Premed · Premed · Anatomy Physiology 2
Lecture 8: Innate Immunity
Anatomy and Physiology II
Learning Objectives
By the end of this lecture, students will be able to:
- Distinguish between innate and adaptive immunity
- Describe the physical and chemical barriers of the first line of defense
- Explain the cells and mechanisms of the second line of defense
- Describe the process of phagocytosis and identify the major phagocytic cells
- Explain the inflammatory response and its cardinal signs
- Describe the complement system and its activation pathways
- Explain the role of interferons and fever in innate defense
Lecture Content
I. Overview of Immune Defense
The immune system protects the body against pathogens (bacteria, viruses, fungi, and parasites), abnormal cells, and foreign substances. It operates through two interconnected arms. Innate (nonspecific) immunity provides rapid defense that is present from birth, does not target specific pathogens, and lacks immunological memory. Adaptive (specific) immunity mounts a slower initial response that targets specific antigens and develops memory for faster responses upon re-exposure (covered in Lecture 9). Innate immunity comprises two lines of defense: the first line consists of surface barriers (skin and mucous membranes), and the second line encompasses internal defenses including immune cells, antimicrobial proteins, the inflammatory response, and fever.
II. First Line of Defense — Surface Barriers
Skin (Integument)
The skin provides formidable physical, chemical, and biological barriers to infection. As a physical barrier, its keratinized stratified squamous epithelium forms a tough, largely impermeable surface that resists penetration. The constant shedding of dead keratinized cells from the surface (desquamation) removes attached microbes.
As a chemical barrier, the skin maintains an acidic pH of approximately 3 to 5 thanks to the acid mantle created by sebum and sweat, which inhibits bacterial growth. Sebum from sebaceous glands contains lipids with antimicrobial properties. Dermcidin, an antimicrobial peptide secreted in sweat, and defensins, antimicrobial peptides produced by skin cells, provide additional chemical defenses.
The skin also functions as a biological barrier through its resident normal microbiota, communities of commensal microorganisms that compete with potential pathogens for nutrients and space.
Mucous Membranes
Mucous membranes line body cavities that open to the exterior, including the respiratory, digestive, urinary, and reproductive tracts. Their continuous epithelial lining, reinforced by tight junctions in some areas, provides a physical barrier. Mucus, a sticky secretion produced by goblet cells and mucous glands, traps microbes and particles. In the respiratory tract, cilia on the epithelial surface propel mucus and trapped debris toward the pharynx in a mechanism known as the mucociliary escalator.
Several chemical barriers enhance mucosal defense. Lysozyme, an enzyme found in tears, saliva, nasal secretions, and sweat, destroys bacterial cell walls by cleaving peptidoglycan. Lactoferrin binds iron, depriving bacteria of an essential nutrient. Hydrochloric acid in the stomach creates a pH of 1.5 to 3.5 that destroys most ingested pathogens. Defensins and other antimicrobial peptides are present in mucosal secretions, and IgA antibodies in mucosal secretions provide a bridge to adaptive immunity. Normal microbiota, particularly in the gut, skin, and vagina, also compete with pathogens for resources.
III. Second Line of Defense — Cells of Innate Immunity
Phagocytes
Phagocytes are cells that engulf and destroy pathogens and cellular debris through phagocytosis. Neutrophils are the most abundant white blood cell and the first to arrive at sites of infection. They are short-lived, surviving only hours to days in the tissues, and kill ingested microbes through a respiratory burst that produces reactive oxygen species (superoxide, hydrogen peroxide, and hypochlorite), as well as through defensins and lysozyme in their granules. Neutrophils can also release NETs (neutrophil extracellular traps), webs of chromatin fibers that trap bacteria extracellularly.
Macrophages develop from monocytes that migrate into tissues and differentiate. They are named according to their location: Kupffer cells in the liver, alveolar macrophages in the lungs, microglia in the central nervous system, and osteoclasts in bone. Macrophages are longer-lived and more potent phagocytes than neutrophils. They also function as antigen-presenting cells (APCs), forming a critical bridge between innate and adaptive immunity, and they secrete cytokines that promote inflammation and recruit other immune cells.
