9.5 From Notes - Innate and Adaptive Immunity

• The human body defends itself against damage and infection using innate and adaptive immunity.

Innate vs Adaptive Immunity

• Innate immunity is the first and second line of defense, providing rapid and non-specific responses.
• Adaptive immunity is the third line, initiated by the innate system, characterized by specificity and memory, and provides long-term immunity.

First Line of Defense

• The first line of defense in innate immunity includes physical, mechanical, and biochemical barriers as well as the normal microbiome, preventing pathogen entry.

Physical and Mechanical Barriers

• Epithelial cells form the skin and linings of the gastrointestinal, genitourinary, and respiratory tracts.
• Mucus traps microorganisms, and cilia remove them from the respiratory tract.
• The skins low temperature and acidic pH inhibits microbial growth.

Biochemical Barriers

• Substances such as mucus, perspiration, saliva, tears, and earwax trap and kill microorganisms.
• Sebaceous glands secrete antibacterial and antifungal fatty acids and lactic acid which leads to a inhospitable acidic skin.
• Perspiration, tears, and saliva contain lysozyme, which attacks gram-positive bacteria cell walls.
• Antimicrobial peptides, including cathelicidins (linear α-helical) and defensins (triple-stranded β-sheet), are toxic to bacteria, fungi, and viruses.
• The lungs produce collectins, including surfactant proteins A through D and mannose-binding lectin, enhancing pathogen recognition and phagocytosis by macrophages.
• Mannose-binding lectin (MBL) also activates the complement system.
• Other epithelial antimicrobials include resistin-like molecule β, bactericidal/permeability-inducing (BPI) protein, and antimicrobial lectins.

Normal Microbiome

• Non-disease-causing microorganisms colonize the body's surfaces.
• They aid in digestion, produce vitamins, assist in ion absorption, compete with pathogens, block pathogen attachment, and produce bacteriocins.
• Disruption of the microbiome by broad-spectrum antibiotics leads to opportunistic pathogen overgrowth.
• Gut microbiome helps train the adaptive immune system.
• Lactobacillus in the vagina prevents urologic and vaginal infections.
• Pseudomonas aeruginosa on the skin protects against other bacteria.

Second Line of Defense: Inflammation

• Inflammation is a programmed response to cellular or tissue damage.
• It limits damage, destroys contaminants, initiates adaptive immunity, and begins healing.
• Inflammation occurs in vascularized tissues, activates rapidly, depends on cellular and chemical components, and is nonspecific.

Vascular Response

• Injury to vascularized tissue triggers inflammation.
• Acute inflammation symptoms include redness, heat, swelling, and pain, with possible loss of function.
• Microcirculation near the injury undergoes vasodilation and increased vascular permeability, which allows leukocytes and plasma to enter surrounding tissue.
• Mast cell degranulation, activation of plasma systems, and release of cellular products from damaged cells initiate vascular changes.

Plasma Protein Systems

• Key plasma protein systems include the complement, clotting, and kinin systems.

Complement System

• Plasma proteins destroy pathogens and collaborate with innate and adaptive immunity.
• Activated through the classical (by antibodies), lectin (by mannose-binding lectin), or alternative (by bacterial/fungal polysaccharides) pathways.
• Activation converges at C3, leading to production of fragments with various functions.
• Key functions include anaphylatoxin activity (C3a, C5a), leukocyte chemotaxis (C5a), opsonization (C3b), and cell lysis (C5b-C9, forming the MAC).

Clotting System

• Plasma proteins form a blood clot (fibrin meshwork) at the injured site.
• This prevents infection spread, traps microorganisms, stops bleeding, and provides a repair framework.
• Activated by the tissue factor (extrinsic) or intrinsic (contact) pathway.
• Activation leads to fibrin formation and releases fibrinopeptides A and B, which are chemotactic for neutrophils and increase vascular permeability.

Kinin System

• Augments inflammation, with bradykinin as the primary product.
• Bradykinin causes vasodilation, stimulates nerve endings to induce pain, causes smooth muscle contraction, increases vascular permeability, and may increase leukocyte chemotaxis.
• Activated by the plasma kinin cascade, initiated by factor XIIa from the clotting system.
• The three plasma protein systems are interactive, with activation of one leading to activation of others.
• Regulatory mechanisms ensure efficient activation at the injury site while limiting widespread effects.
• Examples of regulatory mechanisms include enzymes that degrade mediators and inhibitors of the cascades.

