9.5 Recorded Lecture Human Defense Mechanisms

Human Defense Mechanisms

• Innate immunity is the natural epithelial barrier and inflammation conferring resistance and protection.
• Adaptive immunity is a long-term, effective immunity to infecting organisms.

Natural Barriers

• First line of defense.
• Physical, mechanical, or biochemical barriers.
• Examples: skin, GI tract lining, genitourinary tract, and respiratory tract.
• Tightly associated epithelial cells prohibit microorganism passage.
• Cell turnover and washing mechanically remove microorganisms, such as skin sloughing and urination.
• Goblet cells produce mucus, trapping organisms removed by cilia.
• Low pH of skin and stomach inhibits microorganisms.
• Epithelial surfaces secrete chemicals to trap and destroy microorganisms.
• Sebaceous glands secrete antibacterial and anti-fungal fatty acids, as well as lactic acid.
• Perspiration, tears, and saliva contain lysozyme that attacks gram-positive bacteria.
• Antimicrobial peptides are secreted from multiple locations.
• Normal microbiome inhibits pathogen colonization by releasing chemicals preventing infection.

Inflammation

• Programmed response to cellular or tissue damage, occurring in vascularized tissue.
• Rapidly activated.
• Depends on cellular and chemical components.
• Nonspecific.
• Pathologic invasion causes release of cellular products or mast cell degranulation.
• Leads to vasodilation, increased vascular permeability, cellular infiltration, thrombosis, and pain.
• Mediated by inflammatory mediators.
• Three changes in microcirculation include vasodilation, increased permeability, and white blood cell adhesion/migration.
• Prevents infection and further damage by diluting toxins.
• Activates plasma protein systems.
• Influx of neutrophils and macrophages to phagocytose.
• Interacts with adaptive immune system to elicit specific responses.

Plasma Protein Systems

• Each has unique role in inflammation.
• Function as a cascade, where activation of one component activates others.

Complement System

• Produces factors to destroy pathogens directly.
• Activates or collaborates with innate and adaptive immune systems.
• Potent defender against bacterial infection.
• Classic pathway: preceded by antigen-antibody complex formation, or activated by heparin, DNA, RNA, and C-reactive protein.
• Lectin pathway: similar to classical, antibody-dependent, activated by mannose-binding lectin.
• Alternate pathway: activated by gram-negative bacterial and fungal cell wall polysaccharides.
• Functions: mast cell degranulation, inflammation, white blood cell chemotaxis, opsonization (tagging for destruction), and cell lysis.

Clotting Cascade

• Meshwork containing platelets, erythrocytes, phagocytes, and microorganisms.
• End product is fibrin forming a fibrous mesh network.
• Intrinsic pathway: activated by vessel wall damage.
• Extrinsic pathway: activated by tissue factor released by damaged endothelial cells.
• Pathways converge at factor X to form the common pathway.

Kinin System

• Main product is bradykinin.
• Causes blood vessel dilation.
• Increases vascular permeability, leading to inflammation.
• Causes pain through nerve ending stimulation.
• Activated by factor XII (Hageman factor) of the clotting cascade.

Interactions of Plasma Protein Systems

• Must be highly regulated and interactive due to critical role and potential detriment if unregulated.
• Activation of one system interacts with others.
• Hageman factor is essential in the intrinsic cascade.
• Factor XII activates intrinsic pathway, plasminogen, and the kinin system.
• Systems controlling clotting, immunity, and inflammation are interdependent.

Cellular Mediators of Inflammation

• Mast cells: important activators of inflammation, located in loose connective tissue.
• Leukocytes: granulocytes, monocytes, and lymphocytes.
• Monocytes: precursors to macrophages.
• Lymphocytes: participate in innate and adaptive immune responses.

Cellular Products of Inflammation

• Cytokines: bind to cell membrane receptors, with action dependent on the receptor (pro- or anti-inflammatory).
• Chemokines: chemotactic cytokines attracting leukocytes.
• Interleukins: biochemical messengers produced by macrophages and lymphocytes, regulating inflammation.
• Interferons: protect against viral infections and modulate inflammation, prevent infection of neighboring cells.

