Chapter 14: The Innate and Adaptive Immune System – Microbiology Study Notes

Glimpse of History

Ilya Metchnikoff and the Discovery of Phagocytes

The study of immunity began with the pioneering work of Ilya Metchnikoff, a Russian-born scientist who observed immune responses in starfish larvae. His research laid the foundation for our understanding of how the body defends itself against microbial invaders.

• Phagocytes: Metchnikoff identified motile, ameba-like cells capable of ingesting and destroying foreign material. He termed these cells phagocytes ("cells that eat").

• He proposed that phagocytes are responsible for destroying invading microbes.

• Studied phagocytes in water fleas, observing their destruction of yeast cells.

• Published his findings in 1884 and was awarded the Nobel Prize in 1908 for his studies of immunity.

The Immune System: Innate and Adaptive Immunity

Overview and Key Concepts

The human body is constantly exposed to microbes, yet most internal tissues remain sterile due to robust immune defenses. The immune system is divided into innate and adaptive components, each with distinct roles in protection.

• Innate Immunity: Provides routine, non-specific protection. It relies on pattern recognition of molecules commonly found on pathogens.

• Adaptive Immunity: Develops throughout life and is highly specific. Antigens trigger adaptive responses, leading to the production of antibodies that bind to and neutralize invaders. Adaptive immunity can also target and destroy infected host cells.

Overview of the Innate Defenses

Barriers and Sensor Systems

Innate defenses are organized into layers that block entry, detect invaders, and initiate destruction.

• First-line defenses: Physical and chemical barriers such as skin and mucous membranes prevent microbial entry.

• If invaders breach these barriers, sensor systems detect their presence and send signals to activate further defenses.

• Innate effector actions: These mechanisms work to eliminate the invaders.

Summary Table: Innate Defense Overview

Defense Layer	Main Components	Function
First-line defenses	Skin, mucous membranes	Prevent microbial entry
Sensor systems	Pattern recognition receptors (PRRs), complement system	Detect microbial invasion, activate responses
Innate effector actions	Phagocytosis, inflammatory response, interferon response	Destroy invaders

First-Line Defenses

Physical Barriers

Physical barriers are the body's initial protection against infection.

• Skin: Composed of the dermis (tightly woven connective tissue) and epidermis (multiple layers of epithelial cells). The outermost cells are dead and filled with keratin, which repels water and creates a dry environment hostile to microbes.

• Skin cells are continually shed, removing attached microbes.

Mucous Membranes

Mucous membranes line the digestive, respiratory, and genitourinary tracts, providing additional protection.

• Constantly bathed in secretions (e.g., mucus) that trap and remove microbes.

• Peristalsis in the intestines and the mucociliary escalator in the respiratory tract help expel pathogens.

Antimicrobial Substances

Chemical defenses further protect skin and mucous membranes.

• Salt: Accumulates from perspiration, inhibiting microbial growth.

• Lysozyme: Enzyme that degrades peptidoglycan in bacterial cell walls.

• Peroxidase enzymes: Break down hydrogen peroxide, producing reactive oxygen species.

• Lactoferrin: Binds iron, making it unavailable to microbes.

• Defensins: Small peptides that form pores in microbial membranes, leading to cell death.

Normal Microbiota (Flora)

The normal microbiota competes with pathogens and produces substances that inhibit their growth.

• Competitive exclusion: Microbiota cover binding sites and consume nutrients, preventing pathogen colonization.

• Toxic compounds: Propionibacterium produce fatty acids; E. coli synthesize colicins; Lactobacillus creates a low pH in the vagina.

• Disruption of microbiota (e.g., by antibiotics) can lead to infections by Clostridium difficile or Candida albicans.

The Cells of the Immune System

Hematopoiesis and Blood Cell Types

All blood cells originate from hematopoietic stem cells in the bone marrow, which differentiate under the influence of colony-stimulating factors (CSFs).

• Red blood cells (erythrocytes): Carry oxygen.

• Platelets: Involved in blood clotting.

• White blood cells (leukocytes): Crucial for host defense.

Types of Leukocytes

• Granulocytes: Contain cytoplasmic granules.

  • Neutrophils: Engulf and destroy bacteria and other material.

  • Basophils: Involved in allergic reactions and inflammation.

  • Mast cells: Similar to basophils, found in tissues.

  • Eosinophils: Fight parasitic worms and participate in allergic reactions.

• Mononuclear Phagocytes: Include monocytes (circulate in blood) and cells that develop as they leave the bloodstream (macrophages, dendritic cells).

• Dendritic Cells: Sentinel cells that engulf material and present it to adaptive immune cells.

• Lymphocytes: Responsible for adaptive immunity. B cells and T cells are highly specific; Natural Killer (NK) cells lack specificity.

Cell Communication

Mechanisms of Immune Coordination

Effective immune responses require communication between cells.

• Surface receptors: Proteins that span the cell membrane and bind specific ligands, triggering cellular responses.

• Adhesion molecules: Enable cells to adhere to one another, facilitating migration and interaction.