Cellular Mediators of Inflammation

• Cellular mediators contributing to inflammation include mast cells, basophils, endothelium, platelets, phagocytes, dendritic cells, NK cells and lymphocytes.

Mast Cells and Basophils

• Mast cells, located in loose connective tissues near blood vessels, are key activators of inflammation.
• Activated by physical injury, chemical agents, immunologic means, and TLR activation
• Activation leads to degranulation (releasing histamine, chemotactic factors, and cytokines) and synthesis of other mediators.
• Histamine causes temporary smooth muscle constriction and postcapillary venule dilation.
• Basophils in the blood have similar functions to mast cells and are an important source of IL-4.

Endothelium

• Endothelial cells regulate normal blood flow and interact with inflammatory mediators.
• Damage exposes the subendothelial matrix, initiating clotting.
• Proinflammatory mediators cause leukocyte adherence, tissue invasion, and plasma efflux.
• Endothelial cells also produce nitric oxide (NO) and prostacyclin (PGI2) that maintain blood flow and inhibit platelet activation.

Platelets

• Anucleate cell fragments involved in blood clotting.
• Activated by collagen, thrombin, thromboxane, PAF, and antigen-antibody complexes.
• Activated platelets release serotonin, synthesize thromboxane A2, and relocate phosphatidylserine to their surface for coagulation.
• They also contain granules with polypeptides affecting inflammation and growth factors for healing.

Phagocytes (Neutrophils, Eosinophils, Monocytes/Macrophages)

• These cells ingest and dispose of damaged cells and foreign material.
• Neutrophils (PMNs) are the predominant early responders, phagocytosing bacteria and debris.
• They are attracted by bacterial proteins, C3a, C5a, and mast cell chemotactic factor.
• They are short-lived at the inflammatory site and form pus.
• Eosinophils are mildly phagocytic but primarily defend against parasites and regulate vascular mediators released by mast cells by degrading them with enzymes.
• Monocytes in the blood migrate to the inflammatory site and develop into macrophages.
• Macrophages are more active phagocytes and appear later (24 hours to 3-7 days).
• Macrophages survive and divide in the inflammatory site and are involved in activating adaptive immunity and wound repair.
• Phagocytosis involves opsonization, engulfment, phagosome formation, fusion with lysosomes (phagolysosome), and destruction of the target by oxygen-dependent and oxygen-independent mechanisms.
• Macrophages can be activated to M1 phenotype (bacterial killing) by TLRs and IFN-γ, or M2 phenotype (healing and repair) by cytokines like IL-4 and IL-13.

Dendritic Cells

• Located in peripheral organs and skin, they phagocytose molecules from infectious agents, recognize them through PRRs, and then migrate to lymphoid tissue to interact with T lymphocytes, linking innate and adaptive immunity.

Natural Killer (NK) Cells and Lymphocytes

• NK cells recognize and eliminate virus-infected and abnormal cells.
• Lymphocytes participate in innate (NK cells) and adaptive immunity (B and T cells).

Cellular Receptors

• Cells of innate and adaptive immunity have surface receptors that bind soluble substances (ligands) produced during damage or infection, leading to cell activation.
• Innate immune cells have pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) on microbes and damage-associated molecular patterns (DAMPs) from stressed cells.
• Examples include Toll-like receptors (TLRs), complement receptors (CRs), scavenger receptors, glucan receptors, and mannose receptors.
• Cytoplasmic NOD-like receptors (NLRs) recognize microbial products and damaged cells intracellularly, forming inflammasomes that control the activation and secretion of inflammatory cytokines like IL-1β.

Cellular Products

• Intercellular communication in inflammation relies on cytokines, a large family of small, soluble signaling molecules.
• Cytokines regulate innate and adaptive immunity and can be proinflammatory or antiinflammatory.
• Chemokines are chemotactic cytokines that attract leukocytes to inflammatory sites.
• Interleukins (ILs) are produced by macrophages and lymphocytes and have diverse effects on cell adhesion, chemotaxis, and leukocyte proliferation and maturation.
• Tumor necrosis factor-alpha (TNF-α), secreted by macrophages and mast cells, induces proinflammatory effects, fever, and increased synthesis of serum proteins.
• Interferons (IFNs) protect against viral infections and modulate inflammation.
• Type I IFNs (IFN-α, IFN-β) are produced by virus-infected cells and induce antiviral proteins in neighboring cells.
• Type II IFN (IFN-γ), produced by lymphocytes, activates macrophages and enhances acquired immune responses.