Dendritic cells are found in the skin (where they are called Langerhans cells), mucous membranes, and lymphoid organs. They serve as sentinel cells that constantly sample the surrounding environment, phagocytize pathogens, and present antigens to T cells in lymph nodes. Dendritic cells are the most important antigen-presenting cell for initiating adaptive immune responses.
The Phagocytosis Process
Phagocytosis proceeds through a series of defined steps. Chemotaxis draws the phagocyte toward the pathogen along a chemical gradient created by complement fragments, bacterial products, and cytokines. Adherence occurs when surface receptors on the phagocyte bind to the pathogen, a process that is greatly enhanced by opsonization, the coating of the pathogen with opsonins such as complement protein C3b or antibodies. Ingestion follows as pseudopods extend around the pathogen, engulfing it into a membrane-bound vesicle called a phagosome. Digestion occurs when the phagosome fuses with a lysosome to form a phagolysosome, where lysosomal enzymes and reactive oxygen species destroy the pathogen. Finally, indigestible residues are expelled from the cell by exocytosis.
Natural Killer (NK) Cells
Natural killer cells are large granular lymphocytes that, despite belonging to the lymphocyte family, function as part of innate immunity because they lack antigen-specific receptors. They target virus-infected cells and cancer cells by recognizing cells that lack MHC class I molecules, a phenomenon called "missing self." NK cells kill their targets by releasing perforin, which forms pores in the target cell membrane, and granzymes, which enter through these pores and trigger apoptosis. Their activity is enhanced by interferons and interleukins such as IL-2 and IL-12.
<image>A step-by-step diagram of phagocytosis. Panel A: Chemotaxis — a neutrophil migrating along a gradient of chemical signals toward a bacterium. Panel B: Adherence — the phagocyte's surface receptors binding to the bacterium, with an inset showing opsonization (C3b complement proteins and antibodies coating the bacterium to enhance binding). Panel C: Ingestion — pseudopods extending around the bacterium forming a phagosome. Panel D: Digestion — the phagosome fusing with a lysosome to form a phagolysosome, with lysosomal enzymes and reactive oxygen species labeled. Panel E: Killing — residual body being expelled by exocytosis. Each step is numbered and clearly labeled with arrows showing the sequence.</image>
IV. The Inflammatory Response
Inflammation is a nonspecific response triggered by tissue injury or infection. Its cardinal signs are redness (rubor), heat (calor), swelling (tumor), pain (dolor), and sometimes loss of function (functio laesa).
Steps of the Inflammatory Response
The first step involves vasodilation and increased vascular permeability. Damaged cells, mast cells, and macrophages release chemical mediators. Histamine from mast cells and basophils causes vasodilation and increased capillary permeability. Prostaglandins intensify and prolong inflammation while contributing to pain and fever. Leukotrienes increase vascular permeability and attract neutrophils. Kinins such as bradykinin cause vasodilation, increased permeability, and pain. Complement fragments (C3a, C5a) further promote inflammation. Vasodilation increases blood flow, producing redness and heat, while increased permeability allows plasma and proteins to leak into the tissues, creating edema (swelling). This protein-rich exudate dilutes toxins and delivers immune components to the injured area.
The second step is leukocyte recruitment and migration. White blood cells undergo margination, adhering to the endothelial wall of blood vessels near the injury through selectin and integrin molecules. They then squeeze between endothelial cells in a process called diapedesis (emigration) and follow chemical gradients to the site of injury through chemotaxis. Neutrophils arrive first within hours, followed by monocytes and macrophages over hours to days.
The third step involves phagocytosis and pathogen destruction. Neutrophils and macrophages engulf and destroy pathogens and debris. The accumulation of dead neutrophils, dead cells, tissue fluid, and bacteria forms pus.
The fourth and final step is tissue repair. Once pathogens have been cleared, anti-inflammatory signals promote healing. Macrophages clean up dead cells and debris, and the tissue either regenerates or is replaced by fibrosis (scar tissue).
Acute vs. Chronic Inflammation
Acute inflammation has a rapid onset (minutes to hours), is short in duration (days), and is dominated by neutrophils. Chronic inflammation persists for weeks to months or even years, is dominated by macrophages and lymphocytes, can cause tissue damage, and is associated with autoimmune diseases and persistent infections.
