Elements of Innate and acquired Immunity

1. Elements of Innate and acquired Immunity • Innate (nonspecific) Immunity • Physiological and Chemical Barriers • Skin and mucous membranes • Acid pH • Fatty acids • Hydrolytic enzymes (lysozyme) • Proteolytic enzyems and bile • Interferons – proteins made by cells in response to virus infection that induced a generalized antiviral state in surrounding cells • Complement system – 20 proteins in a controlled enzymatic cascade which targets the membrane of pathogenic organisms and targets theme for destruction

2. Innate Immunity – Cellular Defenses • Phagocytosis and Extracellular Killing – internalization of foreign macromolecules and cells • Endocytosis – process whereby macromolecules present in the extracellular tissue fliud are ingested by cells • Pinocytosis – nonspecific membrane invagination • Receptor-mediated endocytosis – selective binding of macromolecules to specific membrane recptors • Endosomes (acidic) + Lysosomes (nucleases, lipases, proteases)  secondary lysosomes for breakdown

3. Innate Immunity – Cellular Defenses • Phagocytosis – ingestion and destruction by individual cells of invading foreign particles (bacteria) • Opsonins – factors that enhance phagocytosis of the particle • Phagosome + Lysosome  digest particle

4. Phagocytic Cells • Polymorphonuclear leukocytes (PMN) • Macrophages • Phagocytic monocytes • Fixed macrophages of the reticuloendothelial system • All these cells release cytokines upon activation

5. Phagocytic Cells • Polymorphonuclear leukocytes (PMN) • Granulocytes • Include – basophils, mast cells, eosinophils, neutrophils • Short-lived phagocytic cells that contain lysosomes • Produce peroxide and superoxide radicals • Bactericidal proteins – lactoferrin • PMNs play a major role in protection a/g infection • Defects – chronic or recurrent infection

6. Phagocytic Cells • Macrophages – phagocytes derived from blood monocytes • Migration from blood to tissues  differentiation • Kupffer cells in the liver • Alveolar macrophages in the lung • Splenic macrophages in the white pulp • Peritoneal macrophages free floating in peritoneal fluid • Microglial cells in the CNS

7. Phagocytic Cells • Reticuloendothelial System (RES) • Includes each of these macrophage populations • Widely distributed throughout the body – usually located along capillaries • Phagocytize microorganims and foreign substances in bloodstream and tissues • Destruction of aged and imperfect cells such as RBC

8. Phagocytic Cells • Cells of the macrophage series have two major functions • Engulf and digest microorganisms and foreign particles • Antigen presentation • Take up Ag and process for presentation to T cells • Other Ag presenting cells (hematopoietic precursor, not very phagoctic) • Dendritic cells in spleen and lymph nodes • Interdigitating cells of the thymus • Langerhans cells in the skin

9. Cellular Defenses • Monocytes • central role in innate immunity • Key role in afferent (induction) limb of the acquired immune response by initiating T cell responses • Macrophages – role in efferent or effector limb of the acquired immune response as the end cells that become activated by T-cell released cytokines that enhance killing of pathogens

10. Innate Cellular Defenses • Extracellular Killing • Natural Killer Cells – component of the innate immune system • Similar function as cytotoxic T cells of acquired immune system • Recognize “altered” features of the membranes of abnormal cells (virus-infected or cancer cells) • Destroy target cells by release of biologically potent molecules that kill target cell within a very short time

11. Extracellular Killing • Natural Killer (NK) cells • Role in early viral infection or tumorogenesis before activation of acquired immunity • Large granular lymphocytes • Able to lyse without prior stimulation • Lack Ag specific receptors • Killer-cell inhibitory receptors (KIR) bind to Class I MHC • By cell-cell contact can determine if a potential target has lost its self Ag (MHC) • Infected or transformed (tumor) cells have reduced Class I MHC on their surface – fail to engage KIR and become susceptible to NK cell mediated cytotoxicity

12. Natural Killer (NK) Cells • Killing is achieved by the release of • Cytotoxic molecules that cause pores in the target cells leading to lysis • Other molecules enter target cell and induce apoptosis (programmed cell death) by enhanced fragmentation of the target cells nuclear DNA • Killing is enhanced by IL-2, IL-12 and interferons

13. Inflammation • Major component of innate and acquired defense • Involves phagocytosis and mediators excereted by phagocytic cells • Initiated by tissue damage • Mechanical (e.g. burn) • Chemical ( e.g. exposure to corrosive chemical) • Biological (e.g. infection by microorganims) • Immunologic injury (e.g. hypersensitivity) • Protective response to injury to restore normal state

14. Hallmark Signs of Inflammation • Swelling (tumor) • Redness (rubor) • Heat (calor) • Pain ( dolor) • Loss of function to the area • Occur within minutes after injury through activation and increased concentration of acute-phase proteins • Localized Inflammatory Responses • Activation of clotting • Kinin-forming pathways • Fibrolytic pathways

15. Kinins have several important effects: • Act directly on local smooth muscle and cause muscle contraction • Act on exons to block nervous impulses, leading to distal muscle relaxation • Most importantly, they act on vascular endothelial cells, causing them to contract, leading to increae in vascular permeability, and to express endothelial cell adhesion molecules (ECAMs) leading to leukocyte adhesion and extravasation. • Very potent nerve stimulators and are the molecules most responsible for pain (and itching). • Kinins are rapidly inactivated by proteases that are generated during the localized repsonse.

16. Systemic Inflammatory Response • Induction of fever – • Caused by many bacterial products (endotoxins from G(-) bacteria) • Endogenous pyrogens from monocytes and macrophages (IL-1 and certain interferons) • Increased WBC production • Increased sysnthesis of hydrocortisone and adrenocorticotropic hormone (ACTH) • Production of acute phase proteins  C-reactive protein binds to membranes of certain microorganisms to activate the complement system

17. Cytokines play a key role in Inflammation • IL-1, IL-6 and tumor necrosis factor a (TNF-a) • Released by activated macrophages • Induce adhesion molecules on the walls of vascular endothelial cells to which neutrophils, monocytes and lymphocytes adhere before moving out of the vessel (extravasation) to affected tissue • Induce coagulation and vascular permeability • Increased chemotaxis for leukocytes and increased phagoctosis (IL-8 and interferon-g) • All these effects result in accumulation of fluid (edema) and leukocytic cells in the injured area. • Amplify response by transporting other biologically active compounds to site and accumulated cells attracting and activating more cells

18. Other Biologically Activated Substances • Degradative enzymes • Toxic free radicals • Acids • Growth inhibitors • Acute phase proteins • Interferons • Harmful to microorganins • Influenced by age, race and hormonal and metabolic status

19. Most cells involved in inflammation are phagocytic cells: • At first, mainly polymorphonuclear leukocytes • Accumulate within 30-60 minutes • Phagocytosis of intruder and damaged tissue • Release of lysosomal enzymes • If inflammation persists • Within 56 hrs infiltration by mononuclear cells (macrophages and lymphocytes) • Macrophages • supplement activity of PMNs • Ag presentation to T cells • As injury or invasion continues, inflammatory response is supplemented and augmented by elements of acquired immunity  Abs and CMI (Abs also initiate complement) Repair

20. Chronic Inflammation • Chronic infection (tuberculosis) • Chronic activation of the immune response (rheumatoid arthritis and glomerulonephritis) • Anti-inflammatory drugs • Aspirin, ibuprofen, or cortisone • Mediate inflammation, but do not affect the root cause of the inflammation