Chapter 6 Innate Immunity: Inflammation
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Chapter 6 Innate Immunity: Inflammation Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. Immunity First line of defense Second line of defense Innate resistance Inflammation Third line of defense Adaptive (acquired) immunity Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 2 First Line of Defense Physical and mechanical barriers Skin Linings of the gastrointestinal, genitourinary, and respiratory tracts • Sloughing off of cells • Coughing and sneezing • Flushing • Vomiting • Mucus and cilia Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 3 First Line of Defense Biochemical barriers Synthesized and secreted saliva, tears, earwax, sweat, and sebum Antimicrobial peptides • Cathelicidins, defensins (α defensins in neutrophil granules), and collectins (lungs) Normal bacterial flora • Vaginal: lactobacillus • Intestinal: produce ammonia, phenols, indols, etc. that inhibit colonization by pathogens Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 4 Second Line of Defense Inflammatory response Causes • Infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, radiation, etc. Local manifestations Vascular response • Blood vessel dilation, increased vascular permeability and leakage, WBC adherence to the inner walls of the vessels and migration through the vessels Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 5 Inflammation Goals Limit and control the inflammatory process Prevent and limit infection and further damage Control bleeding Interact with components of the adaptive immune system Prepare the area of injury for healing Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 6 Plasma Protein Systems Protein systems Complement system Coagulation system Kinin system All contain inactive enzymes (proenzymes) Sequentially activated • First proenzyme is converted to an active enzyme • Substrate of the activated enzyme becomes the next component in the series Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 7 Plasma Protein Systems Complement system Can destroy pathogens directly Activates or collaborates with every other component of the inflammatory response Pathways • Classical • Lectin • Alternative Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 8 Plasma Protein Systems Coagulation (clotting) system Forms a fibrinous meshwork at an injured or inflamed site • Prevents the spread of infection • Keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activity • Forms a clot that stops bleeding • Provides a framework for repair and healing Main substance is an insoluble protein called fibrin Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 9 Plasma Protein Systems Kinin system Functions to activate and assist inflammatory cells Primary kinin is bradykinin Causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 10 Plasma Protein Systems Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 11 Cellular Mediators of Inflammation Cellular components Granulocytes, platelets, monocytes, and lymphocytes Cell surface receptors Pattern recognition receptors (PRRs) Pathogen-associated molecular patterns (PAMPs) Toll-like receptors Complement receptors Scavenger receptors Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 12 Mast Cells Cellular bags of granules located in loose connective tissues close to blood vessels Skin, digestive lining, respiratory tract Activation Physical injury, chemical agents, immunologic processes, Toll-like receptors Chemical release in two ways • Degranulation and synthesis of lipid-derived chemical mediators Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 13 Mast Cell Degranulation Histamine Vasoactive amine that causes temporary, rapid constriction of the large blood vessels and the dilation of the postcapillary venules Retraction of endothelial cells lining the capillaries Receptors • H1 receptor (proinflammatory) • H2 receptor (anti-inflammatory) Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 14 Histamine Receptors H1 receptor • Proinflammatory • Present in smooth muscle cells of the bronchi H2 receptor • Anti-inflammatory • Present on parietal cells of the stomach mucosa Induces the secretion of gastric acid Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 15 Mast Cells Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 16 Mast Cell Degranulation Chemotactic factors Neutrophil chemotactic factor • Attracts neutrophils Eosinophil chemotactic factor of anaphylaxis (ECF-A) • Attracts eosinophils Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 17 Mast Cell Synthesis of Mediators: Late Response Leukotrienes Prostaglandins Product of arachidonic acid from mast cell membranes Similar effects to histamine in later stages Similar effects to leukotrienes; they also induce pain Platelet-activating factor Similar effect to leukotrienes and platelet activation Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 18 Mast Cells Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 19 Phagocytosis Process by which a cell ingests and disposes of foreign material Production of adhesion molecules Margination (pavementing) Adherence of leukocytes to endothelial cells Diapedesis Emigration of cells through the endothelial junctions Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 20 Phagocytosis Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 21 Phagocytosis Steps Opsonization, recognition, and adherence Engulfment Phagosome formation Fusion with lysosomal granules Destruction of the target Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 22 Phagocytes Neutrophils Also referred to as polymorphonuclear neutrophils (PMNs) Predominate in early inflammatory responses Ingest bacteria, dead cells, and cellular debris Cells are short lived and become a component of the purulent exudate Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 23 Phagocytes Monocytes and macrophages Monocytes produced in bone marrow, enter circulation, and migrate to the inflammatory site, where they develop into macrophages Macrophages typically arrive at inflammatory site 3 to 7 days after neutrophils Macrophage activation results in increased size, plasma membrane area, glucose metabolism, number of lysosomes, and secretory products Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 24 Phagocytes Eosinophils Mildly phagocytic Duties • Defense against parasites and regulation of