Chapter 21A

The Immune System

Overview of the Immune System

• The immune system provides resistance to disease and is composed of two intrinsic systems:

  • Innate (nonspecific) defense system:

  • Constitutes the first and second lines of defense against pathogens.

    • First line of defense:

    • Comprises external body membranes, notably skin and mucosae.

    • Second line of defense:

    • Involves antimicrobial proteins, phagocytes, and other immune cells that inhibit the spread of invaders. The inflammation response is considered the most vital mechanism here.

  • Adaptive (specific) defense system:

  • Represents the third line of defense, which attacks specific foreign substances and takes longer to react compared to innate defenses.

Nature of the Immune System

• The immune system is classified as a functional system rather than solely an organ system.

• Innate and adaptive defenses are closely intertwined:

  • Both systems release and recognize many of the same defensive molecules.

  • Innate defenses coordinate specific pathways for certain substances.

  • Innate responses release proteins that alert cells of the adaptive system regarding foreign molecules.

Part 1 – Innate Defenses

• The innate system employs the first and second lines of defense to thwart attacks by pathogens (disease-causing microorganisms).

First Line of Defense: Surface Barriers

1. Surface barriers consist of skin and mucous membranes, along with their secretions:

   • They act as a physical barrier to most microorganisms.

   • Keratin in the skin is resistant to weak acids, bases, bacterial enzymes, and toxins.

   • Mucosae provide similar mechanical barriers against pathogens.

2. **Protective Chemical Secretions:

   • The skin and mucous membranes produce chemicals that inhibit or destroy microorganisms:

     • Acid: The acidity of skin and some mucous secretions inhibits the growth of microbes, known as the acid mantle.

     • Enzymes: Lysozyme found in saliva and respiratory mucus can kill many microorganisms; enzymes in the stomach also kill various microbes.

     • Mucin: Sticky mucus lines the digestive and respiratory tracts, trapping microorganisms.

     • Defensins: Antimicrobial peptides that inhibit microbial growth.

     • Other chemicals: Lipids in sebum and dermicidin in sweat are toxic to some bacteria.

3. Respiratory System Defenses:

   • Mucus-coated hairs in the nose trap inhaled particles.

   • Cilia in the upper respiratory tract sweep dust and bacteria-laden mucus toward the mouth.

4. Breach of Surface Barriers:

   • When surface barriers are damaged (e.g., nicks or cuts), the second line of defense is activated to protect deeper tissues.

Second Line of Defense: Cells and Chemicals

1. The innate system activates mechanisms necessary when microorganisms invade deeper tissues, comprising:

   • Phagocytes: Specialized white blood cells that ingest and digest foreign materials.

   • Natural killer (NK) cells: Attack infected or cancerous cells.

   • Inflammatory response: Comes into play through various cells (macrophages, mast cells, white blood cells) and inflammatory chemicals.

   • Antimicrobial proteins: Includes interferons and complement proteins.

   • Fever: Systemic reaction in response to pathogens.

2. Pattern Recognition:

   • Many components of the second line of defense have pattern recognition receptors that recognize and bind to microbial structures, disarming them before they cause harm.

   • A key class of receptors, Toll-like receptors (TLRs), triggers immune responses; humans have 11 different TLRs, each recognizing specific classes of microbes.

Phagocytes

• Phagocytes:

  • White blood cells that ingest foreign invaders:

  • Neutrophils: The most abundant phagocytes that die fighting and become phagocytic when exposed to infection.

  • Macrophages: Develop from monocytes and are the chief phagocytic cells, robust in their ability to engulf pathogens.

    • Free macrophages: Wander through tissue spaces (e.g., alveolar macrophages in the lungs).

    • Fixed macrophages: Permanent residents in certain organs (e.g., stellate macrophages in the liver, microglia in the brain).

Phagocytosis Process

1. Recognition: Phagocytosis begins when the phagocyte recognizes and adheres to the carbohydrate “signature” of a pathogen.

   • Note: Some microorganisms possess external capsules that prevent phagocytosis.

   • Opsonization: The immune system uses antibodies or complement proteins as opsonins, coating pathogens to enhance phagocytosis.

2. Engulfment:

   • Cytoplasmic extensions (pseudopods) bind to and engulf the particle within a vesicle called a phagosome.

3. Formation of Phagolysosome:

   • The phagosome fuses with lysosomes to form a phagolysosome.

4. Digestion:

   • The phagolysosome is acidified; lysosomal enzymes then digest the engulfed particle.

5. Exocytosis of Waste:

   • Indigestible and residual waste is expelled from the phagocyte through exocytosis.

6. Pathogen Resistance:

   • Some pathogens (e.g., tuberculosis bacteria) resist destruction by acidified lysosomal enzymes. Helper T cells can stimulate macrophages to execute a respiratory burst that kills stubborn pathogens via:

     • Releasing cell-killing free radicals.

     • Producing oxidizing chemicals (e.g., H₂O₂).

     • Increasing pH and osmolarity of the phagolysosome.

     • Defensins in neutrophils assist by piercing the pathogen's membrane.

