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The Innate Immune Response

The Innate Immune Response. Chapter 15. 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.

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The Innate Immune Response

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  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

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