• Cytokines: Small proteins that act as "voices" of the cell, inducing changes such as growth, differentiation, movement, or cell death. They act at low concentrations and can have local, regional, or systemic effects.

Types of Cytokines

• Chemokines: Induce chemotaxis of immune cells.

• Colony-stimulating factors (CSFs): Stimulate multiplication and differentiation of leukocytes.

• Interferons (IFNs): Control viral infections and regulate inflammatory responses.

• Interleukins (ILs): Produced by leukocytes; important in both innate and adaptive immunity.

• Tumor necrosis factor (TNF): Involved in inflammation and apoptosis.

Pattern Recognition Receptors (PRRs)

Detection of Microbial Invaders

PRRs are proteins that recognize pathogen-associated molecular patterns (PAMPs) or microbe-associated molecular patterns (MAMPs), which are unique to microbes. Some PRRs also detect danger-associated molecular patterns (DAMPs) from damaged host cells.

• Recognize cell wall components (lipopolysaccharide, peptidoglycan), flagellin, and viral RNA.

Types of PRRs

• Toll-like receptors (TLRs): Located in membranes of sentinel cells (macrophages, dendritic cells). Detect PAMPs in the extracellular environment or within phagosomes/endosomes.

• NOD-like receptors (NLRs): Found in the cytoplasm; detect bacterial components and cell damage. Can form inflammasomes to activate inflammatory responses.

• RIG-like receptors (RLRs): Cytoplasmic sensors of viral RNA, especially double-stranded RNA with uncapped 5' ends. Trigger production of interferons and antiviral proteins.

The Complement System

Activation and Pathways

The complement system consists of proteins (C1–C9) that circulate in blood and tissue fluids, enhancing adaptive immunity. Activation occurs via three pathways, all leading to the formation of C3 convertase:

• Alternative pathway: Triggered when C3b binds to foreign cell surfaces.

• Lectin pathway: Mannose-binding lectins (MBLs) bind to microbial mannose, activating complement.

• Classical pathway: Activated by antibodies bound to antigens.

Major Outcomes of Complement Activation

• Opsonization: C3b binds to microbes, enhancing phagocytosis.

• Inflammatory response: C5a attracts phagocytes; C3a and C5a increase blood vessel permeability and induce mast cells to release cytokines.

• Lysis of foreign cells: Membrane attack complexes (MACs) formed by C5b, C6, C7, C8, and C9 create pores in microbial membranes, especially Gram-negative bacteria.

Regulation of Complement

• Host cells express regulatory proteins that inactivate C3b, preventing accidental damage.

Phagocytosis

Steps in Phagocytosis

Phagocytes engulf and digest pathogens through a multi-step process:

1. Chemotaxis: Phagocytes are attracted by chemoattractants (microbial products, host cell phospholipids, chemokines, C5a).

2. Recognition and Attachment: Direct (receptors bind to microbial molecules) or indirect (binding to opsonins like C3b).

3. Engulfment: Pseudopods surround the microbe, forming a phagosome.

4. Phagosome Maturation and Phagolysosome Formation: Fusion with lysosomes introduces degradative enzymes and lowers pH.

5. Destruction and Digestion: Reactive oxygen species (ROS), nitric oxide, and enzymes degrade the invader; defensins damage membranes; lactoferrin sequesters iron.

6. Exocytosis: Expulsion of digested material.

Specialized Phagocytes

• Macrophages: Scavengers and sentinels; phagocytize dead cells and debris, destroy invaders, and can form granulomas with T cells if invaders resist destruction (e.g., tuberculosis).

• Neutrophils: Rapid responders; first to arrive at sites of infection, highly effective but short-lived. Can release neutrophil extracellular traps (NETs) to ensnare and destroy microbes.

The Inflammatory Response

Purpose and Process

Inflammation is a protective response to tissue damage, aiming to contain the damage, eliminate invaders, and restore function.

• Characterized by swelling, redness, heat, pain, and sometimes loss of function.

• Triggered by PRRs detecting PAMPs or DAMPs, leading to release of inflammatory mediators (cytokines, histamine, bradykinin).

• Blood vessel dilation increases blood flow and permeability, allowing leukocytes to migrate to tissues (diapedesis).

• Clotting factors wall off infection; dead cells and debris accumulate as pus.

• Acute inflammation is short-term; chronic inflammation involves granuloma formation.

Damaging Effects of Inflammation

• Enzymes and toxic compounds released by phagocytes can damage host tissues.

• Damage is usually minimal but can be severe in sensitive areas (e.g., brain, spinal cord).

Cell Death and Inflammation

• Apoptosis: Programmed cell death without inflammation.

• Pyroptosis: Inflammatory cell death triggered by PRRs.

Fever

Role in Host Defense

Fever is a systemic response to infection, especially bacterial. It is regulated by the brain in response to pyrogens.

• Endogenous pyrogens: Cytokines produced by macrophages after detecting microbial products.

• Exogenous pyrogens: Produced by microbes.

• Fever inhibits microbial growth and enhances immune functions (phagocytosis, lymphocyte multiplication, interferon production).

Example: During bacterial infection, fever slows bacterial growth and gives the immune system more time to respond.