Innate Immunity: First and Second Lines of Defense in the Immune System

Innate Immunity and the Immune System

Overview of Immune Responses

The immune response is a physiological process coordinated by the immune system to eliminate antigens. Immunity refers to specific protection conferred by immune responses, while susceptibility means a lack of immunity to a given pathogen, allowing infection. The immune system is composed of innate and adaptive immunity, both of which:

• Recognize diverse pathogens

• Eliminate identified invaders

• Discriminate between self and foreign antigens

Innate vs. Adaptive Immunity

• Innate Immunity: Inborn, generalized, and non-specific responses. Found in all eukaryotes. Acts immediately upon infection.

• Adaptive Immunity: Develops only in vertebrates, matures over time, and tailors responses to specific pathogens. Typically requires 4–7 days to fully activate and exhibits memory.

Role of Normal Microbiota

• Normal microbiota play a central role in inducing, training, and calibrating immune responses.

• The good hygiene hypothesis suggests that reduced diversity and levels of microbes in our microbiota may negatively affect immune responses.

• Studies in germ-free animals show that microbe-free environments lead to underdeveloped immune systems.

Lines of Immune Defense

Three Lines of Defense

1. Innate Barrier Defenses (First-line): Prevent pathogen entry.

2. Innate Cellular and Molecular Defenses (Second-line): Respond to pathogens that breach barriers.

3. Adaptive Defense (Third-line): T and B lymphocytes coordinate a specific response.

First-Line Defenses

First-line defenses are subdivided into mechanical, chemical, and physical barriers.

• Mechanical Barriers: Rinse, flush, or trap pathogens.

  • Tears wash pathogens from eyes.

  • Urine flushes microbes out of the body.

  • Saliva limits microbial adherence.

  • Mucus membranes trap microbes.

  • Mucociliary escalator: Ciliated cells sweep mucus away from lungs toward the mouth.

• Chemical Barriers: Directly attack invaders or create hostile environments.

  • Lysozyme: Enzyme in tears, saliva, and breast milk that breaks down bacterial cell walls.

  • Hydrochloric acid: In the stomach, destroys pathogens.

  • Skin: Dry, salty, and slightly acidic.

  • Fatty acids: In sweat and earwax, inhibit microbial growth.

  • Antimicrobial peptides (AMPs): Proteins that destroy a wide spectrum of microbes. Example: Defensins.

• Physical Barriers: Structures that block pathogen entry.

  • Skin: Tightly packed dead epithelial cells form a tough barrier.

  • Epidermis: Outermost skin layer, critical for defense.

Second-Line and Third-Line Defenses

• Second-line defenses: Molecular factors and leukocytes (white blood cells) respond to pathogens that breach first-line barriers.

• Third-line defenses: T and B lymphocytes coordinate the adaptive immune response.

Lymphatic System and Immune Tissues

Lymphatic System

• Collects, circulates, and filters fluid in body tissues before returning it to the blood.

Primary Lymphoid Tissues

• Thymus: Site of T cell maturation, located behind the sternum.

• Bone marrow: Site of red and white blood cell production, found in long bones and pelvis.

Secondary Lymphoid Tissues

• Lymph nodes: 500–700 in humans, clustered in neck, underarm, and groin. Filter lymph and screen for pathogens. Swollen nodes indicate infection.

• Spleen: Filters blood, located in the upper left abdomen.

• Mucosa-associated lymphoid tissue (MALT): Found in mucosal linings (e.g., tonsils, appendix, Peyer’s patches, GALT).

Blood Cells and Leukocytes

Blood Components

• Erythrocytes: Deliver oxygen to tissues.

• Platelets: Clump to stem blood loss.

• Leukocytes: Essential immune cells, classified as granulocytes or agranulocytes.

Leukocyte Types

• Granulocytes: Contain visible granules.

  • Neutrophils: Most numerous, phagocytic, first responders to infection. Elevated in bacterial infections (neutrophilia).

  • Eosinophils: Bilobed nucleus, moderate phagocytic activity, combat parasites, involved in allergies.

  • Basophils: Least common, release histamine, involved in allergic responses and fighting parasites.

  • Mast cells: Reside in tissues, release histamine, conduct phagocytosis, common near body openings.

• Agranulocytes: Lack visible granules.

  • Monocytes: Largest, mature into macrophages, increase in chronic infections and inflammation.

  • Macrophages: Highly phagocytic, can be fixed (in tissues) or wandering (move through tissues).

  • Dendritic cells: Highly phagocytic, patrol tissues, present antigens.

  • Lymphocytes: ~25% of WBCs, include natural killer (NK) cells (innate), B cells, and T cells (adaptive).

