The Innate Immune Response

1. The Innate Immune Response Chapter 15

2. 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

3. Overview of Innate Defenses • Sensor system signals when first line barriers have been breached • Two important groups of receptors • Toll-like receptors and NOD proteins • Cell membrane proteins that recognize and bind to families of compounds unique to microbes • nucleotide-oligomerization domains • Complement System

4. Overview of Innate Defenses • Toll-like receptors and NOD proteins • Found on variety of cells • Recognize families of compounds • Enables cells to sense invasion • Sends signal to body to respond

5. Overview of Innate Defenses • Complement System • Acts in response to stimuli • Activation sets off chain reaction that results in destruction or removal of invader

6. Overview of Innate Defenses • Phagocytes are specialized cells that engulf and digest microbes and cellular debris • Act as sentries • Alerted to signs of invasion • Release cytokine chemicals • More phagocytes can be recruited from bloodstream • Attracted by chemical gradient of the released cytokines • Phagocytosis movie

7. Overview of Innate Defenses • Cells of the immune system have an elaborate communication system • Communication achieved through productions of proteins • Proteins act as chemical messengers • Called cytokines • Cytokines from one cell diffuse to another • Bind to cytokine receptor on cell • Receptor transmits signal to cell interior • Induces changes in cellular activities

8. Overview of Innate Defenses • Inflammation is initiated by microbial invasion or tissue damage • During inflammation cells in blood vessels undergo changes that allow certain immune particles to leak out of the blood

9. First Line of Defense • Physical barriers • Skin is most visible barrier • Covers majority of surfaces in obvious contact with environment • Mucous membranes barrier that lines digestive tract, respiratory tract and genitourinary tract • Mucous protects these surfaces from infections

10. 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 become increasingly flat • Outermost sheets of cells embedded with keratin • Makes skin water repellent • Outer layers slough off taking microbes with it

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

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

13. First Line of Defense • Normal 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 • Completes for nutrients • Nutrients unavailable for pathogens

14. 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

15. 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

16. Cells of the Immune System • Granulocytes • Contain cytoplasmic granuals • Divided into three types • Neutrophils • Basophils • Eosinophils

17. Cells of the Immune System • Neutrophils • Most abundant and important in innate response • Sometimes called polymorphonuclear neutrophilic leukocytes (PMNs) • Basophils • Involved in allergic reaction • Eosinophils • Important in expelling parasitic worms • Active in allergic reactions

18. Cells of the Immune System • Mononuclear phagocytes • Constitutes collection of phagocytic cells called mononuclear phagocyte system • Includes monocytes • Circulates in blood • Macrophages differentiate from monocytes • Present in most tissues • Abundant in liver, spleen, lymph nodes, lungs and peritoneal cavity

19. Cells of the Immune System • Dendritic cells • Branched cells involved in adaptive immunity • Functions as scout in tissues • Engulf materials in tissue and bring it to cells of adaptive immunity

20. Cells of the Immune System • Lymphocytes • Involved in adaptive immunity • Two major groups • B lymphocytes • B cells • T lymphocytes • T cells • Another type • Natural killer • Lacks specificity of B and T cells

21. Cell Communication • In order for immune system to respond cells must communicate with environment and with each other • Cell surface receptors are the “eyes” and “ears” of the cell • Cytokines are the “voice” • Adhesion molecules act as the “hands”

22. 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 send signal to cell • Cell responds by initiating some action

23. Cell Communication • Cytokines • Cytokines bind to surface receptors regulate cell function • Numerous cytokine classes • Chemokines = important in chemotaxis • Enhance ability of cells to migrate to appropriate site in body • Colony stimulating factors = important in multiplication and differentiation of leukocytes • During immune response directs immature leukocytes to correct maturation pathway • Interferons = important in control of viral infections • Also associated with inflammatory response • Interleukins = produced by leukocytes • Important in innate and adaptive immunity • Tumor necrosis factor = kill tumor cells • Instrumental in initiation of inflammation

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

25. Sensor Systems • System within blood and tissue detect signs of tissue damage or microbial invasion • Responds to patterns associated with danger by • Directly destroy invading microbe • Recruiting other host defenses

26. 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

27. 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

28. Sensor Systems • 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

29. 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

30. Sensor Systems • Classical pathway • Activation requires antibodies • Antibodies interact with complement C1 • Activates protein • Leads to activation of all complex proteins

31. Sensor Systems • Complement • Complement system composed of nine proteins • C1 – C9 • Numbered as discovered not order of activation • Certain proteins split into “a” and “b” fragments after activation • C3 can spontaneously split to C3a and C3b • Insures enough C3b for activation of alternative pathway • Activation of complement leads to major protective outcomes • Inflammation • Opsonization • Lysis of foreign cells

32. Sensor Systems • Inflammation • Complement components C3a and C5a induce changes in endothelial cells • Effects vascular permeability associated with inflammation • Opsonization • C3b binds foreign material • Allows phagocytes to easily “grab” particles

33. 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

34. 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

35. 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

36. Inflammation • Factors that initiate inflammatory response • Microbial products trigger toll-like receptors of macrophages • Causing release of pro-inflammatory cytokines • Microbial cell surface can trigger complement • Leads to the production of C3a and C5a • Tissue damage results in enzymatic cascade • Cascades initiate inflammation

37. 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 • Resulting in increased blood flow • Increased blood flow responsible for cardinal signs of inflammation

38. 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 cell 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 sever • Inflammation around brain and spinal cord can lead to meningitis

39. 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

40. 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