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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