Innate Nonspecific Host Defenses

Overview of Nonspecific Innate Immune Defenses

• Nonspecific Innate Immunity: Provides the first line of defense against pathogens. It is "nonspecific" because it does not target specific individual pathogens but acts against broad classes of microbes. It is "innate" because it is built-in and present from birth.

• Categories of Innate Defenses:

  • Physical Defenses: Includes physical barriers, mechanical defenses, and the microbiome.

  • Chemical Defenses: Includes chemicals and enzymes in body fluids, antimicrobial peptides (AMPs), plasma protein mediators, cytokines, and inflammation-eliciting mediators.

  • Cellular Defenses: Includes granulocytes and agranulocytes (Leukocytes).

Physical Defenses of Nonspecific Innate Immunity

• Physical Barriers: These structures deny entry to pathogens.

  • Cell Junctions: Human tissues have multiple types of cell junctions to regulate the passage of materials.

    • Tight Junctions: These rivet two adjacent cells together, preventing or limiting material exchange through the spaces between them.

    • Desmosomes: These contain intermediate fibers that act like shoelaces, tying two cells together while allowing small materials to pass through the resulting spaces.

    • Gap Junctions: These are channels between two cells that permit direct communication via signals.

  • Human Skin: Composed of three layers that provide a thick barrier between the external environment and deeper tissues:

    1. Epidermis: The outermost layer. Dead skin cells on the surface are continually shed, carrying away microbes.

    2. Dermis: The middle layer.

    3. Hypodermis: The deepest layer.

  • Endothelial Cells: Tight-fitting cells that line the blood vessels and other internal surfaces, acting as a cellular barrier.

• Mechanical Defenses: Physical actions that remove pathogens from potential sites of infection.

  • Shedding of skin cells: Continual removal of dead cells from the epidermis.

  • Mucociliary Sweeping: In the human trachea, ciliated epithelial cells push mucus away from the lungs. This "mucociliary escalator" moves mucus, debris, and trapped microorganisms up toward the esophagus where they can be swallowed.

  • Mucus Production: Goblet cells in the epithelium (such as in the intestines) produce and secrete sticky mucus to trap microbes.

  • Peristalsis: The rhythmic contraction of the digestive tract that moves materials through the system.

  • Flushing Action:

    • Tears: Flush microbes away from the surface of the eye.

    • Urine: Washes microbes out of the urinary tract; this flushing action ensures the urinary system is normally sterile.

• Microbiome:

  • Role: Resident bacteria located in the skin, upper respiratory tract, gastrointestinal tract, and genitourinary tract.

  • Function: Competes with pathogens for nutrients and cellular binding sites, effectively preventing their colonization.

Chemical Defenses of Nonspecific Innate Immunity

• Chemicals and Enzymes in Body Fluids:

  • Sebum: Secreted by sebaceous glands. It is a chemical mediator that lubricates and protects the skin. It serves as a food source for resident microbes that produce oleic acid.

  • Oleic Acid: An exogenously produced mediator (by skin microbiota) that lowers the pH of the skin to inhibit pathogen growth.

  • Lysozyme: Found in various secretions; kills bacteria by attacking and breaking down the bacterial cell wall.

  • Acidic Environments: Low pH in the stomach, urine, and vagina inhibits or kills pathogens.

  • Digestive Enzymes and Bile: Act in the GI tract to kill bacteria.

  • Lactoferrin and Transferrin: Chemically bind and sequester iron, depriving bacteria of a necessary nutrient and inhibiting growth.

  • Surfactant: Present in the lungs to kill bacteria.

• Antimicrobial Peptides (AMPs): Short-chain peptides with broad-spectrum antimicrobial properties.

  • Bacteriocins: Secreted by resident microbiota in the GI tract; disrupt bacterial membranes.

  • Cathelicidin: Secreted by epithelial cells and macrophages on the skin; disrupts membranes of bacteria and fungi.

  • Defensins: Secreted by epithelial cells, macrophages, and neutrophils throughout the body; disrupt the membranes of fungi, bacteria, and many viruses.

  • Dermicidin: Secreted by sweat glands on the skin; disrupts membrane integrity and ion channels of bacteria and fungi.

  • Histatins: Secreted by salivary glands in the oral cavity; disrupt intracellular functions of fungi.

• Plasma Protein Mediators and Acute-Phase Proteins: Proteins primarily produced in the liver and secreted into the blood in response to inflammatory signals.

  • C-reactive protein (CRP) and Serum amyloid A: Coat bacteria (opsonization), preparing them for ingestion by phagocytes.

  • Ferritin and Transferrin: Bind and sequester iron to inhibit pathogen growth.

  • Fibrinogen: Involved in the formation of blood clots that trap bacterial pathogens.

  • Mannose-binding lectin: Activates the complement cascade.

• Complement System: A group of plasma proteins that can be activated in three different pathways. All pathways converge on the activation of protein C3.

  • Activation: Triggers lead to the cleavage of $C3$ into $C3a$ and $C3b$.

  • Opsonization: $C3b$ (and $C4b$) binds to the surface of target cells to aid phagocytosis.