<image>A diagram of the inflammatory response in a blood vessel adjacent to a site of tissue injury. Panel A: The initial tissue damage with mast cells releasing histamine and other mediators. Panel B: Vasodilation and increased permeability — the vessel widens, gaps appear between endothelial cells, and plasma (exudate) leaks into the interstitial space, causing edema. Panel C: Leukocyte margination — neutrophils rolling along and adhering to the endothelium via selectins and integrins. Panel D: Diapedesis — neutrophils squeezing through endothelial gaps into the tissue. Panel E: Phagocytosis — neutrophils and macrophages at the injury site engulfing bacteria. The four cardinal signs are annotated at their relevant locations (redness from vasodilation, heat from increased blood flow, swelling from edema, pain from prostaglandins and bradykinin).</image>
V. Antimicrobial Proteins
Complement System
The complement system consists of approximately 30 plasma proteins, synthesized mainly by the liver, that circulate in inactive forms and activate in cascades to destroy pathogens. Three activation pathways exist. The classical pathway is activated by antibody-antigen complexes, bridging innate and adaptive immunity. The alternative pathway is activated spontaneously on pathogen surfaces through C3 hydrolysis. The lectin pathway is activated when mannose-binding lectin (MBL) binds to mannose residues on pathogen surfaces.
All three pathways converge to form C3 convertase, which cleaves C3 into two functionally important fragments. C3a acts as an inflammatory mediator (anaphylatoxin) that promotes mast cell degranulation, while C3b functions as an opsonin, coating pathogens to enhance phagocytosis. C3b also contributes to forming C5 convertase, which cleaves C5 into C5a, a potent anaphylatoxin and chemotactic agent, and C5b, which initiates assembly of the membrane attack complex (MAC). The MAC, composed of C5b, C6, C7, C8, and multiple C9 molecules, forms a transmembrane pore in the pathogen membrane, causing cell lysis. This mechanism is especially effective against gram-negative bacteria.
Interferons (IFNs)
Interferons are proteins released by virus-infected cells that protect neighboring uninfected cells. Type I interferons (IFN-alpha and IFN-beta) are released by virus-infected cells and bind to receptors on neighboring cells, stimulating them to produce antiviral proteins that block viral replication should they become infected. Type I interferons also activate NK cells and macrophages and increase MHC class I expression. Type II interferon (IFN-gamma), released by T cells and NK cells, activates macrophages and enhances their killing ability.
Other Antimicrobial Proteins
Transferrin and lactoferrin bind iron in body fluids, limiting the availability of this essential nutrient to bacteria. Collectins and pentraxins are pattern recognition molecules that contribute to innate immune surveillance.
VI. Fever
Fever is an elevation of body temperature above the normal 37.2 degrees Celsius (measured orally) and is triggered by pyrogens. Exogenous pyrogens are substances such as bacterial toxins (lipopolysaccharide/endotoxin) that originate outside the body. Endogenous pyrogens are cytokines released by immune cells, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). These pyrogens act on the hypothalamus to raise the thermostat set point. The body then generates heat through vasoconstriction (to conserve heat) and shivering (to produce heat).
Moderate fever is beneficial: it increases the metabolic rate, speeding immune cell activity, and inhibits the reproduction of many temperature-sensitive bacteria and viruses. Fever also enhances interferon production and promotes the liver's sequestration of iron and zinc, further limiting bacterial growth. However, excessive fever above 40 degrees Celsius is dangerous because it can denature proteins and cause seizures.
VII. Pattern Recognition — Toll-Like Receptors (TLRs)
Innate immune cells recognize pathogens through pattern recognition receptors (PRRs), of which Toll-like receptors (TLRs) are a major family. Located on phagocyte surfaces and within endosomes, TLRs recognize conserved molecular patterns on pathogens called PAMPs (pathogen-associated molecular patterns). Examples include lipopolysaccharide of gram-negative bacteria (recognized by TLR4), flagellin (TLR5), double-stranded RNA of viruses (TLR3), and peptidoglycan (TLR2). TLR activation triggers phagocytosis, cytokine release to drive the inflammatory response, and activation of adaptive immune responses. TLRs also recognize DAMPs (damage-associated molecular patterns) released from injured or dying host cells.
