Innate Immune Response

1. Innate Immune Response Chapter 15

2. What am I?

3. Overview of Innate Defenses • First line of defense are barriers that shield interior of body from external surroundings • Anatomical barriers include skin and mucous membranes • Provide physical separation • Membranes bathed in antimicrobial secretions • Antimicrobial substances and Normal Flora • pH changes

4. First Line of Defense • Skin • Provides the most difficult barrier to penetrate • Composed of two main layers • Dermis • Contains tightly woven fibrous connective tissues • Makes extremely tough • Epidermis • Composed of many layers of epithelial cells • As cells reach surface, they become increasingly flat • Outermost sheets of cells embedded with keratin • Makes skin water-repellent • Outer layers slough off, taking microbes with it

5. First Line of Defense • Mucous membranes • Constantly bathed with mucus • Help wash surfaces • Some mucous membranes have mechanisms (cilia)to propel microorganisms and viruses to areas where they can be eliminated

6. First Line of Defense • Antimicrobial substances • Both skin and mucous membranes are protected by variety of antimicrobial substances including • Lysozyme • Enzymes that degrade peptioglycan • Found in tears, saliva, blood and phagocytes • Peroxidase • Found in saliva, body tissues and phagocytes • Breaks down hydrogen peroxide to produce reactive oxygen • Lactoferrin • Sequesters iron from microorganisms • Iron essential for microbial growth • Found in saliva, some phagocytes, blood and tissue fluids • Defensins • Antimicrobial peptides inserted into microbial membrane • Found on mucous membranes and in phagocytes

7. First Line of Defense • Normal Microbiota (Flora) • Defined as microorganisms found growing on body surfaces of healthy individuals • Not technically part of immune system • However, provides significant protection • Protects through competitive exclusion • Covers binding sites • Pathogens can’t bind • Competes for nutrients • Nutrients unavailable for pathogens

8. Cells of the Immune System • Always found in normal blood • Numbers increase during infection • Some cells play dual roles in both innate and adaptive immunity • Blood cell formation called hematopoiesis • Blood cells including immune cells originate from hematopoietic stem cells in bone marrow • Blood cells stimulated to differentiate by colony-stimulating factor

9. Cells of the Immune System • General categories of blood cells • Red blood cells (RBC) • a.k.a erythrocytes • Carry oxygen in blood • Platelets • Fragments of megakaryocytes • Important component in blood clotting • White blood cells (WBC) • a.k.a leukocytes • Important in host defenses • Divided into four categories • Granulocytes - Mononuclear phagocytes • Dendritic cells - Lymphocytes

10. Cells of the Immune System

11. Granulocytes • Contain cytoplasmic graduals • Divided into three types • Neutrophils • Basophils • Eosinophils

12. Cells of the Immune System • Granulocytes • Contain cytoplasmic graduals • Neutrophils • Most abundant and important in innate response • Granules contain chemicals which kill microbes • Sometimes called polymorphonuclearneutrophilic leukocytes (PMNs)

13. Cells of the Immune System • Basophils • Granules contain histamine and other chemicals which increase capillary permeability. • Similar to mast cells • Involved in allergic reaction • Eosinophils • Important in expelling parasitic worms • Active in allergic reactions • Granules contain histamase and antimicrobial chemicals

14. Cells of the Immune System • Mononulcear phagocytes • Constitute collection of phagocytic cells called mononuclear phagocyte system • Include monocytes • Circulate in blood • Macrophages differentiate from monocytes • Present in most tissues • Abundant in liver, spleen, lymph nodes, lungs and peritoneal cavity • Dendritic cells • Branched cells involved in adaptive immunity • Function as scout in tissues • Engulf material in tissue and bring it to cells of adaptive immunity

15. Cells of the Immune System • Lymphocytes • Involved in adaptive immunity • Two major groups • B lymphocytes • B cells-mature in bone marrow • T lymphocytes • T cells-mature in the thymus • Another type • Natural killer • Lacks specificity of B and T cells

16. Cell Communication • Surface receptors • Membrane proteins to which signal molecules bind • Receptors specific to molecule to which it bonds • Binding molecules called ligands • When ligand binds, receptor becomes modified and sends signal to cell • Cell responds by initiating some action

17. Cell Communication • Cytokines • Cytokines bind to surface receptors and regulate cell function • Numerous cytokine classes • Chemokines – important in chemotaxis • Colony stimulating factors – Important in multiplication and differentiation of leukocytes • Interferons – important in control of viral infections • Interleukins – produced by leukocytes • Tumor necrosis factor – kill tumor cells