Mast Cells and Basophils

• Mast cells are located in loose connective tissue.
• Basophils are located in the blood.
• Activated by physical injury, chemical agents, immunologic means, or TLRs.
• Degranulation releases histamine, chemotactic factors, and cytokines.
• Initiate synthesis of leukotrienes, prostaglandins, cytokines, and growth factors.
• Prostaglandins are produced by cyclooxygenase (COX), inhibited by aspirin, NSAIDs, and selective COX-2 inhibitors.

Histamine

• Mediator released by mast cells.
• Rapid constriction of smooth muscle and dilation of post-capillary venules, increasing blood flow.
• Increases vascular permeability.
• Histamine effects are determined by the histamine receptor, such as H1 (proinflammatory) and H2 (anti-inflammatory).
• H1 receptor is present on smooth muscle cells, especially in the bronchi.
• H2 receptor is abundant on parietal cells of the stomach, inducing gastric acid secretion.

Endothelium

• Regulate blood flow by preventing platelet activation through nitric oxide and prostacyclin.
• Nitric oxide is produced from arginine, prostacyclin from arachidonic acid.
• Damage exposes sub-endothelial connective tissue, initiating platelet activation and clot formation.

Platelets

• Assist with coagulation and release biochemical mediators like serotonin.
• Synthesize thromboxane A2, a vasoconstrictor and inducer of platelet aggregation, inhibited by low-dose aspirin.

Granulocytes and Monocyte-Macrophages

• Primary role is phagocytosis.
• Neutrophils: predominant phagocytes in early inflammation, attracted by inflammatory mediators.
• Eosinophils: defend against parasites.
• Basophils: similar to mast cells but circulate in the blood.
• Dendritic cells: phagocytic cells in peripheral organs that migrate to tissues and interact with T lymphocytes.
• Monocytes: develop into macrophages at the inflammatory site (arrive 24 hours, or 3-7 days later commonly).

Phagocytosis

• Opsonization: recognition and adherence to a target.
• Engulfment: formation of a phagosome.
• Fusion: phagosome fuses with a lysosomal granule.
• Destruction: target is destroyed.

Local Manifestations of Inflammation

• Result from vascular changes and leakage into tissue.
• Dilutes toxins and carries proteins/leukocytes to the site.
• Swelling occurs due to fluid accumulation, accompanied by pain.
• Exudate types: serous (watery), fibrinous (thick and clotted), purulent (pus, bacterial infection), and hemorrhagic (RBCs).

Systemic Changes with Acute Inflammation

• Leukocytosis: increased white blood cells, possibly with a "left shift" (immature neutrophils).
• Increased plasma protein synthesis: fibrinogen increases, leading to increased adhesion among erythrocytes.

Chronic Inflammation

• Lasts two weeks or longer.
• May follow unsuccessful acute response or occur without acute inflammation.
• Macrophages wall off the infection, forming a granuloma.

Wound Healing

• Processes to fill, seal, and shrink wounds.
• Primary intention: surgical incisions heal with minimal tissue replacement.
• Secondary intention: larger wounds require more tissue replacement, epithelization, scar formation, and contraction take longer.
• Inflammation: infiltration of platelets, neutrophils, and macrophages.
• Reconstruction: begins 3-4 days after injury
• includes macrophage invasion, fibroblast collagen synthesis, epithelization, and contraction.
• Contraction: noticeable 6-12 days after injury.
• Remodeling and Maturation: begins weeks after injury, up to two years.

Dysfunctional Wound Healing

• Causes: ischemia, bleeding, excessive fibrin, diabetes, obesity, wound infection, inadequate nutrients, drugs, and tobacco.
• Dysfunctional healing results from impairment of any healing processes.
• Excessive collagen can cause hypertrophic scars or keloid formations.