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 cross-

talking . 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-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

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

Th1

Th2

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 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.

fin