White Blood Cell Counts

• Differential WBC count: Diagnostic test to assess immune status.

• Leukocytosis: Increased leukocytes.

• Leukopenia: Decreased leukocytes.

Cytokines and Immune Signaling

Cytokines

• Signaling proteins for cell communication, initiating and coordinating immune actions.

Types of Cytokines

• Chemokines: Induce chemotaxis, attract cells, aid in wound healing, blood vessel formation, and immune responses.

• Interleukins (ILs): Activate immune responses, stimulate hematopoiesis. IL-1 regulates inflammation and fever; IL-2 is central to T cell development and apoptosis.

• Interferons (IFNs): Signal presence of pathogens or tumor cells. IFN-α and IFN-β stimulate antiviral defenses.

• Tumor necrosis factors (TNFs): TNF-α stimulates inflammation, fever, and kills tumor cells.

Iron Sequestration and Microbial Evasion

• Iron is essential for microbes, but host iron-binding proteins (hemoglobin, ferritin, lactoferrin, transferrin) limit its availability.

• Siderophores: Bacterial molecules that sequester iron from host proteins.

• Hemolytic bacteria: Break down red blood cells to access hemoglobin.

Complement System

The complement system consists of over 30 proteins, mainly produced by the liver, that circulate in the blood in an inactive form. When activated, they trigger a cascade of immune responses with three main outcomes:

• Opsonization: Tags invaders for phagocytosis.

• Membrane Attack Complex (MAC) formation: Causes cytolysis of pathogens.

Inflammation and Fever

Inflammation

Inflammation is a key innate defense that develops when tissues are damaged. It is essential for healing and initiates blood-clotting cascades. The three main goals are:

• Recruit immune defenses to the injured tissue

• Limit the spread of infectious agents

• Deliver oxygen, nutrients, and factors for tissue recovery

Cardinal signs: Redness, pain, localized heat, swelling, loss of function.

Phases of Inflammation

1. Vascular changes: Vasodilation and increased vessel permeability; exudate accumulates.

2. Leukocyte recruitment: Chemoattractant guide leukocytes to the site; margination and diapedesis occur.

3. Resolution: Inflammation is toned down, healing begins, and leukocytes undergo apoptosis.

Key Mediators

• Histamine: Pro-inflammatory, increases vessel permeability.

• Kinins: Induce vascular changes, stimulate pain, assist in clotting.

• Eicosanoids: Induce vascular changes and pain (e.g., prostaglandins, leukotrienes).

Fever (Pyrexia)

• Abnormally high systemic body temperature, induced by pyrogens (e.g., bacterial toxins, cytokines).

• Low-grade fever (37.5°C to 38.3°C) is considered protective.

• Benefits: Enhances interferon effects, increases phagocyte efficiency, boosts leukocyte production, limits pathogen growth, promotes tissue repair.

• High fever (>40.5°C) is life-threatening; >43°C is fatal due to protein denaturation.

• Antipyretics (e.g., ibuprofen, acetaminophen) reduce fever by limiting prostaglandin production in the hypothalamus.

Comparison Table: Innate vs. Adaptive Immunity

Feature	Innate Immunity	Adaptive Immunity
Response Time	Immediate (minutes to hours)	Slower (days to weeks)
Specificity	Non-specific	Highly specific
Memory	None	Long-lasting memory
Key Cells	Phagocytes, NK cells, granulocytes	B cells, T cells
Major Functions	First and second lines of defense	Third line of defense

Key Definitions and Examples

• Phagocytosis: "Cell eating"; engulfment of large particles by cells such as neutrophils and macrophages.

• Opsonization: Process of tagging pathogens for easier recognition and ingestion by phagocytes.

• Margination: Leukocytes slow and adhere to blood vessel walls during inflammation.

• Diapedesis: Leukocytes squeeze out of blood vessels to reach affected tissues.

• Siderophores: Bacterial molecules that sequester iron from host proteins.

• Antimicrobial peptides (AMPs): Proteins that destroy a wide range of pathogens (e.g., defensins).

Sample Questions and Applications

• Which of the following is an example of a mechanical barrier? The mucociliary escalator sweeps mucus away from the lungs and toward the mouth.

• Which of the following is part of the second line of defense? Molecular factors such as chemokines; leukocytes.

• What is the effect of a thymus deficiency? The patient would not produce mature T lymphocytes.

• What is a siderophore? An organic molecule made by bacteria that sequesters iron from host iron-binding proteins.

• What are the cardinal signs of inflammation? Redness, pain, localized heat, swelling, loss of function.

• How do antipyretics work? They decrease production of prostaglandins in the hypothalamus.

Additional info: This guide integrates and expands upon the provided notes, adding definitions, examples, and a comparison table for clarity and completeness.