Download The brain and the immune system

The brain and the immune
system
Mind over matter
‫ד"ר יוסי רימר‬
SUPERSYSTEMS
ADAPTIVITY
CNS
IMMUNE SYS
The historical link
ANS
HPA
IMMUNE SYS
A novel link
SNS
Immune sys
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 crosstalking .
 Sterenberg 1989 - Stress system and autoimmune
dis.
Anatomy
The anatomy of the neuroimmune
system
 VPN-CRH and LC-NE
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)
Thinic anatomy II
 Mast cells are accumulated near NE fibers
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 ?
Other
 NE mast cell (SP)
 NE macrophage
 NE T cells
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
Development
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.
NE has an influence on the
immune system maturation
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-1
systemic 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
Alpha receptors
 Only found in JRA, induce IL-6 in response
to stimulation.
Dopamine receptors
 D1-D5 RECEPTORS
 D3-D5 maybe
 Functional role undetermined yet
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
Th2
Th1
Th1 : INF-γ ,IL-2 ,TNF-β
Th2 : IL-4 ,IL-10 ,IL-13,IL-9
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.
Systemically - CAs inhibit
Th1 function selectively !
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 through β2-AR-CAMP
supress type 1 but potentiate type
2 cytokine production
Note:
 Local effect of CA may differ from systemic
ones by α-AR stimulation.
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 activitymacrophage
 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.
fin