18. Cell Communication • Adhesion molecules • Allow cells to adhere to each other • Responsible for the recruitment of phagocytes to area of injury • Epithelia cells lining blood vessels produce adhesion molecules that catch phagocytes as they pass by • Cause phagocytes to slow and leak out of vessels to area of injury

19. Sensor Systems • Systems within blood detect signs of tissue damage or microbial invasion • Respond to patterns associated with danger by • Directly destroying invading microbe • Recruiting other host defenses

20. Sensor Systems • Toll-like receptors (TLR) and NOD proteins • Pattern recognition receptors • TLR allow cells to “see” molecules signifying presence of microbes outside the cell • TLR found in variety of cell types • Recognize distinct “danger” compounds • Signal is transmitted • Results in change of gene expression of cell • NOD proteins do same for inside cell

21. Sensor Systems • Complement system • Series of proteins circulating in blood and fluids • Circulate in inactive form • Augment activities of adaptive immune response • Stimulation of inactive proteins initiates cascade of reactions • Results in rapid activation of components • Three pathways of activation • Alternative pathway • Lectin pathway • Classical pathway

22. Figure 15.7

23. Sensor Systems • Classical pathway • Activation requires antibodies • Antibodies interact complement C1 • Activates protein • Leads to activation of all complex proteins • Alternative pathway • Quickly and easily initiated • Relies on binding of complement protein C3b to cell surface • Initiates activation of other compliment proteins • Allows formation of complement complex • C3b always circulating in blood

24. Sensor Systems • Lectin pathway • Activation requires mannan-binding lectins (MBL) • Pattern recognition molecules • Detect mannan • Polymer of mannose • Found in microbial cells • MBL attaches to surface • Activates complement proteins

25. Sensor Systems • Lysis of foreign cells • Complexes of C5b, C6, C7, C8 and multiple C9 spontaneously assemble • Forms donut-shaped structure called membrane attack complex (MAC) • Creates pores in membrane • Most effective on Gram-negative cells • Little effect on Gram-positive cells

26. Figure 15.8

27. Sensor Systems • Long Double-Stranded RNA (dsRNA) • Induction of alpha and beta interferons • Cells express iAVPs • Leads to apoptosis

28. Phagocytosis • Process of phagocytosis • Chemotaxis • Cells recruited to infection • Recognition/attachment • Use receptors to bind invading microbes • Engulfment • Phagocyte engulfs invader-forming phagosome • Phagosome lysosome fusion • Phagosome binds lysosome, forming phagolysosome • Destruction and digestion • Organism killed due to lack of oxygen and decreased pH • Exocytosis • Phagocyte expels material to external environment

29. Phagocytosis • Role of Neutrophiles • First responders • Granules contain antimicrobial chemicals • NETs-neutrophile extracellular traps • Contain DNA and anti microbial chemicals • Trap bacteria and destroy them with chemicals • Short lived but lots in reserve

30. Inflammation • Inflammation occurs in response to tissue damage • Four cardinal signs • Heat • Pain • Redness • Swelling • Loss of function • Fifth sign that can also be present

31. Inflammation • Factors that initiate inflammatory response • Microbial products trigger toll-like receptors of macrophages • Causes release of pro-inflammatory cytokines • Microbial cell surface can trigger complement • Tissue damage results in enzymatic cascade • Cascades initiate inflammation

32. Inflammation • The inflammatory process • Initiation leads to a cascade of events • Results in dilation of blood vessels, leakage of fluid from vessels and migration of leukocytes and phagocytes • Leakage of phagocytes from blood vessels called diapedesis • Certain pro-inflammatory mediators cause the diameter of blood vessels to increase • Results in increased blood flow • Increased blood flow responsible for cardinal signs of inflammation

33. Inflammation • Outcomes of inflammation • Intent is to limit damage and restore function • Inflammation itself can cause considerable damage • Release of toxic products and enzymes from phagocytic cells is responsible for tissue damage • If inflammation is limited to area of injury, damage is usually nominal • If inflammation results in delicate systems, consequences are more severe • Inflammation around brain and spinal cord can lead to meningitis

34. Inflammation • Apoptosis • Programmed cell death • Destroys cell without eliciting inflammatory response • During apoptosis, cells undergo changes to signal macrophages • Cells are engulfed without triggering inflammatory cascade

35. Fever • One of the strongest indicators of infection • Especially of bacterial infection • Important host defense mechanism • Temperature regulation center of body responds to fever-inducing substances called pyrogens • Fever-inducing cytokines termed endogenous pyrogens • Microbial products termed exogenous pyrogens • Resulting fever inhibits growth of pathogens by • Elevating temperature above maximum growth temperature • Activating and speeding up other body defenses