Natural Killer (NK) Cells

• NK Cells:

  • Nonphagocytic, large granular lymphocytes that monitor blood and lymph for abnormal cells.

  • They can kill cancerous (tumor) and virus-infected cells prior to the activation of the adaptive immune system.

  • Recognize and attack cells lacking “self” cell-surface receptors.

  • Induce apoptosis in abnormal cells and secrete potent chemicals that enhance the inflammatory response.

Inflammation: Tissue Response to Injury

• Inflammation is initiated whenever bodily tissues are injured, caused by trauma, heat, irritating chemicals, or infections:

  • Benefits of Inflammation:

  • Prevents the spread of damaging agents.

  • Disposes of cell debris and pathogens.

  • Alerts the adaptive immune system to potential threats.

  • Prepares the area for repair.

Cardinal Signs of Acute Inflammation

1. Redness

2. Heat

3. Swelling

4. Pain

   • An additional sign, impairment of function, may occur if an area’s movement is hampered.

Stages of Inflammation

1. Inflammatory Chemical Release:

   • Chemicals released into the extracellular fluid (ECF) by injured tissues or immune cells (e.g., histamine from mast cells).

2. Vasodilation and Increased Vascular Permeability:

   • Vasodilation causes hyperemia, leading to redness and heat.

   • Increased capillary permeability causes exudate (fluid containing clotting factors and antibodies) to leak into tissues, causing edema (swelling) and pain due to pressure on nerve endings.

3. Phagocyte Mobilization:

   • Involves the sequential recruitment and activation of phagocytes (neutrophils first, followed by macrophages).

Phagocyte Mobilization Steps

1. Leukocytosis:

   • Release of neutrophils from bone marrow triggered by leukocytosis-inducing factors released from damaged cells.

2. Margination:

   • Endothelial cells in inflamed areas project cell adhesion molecules (CAMs) into vessels that attach to passing neutrophils, causing them to slow down and cling to the vessel wall.

3. Diapedesis:

   • Neutrophils flatten and squeeze between endothelial cells to enter interstitial spaces.

4. Chemotaxis:

   • Inflammatory chemicals act as chemotactic agents that promote neutrophil migration toward the injured area.

   • Monocytes arrive later, transforming into macrophages to replace dying neutrophils and aid in cleanup before repair.

Clinical Implications:

• Pus: A creamy yellow mixture of dead neutrophils, tissue debris, and pathogenic microorganisms may accumulate, leading to abscesses which could require surgical drainage.

• Certain bacteria (e.g., tuberculosis bacilli) can resist macrophage digestion and lead to granulomas, which are infected macrophages surrounded by uninfected macrophages.

Antimicrobial Proteins

• Antimicrobial proteins enhance innate defense by:

  • Attacking microorganisms directly.

  • Hindering the ability of microorganisms to reproduce.

Important Antimicrobial Proteins

1. Interferons (IFN):

   • Family of immune-modulating proteins that are secreted by virus-infected cells to warn neighboring healthy cells.

   • Mechanism of Action:

     • They enter neighboring cells, stimulating them to produce proteins blocking viral reproduction and degrading viral RNA.

     • Types of Interferons:

     • IFN-α (alpha) and IFN-β (beta) enhance NK cell activity.

     • IFN-γ (gamma) is secreted by lymphocytes, activating macrophages and inducing broader immune mobilization.

   • Artificial interferons are utilized for treating diseases such as hepatitis C, genital warts, and multiple sclerosis.

2. Complement Proteins:

   • Comprising about 20 blood proteins circulating in an inactive state, the complement system provides a major mechanism for destroying foreign substances. Activation of complement enhances inflammation and directly destroys bacteria.

   • Activation Pathways:

   1. Classical Pathway:

      • Initiated when antibodies bind to invading organisms and subsequently bind to complement components, leading to complement fixation.

   2. Lectin Pathway:

      • Recognizes foreign invaders through lectins produced by the innate system, activating complement.

   3. Alternative Pathway:

      • Spontaneous activation when certain complement factors bind directly to foreign invaders due to the absence of inhibitors on their surface.

   • Each pathway activates proteins sequentially in a cascade leading to the cleavage of C3 into C3a and C3b, which initiates inflammation, promotes phagocytosis, and causes cell lysis.

Mechanism of Cell Lysis

• Cell lysis begins when C3b binds to the target cell, leading to the insertion of complement proteins (forming the membrane attack complex (MAC)) into the cell membrane, thus creating holes that result in cell lysis.

• Roles of Complement Cleavage Products:

  • C3b causes opsonization.

  • C3a and other cleavage products amplify inflammation by:

  • Stimulating mast cells and basophils to release histamine.

  • Attracting neutrophils and other inflammatory cells to the site of infection.

Fever

• Definition: An abnormally high body temperature that acts as a systemic response to invading microorganisms.

• Mechanism of Action:

  • Leukocytes and macrophages exposed to foreign substances release pyrogens, which act on the hypothalamus to raise body temperature.

• Benefits of Moderate Fever:

  • Causes the liver and spleen to sequester iron and zinc (nutrients required by microorganisms).

  • Increases metabolic rate, which accelerates the rate of tissue repair.