Local Manifestations of Inflammation

• Hallmarks of local inflammation result from vascular changes.
• Vasodilation and increased capillary permeability lead to redness, heat, swelling, and pain.
• Loss of function may also occur.
• Exudate, the fluid accumulating at the inflamed site, varies by composition.
• Can be serous, fibrinous, purulent, or hemorrhagic.

Systemic Manifestations of Acute Inflammation

• These include changes throughout the body.
• Fever is an early systemic response induced by endogenous pyrogens.
• Leukocytosis is a transient increase in circulating leukocytes, often with a "left shift".
• Plasma protein synthesis by the liver is increased, leading to elevated levels of acute-phase reactants.
• Other systemic symptoms include somnolence, malaise, anorexia, and muscle aching.

Chronic Inflammation

• Defined by a duration of 2 weeks or longer.
• Characterized by dense infiltration of lymphocytes and macrophages, persistence of the causative agent, neutrophil degranulation and death, lymphocyte activation, and fibroblast activation leading to tissue repair.
• Some microorganisms resistant to phagocytic degradation or those that survive within macrophages can cause chronic inflammation.
• The body may form a granuloma to wall off and isolate the infected area when macrophages cannot limit damage.
• Granulomas consist of macrophages surrounded by lymphocytes and often encapsulated by fibrous deposits.

Wound Healing

• Wound healing concludes inflammation and involves processes to fill in, seal, and shrink the wound.
• The ideal outcome is tissue regeneration with complete return to normal structure and function.
• Repair takes place if extensive damage occurs or regeneration is not possible, resulting in scar tissue.

Phases of Wound Healing

Phase I: Inflammation

• Begins immediately with coagulation and infiltration of platelets, neutrophils, and macrophages.
• Platelets release growth factors, and neutrophils and macrophages clear debris through débridement.

Phase II: Proliferation and New Tissue Formation (Reconstruction)

• Begins 3-4 days after injury and lasts up to 2 weeks.
• The wound is sealed, and the fibrin clot is replaced by normal or scar tissue.
• Key events include macrophage invasion, recruitment and proliferation of fibroblasts, angiogenesis, epithelialization, wound contraction, and extracellular matrix remodeling by matrix metalloproteinases (MMPs).
• Granulation tissue grows into the wound.

Phase III: Remodeling and Maturation

• Begins several weeks after injury and can last up to 2 years.
• It involves continued cellular differentiation, scar formation, and remodeling of the collagen matrix for increased strength.
• Collagen fibers orient along stress lines, and capillaries disappear from the scar tissue.

Healing by Primary and Secondary Intention

• Primary intention occurs in wounds with minimal tissue loss and close edges, primarily involving collagen synthesis.
• Secondary intention occurs in open wounds with significant tissue loss, requiring more extensive tissue replacement, epithelialization, scar formation, and contraction.
• Repaired tissue may only regain 80% of its original tensile strength.

Dysfunctional Wound Healing

• Can occur during any phase due to factors like ischemia, excessive bleeding, predisposing disorders, wound infection, inadequate nutrients, numerous drugs, and tobacco smoke.
• These factors can impair collagen synthesis, epithelialization, and contraction.

Wound Disruption

• Dehiscence, the pulling apart of a sutured wound, can occur 5-12 days post-surgery, often associated with wound sepsis or excessive strain.
• Excessive collagen synthesis can lead to hypertrophic scars or keloids.

Impaired Epithelialization and Contraction

• Hypoxemia, zinc deficiency, and improper wound care can impair epithelial cell migration.
• Excessive wound contraction can lead to deformities or contractures, especially in burn wounds or internal organs.

Pediatrics: Innate Immunity in the Newborn Child

• Neonates often have transiently depressed inflammatory and immune function due to the transition from a sterile environment.
• This includes impaired neutrophil chemotaxis and bacterial responses, partial deficiency in complement, and low levels of mannose-binding lectin.
• They may be more susceptible to severe infections when maternal antibodies are lacking.