The lung and the innate immune system

1. The lung and the innate immune system Text books Silverthorne 2004, Human Physiology – An Integrated Approach (3rd Edition), Pearson Benjamin Cummings Illustrations from: Immunobiology- the immune system in health and disease, 6th edition, Janeway, Travers, Walport, Shlomchik, Churchhill Livingstone Lecture slides can be found on webct Prof Gerhard Walzl

2. Functions of the immune system • Protection against invaders • Removal of dead or damaged tissues • RBC • Wounds • Recognition and removal of abnormal or foreign cells or substances • Malignancies • Transplanted tissue • Foreign bodies/substances

3. Figure 1-23

4. Some basic concepts in immunology

5. What is an antigen? • Any substance which is recognized in a specific way by the immune system and elicits an immune response • E.g. a micro-organism, a part of it, a product thereof, or a substance that has been injected or taken, i.e. penicillin or poison • It can also be a molecule that is expressed on the surface of a cell What is an epitope? • A specific molecular sequence on the surface of an antigen is the antigenic determinant or epitope. • Antigens have a variety of epitopes on their surfaces which differ from each other – each one binds a different receptor on a cell or antibody in the circulation.

6. CD= cluster of differentiation • CD molecules are found on the surface of cells • Used to classify/characterize cells • i.e. CD3+ cells= T lymphocytes CD4+ T cell= an important T lymphocyte CD8= an important T lymphocyte

7. Organization of the immune system The immune system External defenses Internal defenses Anatomical barriers Body secretions and excretions Normal commensal flora Cilia Innate immunity Adaptive immunity Phagocytic cells Chemicals Complement Acute phase proteins Cytokines etc. Humoral immunity Cell-mediated immunity

8. Antigen presenting cells …Internal defenses Innate immunity Adaptive immunity Phagocytic cells Neutrophils Macrophages Dendritic cells NK cells Chemicals Complement Acute phase proteins Cytokines Humoral immunity B cells Plasma cells Antibody Cell-mediated immunity CD4+ T cells Th1 cells Th2 cells Treg cells Th17 cells CD8+ T cells Subtypes NK T cells Th= T helper cell, are CD4+ cells. Designates the type of cytokines secreted and therefore their function

9. Innate immunity Innate immune system: characteristics -Not inducible -Broad specificity of receptors -No memory generated -Preformed mediators -Immediate effect possible

10. Innate immunity Adaptive immunity Effectors need clonal expansion- takes days Highly specific recognition (T cell receptors and antibody) Memory: enhanced performance during future exposure to same antigen Preformed mediators- immediate effect Non-specific recognition (pattern recognition receptors) No memory, no improvement in performance during future exposure to same antigen

11. Figure 2-4 part 1 of 2 First line of defense: External defenses Many barriers prevent pathogens from crossing epithelia and colonizing tissues.

12. Figure 2-4 part 2 of 2 Epithelial cells joined by tight junctions Movement of mucus by cilia Antibacterial peptides Laminar airflow Many barriers prevent pathogens from crossing epithelia and colonizing tissues

13. Figure 1-7 Anatomy of the immune system Mediastinallymphnodes Left lung Spleen Bone marrow

14. Figure 1-8 part 1 of 2 Anatomy of the immune system

15. Innate immunity Cells -Phagocytic cells Neutrophils Macrophages, including alveolar macrophages Dendritic cells -NK cells Chemicals -Complement -Acute phase proteins -Cytokines

16. Figure 2-9 Movement of cells:Monocytes circulating in the blood recognize blood vessel walls near the site of inflammation and leave the bloodstream to migrate into the tissue toward the site of inflammation. Adhesion molecules

17. Figure 2-5 Phagocytosis The receptors on phagocyte membranes can recognize many different foreign antigens . These are pattern recognition receptors (PRR) which broadly differentiate non-self from self. PRRs recognize pathogen-associated molecular patterns (PAMPs). Macrophages are activated by pathogens and both engulf them and initiate inflammatory responses.

18. Phagocytosis

19. Phagocytosis and its consequences: pathogens are digested inside phagolysosomes (phagosomes fused with lysosomes)

20. Figure 2-8 Infection stimulates macrophages to release cytokines and chemokines that initiate an inflammatory response.

21. Alveolar macrophages (AM) Found in alveolus, separated from wall Function: clean up microorganisms and particles, like dust at one of the major boundaries between body and outside world Highly adaptive, modified by state of differentiation and micro-environment Baseline state of the AM: quiescent, producing little pro-inflammatory cytokines, little phagocytic activity (i.e. downregulated receptor Mac-1), suppress adaptive and humoral immunity. Secrete nitric oxide, prostaglandins, IL-4, IL-10 and TGF-β When activated: stronger respiratory burst than other phagocytes. Also O2-independent microbicidal mechanisms (acid-based), lysozymes, iron-binding proteins, toxic cationic polypeptides and enzymes in their granules and lysosomes, nutrient deprivation mechanisms. Some pathogens, like M. tuberculosis, have specialized to survive in these cells.

