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The brain and the immune system

The brain and the immune system. Mind over matter. ד"ר יוסי רימר. ADAPTIVITY CNS IMMUNE SYS. SUPERSYSTEMS. The historical link. ANS. HPA. IMMUNE SYS. A novel link. SNS. Immune sys. History.

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The brain and the immune system

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  1. The brain and the immune system Mind over matter ד"ר יוסי רימר

  2. ADAPTIVITY CNS IMMUNE SYS SUPERSYSTEMS

  3. The historical link ANS HPA IMMUNE SYS

  4. A novel link SNS Immune sys

  5. 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.

  6. Anatomy

  7. The anatomy of the neuroimmunesystem • VPN-CRH and LC-NE

  8. 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)

  9. Thinic anatomy II • Mast cells are accumulated near NE fibers

  10. 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

  11. Lymph node anatomy • Noradrenergic fibers to cortical and paracortical regions (T cells). • No innervation to medulla or germinal centers (B cells)

  12. Bone marrow anatomy • Not enough information • Nerves end in parenchyma • Nerves mature before immune cells dev. • Maturation of immune cells nerve dependent ?

  13. Other • NE mast cell (SP) • NE macrophage • NE T cells

  14. 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.

  15. 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.

  16. 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

  17. 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

  18. Development

  19. 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.

  20. NE has an influence on the immune system maturation

  21. 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.

  22. 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.

  23. 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.

  24. 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

  25. 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

  26. 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

  27. Alpha receptors • Only found in JRA, induce IL-6 in response to stimulation.

  28. Dopamine receptors • D1-D5 RECEPTORS • D3-D5 maybe • Functional role undetermined yet

  29. 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

  30. 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

  31. Th2 Th1

  32. Th1 : INF-γ ,IL-2 ,TNF-βTh2 : IL-4 ,IL-10 ,IL-13,IL-9

  33. 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.

  34. Systemically - CAs inhibit Th1 function selectively !

  35. 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

  36. 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

  37. CA through β2-AR-CAMP supress type 1 but potentiate type 2 cytokine production

  38. Note: • Local effect of CA may differ from systemic ones by α-AR stimulation.

  39. 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.

  40. This effect is not steroid dependent ! • Patients with CHF – NE levels are very high. A positive correlation of NE levels and NK cells activity.

  41. 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.

  42. 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.

  43. Ca and cellular activity – neutrophil • CA inhibit neutrophils phagocytosis & neutrophils lysosomal release. • Respiratory burst also inhibited • β-AR stimulation decrease rate of superoxide production.

  44. 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

  45. 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

  46. 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.

  47. 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

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