  • Membrane Attack Complex (MAC): $C3b$ works with other proteins to cleave $C5$ into $C5a$ and $C5b$. $C5b$ binds to the cell surface and recruits proteins $C6$, $C7$, $C8$, and $C9$ to form a ring-shaped MAC. This complex punches a hole in the pathogen's membrane, causing it to swell and burst.

  • Chemoattractants: $C5a$ serves as a powerful chemoattractant for phagocytes.

  • Anaphylatoxins: $C3a$ and $C5a$ are proinflammatory mediators.

Cytokines and Inflammation-Eliciting Mediators

• Cytokines: Soluble proteins that act as communication signals between cells.

  • Actions:

    • Autocrine: The cell that secretes the cytokine is the same cell that receives the signal.

    • Paracrine: The cytokine targets nearby cells.

    • Endocrine: The cytokine travels through the circulatory system to distant target cells.

  • Specific Cytokine Groups:

    • Interleukins: Stimulate and modulate most functions of the immune system.

    • Chemokines: Specifically recruit white blood cells to infected areas.

    • Interferons: Cytokines released by virus-infected cells.

• Fever:

  • Mechanism: Macrophages in an infected area release cytokines. These cytokines send signals through the vagus nerve to the Hypothalamus, which resets the body's "thermostat" to a higher temperature to inhibit pathogen growth and stimulate immune responses.

Overview of Nonspecific Innate Immune Defenses

• Nonspecific Innate Immunity: Provides the first line of defense against pathogens. It is "nonspecific" because it does not target specific individual pathogens but acts against broad classes of microbes. It is "innate" because it is built-in and present from birth, encompassing defenses that are always active and never require previous exposure to a pathogen for an immune response.

• Categories of Innate Defenses:

  • Physical Defenses: Deny entry to pathogens through barriers and mechanical actions.

    • Physical Barriers: Includes skin, mucus membranes, and cellular junctions that regulate material passage.

    • Mechanical Defenses: Actions such as shedding skin and mucociliary sweeping effectively remove pathogens.

    • Microbiome: Resident microbes outcompete pathogenic bacteria for resources.

  • Chemical Defenses: Utilize chemicals and enzymes to combat pathogens.

    • Chemicals in Body Fluids: Components like sebum, lysozyme, and acidic environments in the stomach serve to inhibit pathogen growth.

    • Antimicrobial Peptides (AMPs): Such as defensins and cathelicidin disrupt microbial membranes and inhibit growth.

  • Cellular Defenses: Include various leukocytes that play roles in phagocytosis and pathogen destruction.

    • Granulocytes (e.g., neutrophils, eosinophils): Respond to pathogens quickly; neutrophils mainly target bacteria, while eosinophils are involved in responses to parasites.

    • Agranulocytes (e.g., monocytes and lymphocytes): Monocytes differentiate into macrophages and dendritic cells, significant for antigen presentation.

Physical Defenses of Nonspecific Innate Immunity

• Physical Barriers: Deny entry to pathogens primarily through skin and mucous membranes.     

  • Human Skin: The skin is a complex organ with layers that form a barrier. Constant shedding of dead skin cells helps to eliminate microbes. The fatty acids in sebum also support a slightly acidic skin surface, which can inhibit harmful microbes.

• Mechanical Defenses:

  • Shedding of skin cells: Ensures continual elimination of potential pathogens.

  • Mucociliary Sweeping: The action of ciliated cells helps to trap and expel pathogens from the respiratory tract.

  • Peristalsis: Maintains the flow of materials through the digestive tract, aiding in the clearance of pathogens.

• Microbiome:

  • Role: The presence of beneficial microorganisms competes with pathogens, provides a physical barrier, and produces substances that can inhibit pathogen growth.

Chemical Defenses of Nonspecific Innate Immunity

• Chemicals and Enzymes in Body Fluids:

  • Sebum and Skin pH: Serves as a barrier and nourishes beneficial skin bacteria while inhibiting pathogens.

  • Lysozyme Functions: Acts in various secretions like tears and saliva, breaking down bacterial cell walls.

  • Digestive Enzymes: Effectively dismantle bacterial structures, crucial in the gastrointestinal tract.

• Antimicrobial Peptides (AMPs):

  • Mechanisms of Action: AMPs generally disrupt bacterial membranes or inhibit essential metabolic functions.

Cytokines and Inflammation-Eliciting Mediators

• Cytokines:

  • Functions in Immune Response: Mediators such as interleukins enhance the immune response, while chemokines specifically recruit immune cells to sites of infection.

• Fever Mechanism:

  • Role of Cytokines in Fever Production: Important for increasing body temperature to create an environment less favorable for pathogens and enhancing immune cell efficiency.

Study Tips for a College Level Exam

1. Understand Key Terms: Familiarize yourself with definitions of terms such as sebum, lysozyme, AMPs, cytokines, etc. Use spaced repetition to reinforce memory.

2. Visual Aids: Create diagrams or charts depicting the components and functions of the innate immune system for better retention.

3. Practice Questions: Engage in practice exams or quizzes to test your knowledge, focusing on application-based questions.

4. Group Study: Discuss these concepts with peers to reinforce knowledge through teaching and collaborative learning.