22. Chemicals of the innate immune system

23. Injury to blood vessels triggers: • The kinin system: bradykinin (increases vascular permeability and stimulates pain receptors) Plasma prekallikreinPlasma kallikreinBradykininogenBradykinin • The coagulation system (fibrin clots develop that prevent the spread of pathogens).

24. Inflammatory mediators released by macrophages after recognition of invaders • Lipid mediators (prostaglandins, leukotrienes, platelet-activating factor)- produced through macrophages through enzymatic pathways that degrade membrane phospholipids • Followed by cytokines and chemokines.

25. The result of tissue damage: mediators of inflammation Membrane phospholipids Phospholipases (PLA2) Corticosteroids act here Arachidonic acid Cyclo-oxygenase Lipoxygenase NSAIDS act here Non-steroidal anti-inflammatory drugs PGG2 (prostaglandin G2) Leukotrienes PGH2 (prostaglandin H2) LTB4 LTC4 LTD4 LTE4 PGI2 (prostacyclin) TXA2 (tromboxane) PGE2 (prostaglandin E2)

26. Figure 2-39 =IL-8

27. Figure 2-46 Cytokines are released by macrophages and other cells and affect many different body systems TNF-α, IL-1 and IL-6 have a wide spectrum of biological activities that help to coordinate the body’s responses to infection.

28. Figure 2-47 part 1 of 2 The acute phase response produces molecules that bind pathogens but not host cells.

29. Cytokines • Interleukins (ILs) Regulate production and activity of the cells involved in both the non-specific and the specific immune responses. Bind to receptors • Chemokines- a distinct type of cytokine Bring about chemokinesis or chemotaxis (movement of cells in response to chemical stimuli)

30. Interferons- a type of cytokine • IFN and IFN • released by virus infected cells • bind to specific receptors on uninfected cells and stimulate the synthesis of antiviral enzymes (break down viral mRNA) which makes these cells resistant to viral attack. • IFN: clinically used against genital warts, AIDS related Kaposi sarcoma, hepatitis B and C • IFN: used therapeutically in multiple sclerosis. • IFN • produced by activated T-lymphocytes and NK-cells if alerted by the presence of bacteria, viruses, parasites or tumor cells • binds to specific receptors on target cells to stimulate the production of proteins that inhibit viral replication, inhibit tumors and orchestrate the specific immune response. • stimulates macrophages to kills cells infected by bacteria, viruses and parasites, and also tumor cells. • stimulates the production of Class I en II MHC proteins (see later) and thus antigen presentation See other cytokines in lecture on adaptive immune system.

31. Internal defensesNon-specific immunityChemical mediators of inflammationThe complement system

32. Figure 2-18 The complement system-overview

33. Figure 2-19

34. Figure 2-21 The classical pathway of complement activation- the C1 molecule. This molecule recognizes pathogen surfaces or antigen-antibody complexes and activates the enzymes that are part of the complex. The active enzymes then activate further enzymes of the complement system.

35. Figure 2-22 Example of the complement cascade and amplification of the effect. Detailed knowledge not required.

36. Figure 2-24 The mannose binding lectin pathway of complement activation. The recognition/enzyme activation complex of this pathway is shown.

37. Figure 2-26 part 1 of 3 The alternative pathway of complement activation. This pathway is continuously active and is inactivated by inhibitors on own cells that do not occur on pathogen cells. The system is therefore only active on pathogen cells. C3b from the three different pathways amplify the effects

38. Figure 2-33 The small complement cleavage products are mediators of inflammation.

39. Figure 2-35 The final of the 3 effects of all 3 complement pathways is the generation of the membrane attack complex (MAC), which is a pore that is inserted into the pathogen that lyses the bacteria.

40. Summary of innate immune system

41. Soluble factors Complement Monocyte/Macrophages Acute phase proteins Pattern rec. receptors Lipid mediators Neutrophils Kinin system Chemokines Cytokines Adhesion molecules Pathogen External defenses Epithelium Internal non-specific defenses Phagocytes Blood vessel

42. Summary: external defenses in the lung Anatomical barriers Mucous membranes Body secretions and excretions Mucus Tears, saliva (wash action Lysozyme in tears/nose/saliva Cilia Ciliary staircase in lungs Physical properties Laminar air flow Back to main slide

43. Figure 2-47 part 1 of 2 The acute phase response produces molecules that bind pathogens but not host cells. Back to main slide

44. Figure 2-39 Back to main slide

45. Figure 2-9 Monocytes circulating in the blood recognize blood vessel walls near the site of inflammation and leave the bloodstream to migrate into the tissue toward the site of inflammation. Back to main slide

46. Figure 2-19 Back to main slide

47. Membrane phospholipids Phospholipases (PLA2) Corticosteroids act here Arachidonic acid Cyclo-oxygenase Lipoxygenase NSAIDS act here Non-steroidal anti-inflammatory drugs PGG2 (prostaglandin) Leukotrienes PGH2 (prostaglandin) LTB4 LTC4 LTD4 LTE4 PGI2 (prostacyclin) TXA2 (tromboxane) PGE2 (prostaglandin) Back to main slide