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 general
2、ized 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,Innate Immunity Cellular Defenses,Phagocytosis and Extracellular Killing internalization of foreign macromole
3、cules and cellsEndocytosis 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 (nucl
4、eases, lipases, proteases) secondary lysosomes for breakdown,Innate Immunity Cellular Defenses,Phagocytosis ingestion and destruction by individual cells of invading foreign particles (bacteria)Opsonins factors that enhance phagocytosis of the particlePhagosome + Lysosome digest particle,Phagocytic
5、Cells,Polymorphonuclear leukocytes (PMN)Macrophages Phagocytic monocytes Fixed macrophages of the reticuloendothelial systemAll these cells release cytokines upon activation,Phagocytic Cells,Polymorphonuclear leukocytes (PMN) Granulocytes Include basophils, mast cells, eosinophils, neutrophilsShort-
6、lived phagocytic cells that contain lysosomes Produce peroxide and superoxide radicals Bactericidal proteins lactoferrinPMNs play a major role in protection a/g infection Defects chronic or recurrent infection,Phagocytic Cells,Macrophages phagocytes derived from blood monocytesMigration from blood t
7、o 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,Phagocytic Cells,Reticuloendothelial System (RES) Includes each of these macrophage populat
8、ions 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,Phagocytic Cells,Cells of the macrophage series have two major functions Engulf and digest mic
9、roorganisms and foreign particles Antigen presentation Take up Ag and process for presentation to T cellsOther 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,Cellular Defense
10、s,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 enha
11、nce killing of pathogens,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
12、target cells by release of biologically potent molecules that kill target cell within a very short time,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 stimulat
13、ion 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 N
14、K cell mediated cytotoxicity,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
15、DNA Killing is enhanced by IL-2, IL-12 and interferons,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. infe
16、ction by microorganims) Immunologic injury (e.g. hypersensitivity) Protective response to injury to restore normal state,Hallmark Signs of Inflammation,Swelling (tumor) Redness (rubor) Heat (calor) Pain ( dolor) Loss of function to the areaOccur within minutes after injury through activation and inc
17、reased concentration of acute-phase proteinsLocalized Inflammatory Responses Activation of clotting Kinin-forming pathways Fibrolytic pathways,Kinins have several important effects:,Act directly on local smooth muscle and cause muscle contraction Act on exons to block nervous impulses, leading to di
18、stal 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 th
19、e molecules most responsible for pain (and itching). Kinins are rapidly inactivated by proteases that are generated during the localized repsonse.,Systemic Inflammatory Response,Induction of fever Caused by many bacterial products (endotoxins from G(-) bacteria) Endogenous pyrogens from monocytes an
20、d 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,Cytokines play a ke
21、y 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 Induc
22、e 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 si
23、te and accumulated cells attracting and activating more cells,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,Most cells involve
24、d 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) Macrop
25、hages 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,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,