vascular mediators Basophils Role uncertain Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 25 Phagocytes Natural killer (NK) cells Function: recognize and eliminate cells infected with viruses and some function in eliminating cancer cells Platelets Activation results in degranulation and interaction with components of the coagulation system Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 26 Cytokines Interleukins Produced primarily by macrophages and lymphocytes in response to a pathogen or stimulation by other products of inflammation Many types Examples • IL-1 is a proinflammatory cytokine • IL-10 is an anti-inflammatory cytokine Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 27 Cytokines Interferon Protects against viral infections Produced and released by virally infected host cells in response to viral double-stranded RNA Types • INF-α and INF-ß Induce production of antiviral proteins • INF-γ Increases microbiocidal activity of macrophages Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 28 Cytokines Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 29 Cytokines Tumor necrosis factor-α Secreted by macrophages in response to PAMP and Toll-like receptor recognition (i.e., in response to pathogens) • Induces fever by acting as endogenous pyrogen • Increases synthesis of inflammatory serum proteins • Causes muscle wasting (cachexia) and intravascular thrombosis Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 30 Chemokines Induce WBC chemotaxis Produced by macrophages, fibroblasts, endothelial cells Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 31 Local Manifestations of Inflammation Results from vascular changes and corresponding leakage of circulating components into the tissue Heat Redness Swelling Pain Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 32 Vascular Response Transient vasoconstriction—seconds Vasodilation Increased capillary permeability Exudation of fluid and cells Cellular migration (margination/adherence, migration) Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 33 Exudative Fluids Serous exudate Fibrinous exudate Thick, clotted exudate: indicates more advanced inflammation Purulent exudate Watery exudate: indicates early inflammation Pus: indicates a bacterial infection Hemorrhagic exudate Exudate contains blood: indicates bleeding Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 34 Systemic Manifestations of Inflammation Fever Leukocytosis Caused by exogenous and endogenous pyrogens Act directly on the hypothalamus Increased numbers of circulating leukocytes Left shift, increase in immature cells (bands) Increased plasma protein synthesis • Acute-phase reactants C-reactive protein, fibrinogen, haptoglobin, amyloid, ceruloplasmin, etc. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 35 Control of Inflammation Carboxypeptidase—inhibits C3a and C5a Histaminase—inhibits histamine Arylsulfatase—inhibits histamine C-1 esterase inhibitor—inhibits complement Kinins and clotting Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 36 Chronic Inflammation Inflammation lasting 2 weeks or longer Often related to an unsuccessful acute inflammatory response Other causes High lipid and wax content of microorganism Ability to survive inside the macrophage Toxins Chemicals, particulate matter, or physical irritants Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 37 Chronic Inflammation Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 38 Chronic Inflammation Characteristics Dense infiltration of lymphocytes and macrophages Granuloma formation Epithelioid cell formation Giant cell formation Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 39 Resolution and Repair Regeneration Resolution Returning injured tissue to the original structure and function Repair Replacement of destroyed tissue with scar tissue Scar tissue • Composed primarily of collagen to restore the tensile strength of the tissue Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 40 Resolution and Repair Débridement Cleaning up dissolved clots, microorganisms, erythrocytes, and dead tissue cells Healing Filling in the wound Sealing the wound (epithelialization) Shrinking the wound (contraction) Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 41 Healing Primary intention Wounds that heal under conditions of minimal tissue loss Secondary intention Wounds that require a great deal more tissue replacement • Open wound Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 42 Healing Reconstructive phase Fibroblast proliferation Collagen synthesis Epithelialization Contraction • Myofibroblasts Cellular differentiation Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 43 Healing Maturation phase Continuation of cellular differentiation Scar tissue formation Scar remodeling Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 44 Healing Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 45 Dysfunctional Wound Healing Dysfunction during inflammatory response Hemorrhage Fibrous adhesion Infection Excess scar formation Wound sepsis Hypovolemia Hypoproteinemia Anti-inflammatory steroids Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 46 Dysfunctional Wound Healing Dysfunction during reconstructive phase Impaired collagen matrix assembly • Keloid scar • Hypertrophic scar Impaired epithelialization • Anti-inflammatory steroids, hypoxemia, and nutritional deficiencies Impaired contraction • Contracture Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 47 Dysfunctional Wound Healing Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 48 Dysfunctional Wound Healing Wound disruption Dehiscence • Wound pulls apart at the suture line Excessive strain and obesity are causes • Increased risk of wound sepsis Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 49 Pediatrics Neonates have transiently depressed inflammatory and immune function Neutrophils not capable of efficient chemotaxis Neonates express complement deficiency Deficient in collectins and collectin-like proteins Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 50 Older Adults Impaired inflammation likely a result of chronic illness Diabetes, cardiovascular disease, etc. Chronic medication intake decreases the inflammatory response Healing response is diminished due to loss of the regenerative ability of the skin Infections are more common in older adults Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 51
