pathways
Specific G-proteins are expressed in different cells and are activated by AR
Inositol phosphate increase (PLC activation) AC PDE and PKA are the cytosolic
mediators When activated TNF- α IL-12 are inhibited IL-10 production increase
Pathways - the sequel
Theophylline amrinone roliparm- PDE blockers
Prevent NO ,TNF- α ,INF- and IL-12 production after LPS
meaning cAMP connection to proinflammatory mediators
IL-2 production is inhibited by cAMP IL-2 & TNF has NF-Kb. IL-4,IL-10 don’t
CA and cellular immunity - NK
CA have dual effect on NK cells Epinephrine causes short & transient
increase of NK numbers. On the other hand – CA cause inhibition of
NK cell activity. Inhibition is reversed by β2 -AR antagonist.
CRH (increase SNS activity) produce a decrease in NK cell activity.
This effect is not steroid dependent ! Patients with CHF – NE levels are very
high. A positive correlation of NE levels and NK cells activity.
CA and cellular activity-macrophage
Controversial CA inhibits mo.activation by INF-γ CA stimulate mac, to suppress MAI by α2-
AR way. Effect most probably depends on receptors
balance.
CA and cellular activity–mast cells
A close anatomic relationship between sympathetic and peptidergic nerves and macrophage and mast cells.
SP and peripheral CRH are potent mast cell secretagogues.
Stimulation of histamine release by α-AR Inhibition by β-AR. B7 costimulatory T cell receptor is CA
regulated by CAMP levels.
Ca and cellular activity – neutrophil
CA inhibit neutrophils phagocytosis & neutrophils lysosomal release.
Respiratory burst also inhibited β-AR stimulation decrease rate of
superoxide production.
CA and humoral immunity
β2 stimulation elevates CAMP levels
More B cells differentiate into plasma cells B7 molecule is up-regulated Ab production by B cells enhancement. Th2 cells provide the cytokines necessary to
for B cells growth
Major injury
Major injuries or major surgical procedures often lead to immunosupression.
After trauma there is a biphasic response pattern,
I - sympathoadrenal storm. II - HPA axis stimulation
In animal model suppression of cellular immunity is associated with low IL-12 and INF production and increase in IL-10.
Brain trauma cause sympathetic storm and IL-10 elevation. High IL-10 levels correlated with high incidence of infection.
TNF and IL-1 produce a systemic response to endotoxin .
Anti-TNF and IL-1 receptor antagonist show small benefit
healthy volunteeres challenged with endo toxin and pretreated with adrenalin had increased IL-10 levels and decrease TNF levels
Patients with low preoperative IL-12 secretion ,by monocyte , had more sepsis
can immune protocols be used in order to shift cells population ?
Autoimmunity
Several autoimmune disease are characterized by Th1/Th2 imbalance.
The ANS/HPA axis influence autoimmunity in a complex way.
Can hyporeactive SNS cause Th1 shift and facilitate disease states like RA and MS ?
Can hyper-reactive SNS cause Th2 shift and facilitate disease states like SLE ?
TUMOR GROWTH
IL-12 levels are critical for tumor regression Local overproduction of IL-10 inhibits IL-
12 production as well as TNF. CA overproduction inhibits NK cells and Tc
compromising resistance to metastases.