The brain and the immune system Overview

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