Immunology: Non-specific Immunity Notes

Course Introduction and Course Overview

Instructor: Micah Willis, PhD
Topic: Immunology: Non-specific (Innate Immunity)
Subject Material: Agenda covers Innate Immunity as detailed in Chapter 17 of the curriculum.

Learning Objectives

• Name bacterial organisms associated with diseases of the various body systems.
• Compare and contrast bacterial diseases of different body systems, focusing on the mode of transmission, the organs affected, and typical treatment strategies.
• Discuss the differences between intoxications and infections, identifying the specific organisms associated with each.
• Define the terms antibody and antigen.
• Compare the primary and secondary immune responses.
• Perform and describe the mechanisms behind laboratory techniques used to identify bacteria.
• Name the cell types and organs that constitute the immune system.
• Identify various immune system disorders.
• Discuss protocols for specimen collection and transport across different body systems.
• Name parasites and protozoa associated with diseases of different body systems.
• Execute laboratory techniques for identifying clinically relevant microorganisms.
• Identify specific cells important to the immune system within a laboratory setting.

The First Line of Defense: Physical and Chemical Barriers

Humans are confronted daily by pathogens including bacteria, viruses, fungi, protozoa, and worms. The body must defend itself from these pathogens while simultaneously monitoring/regulating its own microbiota.

Physical Defenses of the First Line

The first line of defense consists of structures, chemicals, and processes that prevent pathogens from entering the body. This includes physical barriers and mechanical defenses such as the skin, mucous membranes, and the microbiome.

The Skin: Physical Components

The skin is comprised of three major layers:

1. Epidermis (Outer-most layer):     * Composed of multiple layers of tightly packed cells.     * Very few pathogens can penetrate these compact layers.     * The constant shedding of dead skin cells serves to remove attached microorganisms.     * The environment is dry, salty, and acidic, which inhibits microbial growth.     * Epidermal dendritic cells are present to phagocytize pathogens.
2. Dermis:     * Contains protein fibers called collagen, which provide strength and pliability, helping the skin resist abrasions that could introduce microbes.     * Highly vascularized, allowing defensive cells and chemicals to reach sites of injury.     * Contains cells that secrete antimicrobial peptides and sweat glands that secrete perspiration.     * Secretes Lysozyme and Sebum.
3. Hypodermis:     * A fatty layer containing blood and lymph vessels.

The Skin: Chemical Components

• Perspiration (Sweat Glands):     * Salt: Inhibits pathogen growth by drawing water from their cells via osmosis.     * Lysozyme: An enzyme that destroys the cell walls of bacteria.
• Sebum (Sebaceous/Oil Glands):     * Keeps the skin pliable and prevents tearing.     * Lowers skin pH to a level that is inhibitory to many bacterial species.

Note on Adaptation: Despite these defenses, Staphylococcus epidermidis finds the skin to be a suitable environment for growth and reproduction.

Mucous Membranes

Mucous membranes line all body cavities open to the outside environment, including the nose, mouth, lungs, and the urinary and digestive tracts.

• Structure: Composed of tightly packed epithelial cells to block pathogen entry.
• Mucus: A sticky substance secreted to trap debris and particulate matter.
• Cilia: Hair-like projections that move mucus upward (the mucociliary escalator) to be coughed or sneezed out.
• Regeneration: Epithelial cells are constantly regenerated, carrying attached microbes away as they are shed.
• Chemical Defense: These membranes contain lysozymes and defensins (antimicrobial peptides).

Specific Body System Defenses and Secretions

Secretions and Functions (Table 15.2)

• Saliva (Digestive System): Washes microbes from teeth, gums, tongue, and palate; contains lysozyme.
• Stomach Acid: Digests and/or inhibits microorganisms.
• Gastroferritin: Sequesters iron being absorbed, making it unavailable for microbial use.
• Bile: Inhibitory to most microorganisms.
• Intestinal Secretions: Digest and/or inhibit microorganisms.
• Peristalsis: Constant movement of GI contents to eliminate potential pathogens.
• Defecation/Vomiting: Physical elimination of microorganisms.
• Urine (Urinary System): Contains lysozyme; acidity inhibits growth; flushing action washes microbes from ureters and urethra.

Other First-Line Barriers

• Normal Flora: Helpful microbes like E. coli synthesize colicins and Beta-lysin to inhibit competitors.
• Genetics: Certain genetic traits, such as the Sickle cell trait, provide resistance to specific diseases.
• Acute Inflammation: An immediate response to injury characterized by warmth, redness, swelling, and pain.

The Second Line of Defense: Nonspecific Immunity

If pathogens penetrate the first line of defense, the second line comes into play. It is also nonspecific and targets a wide variety of pathogens. It lacks physical barriers and is instead composed of cells, antimicrobial chemicals, and processes, many of which reside in or originate from the blood.

Blood Composition

Blood is a complex liquid consisting of Plasma and Formed Elements.

• Plasma: Mostly water; contains ions, gases, and nutrients.
• Formed Elements:     1. Erythrocytes (Red Blood Cells): Carry $O_2$ and $CO_2$ throughout the blood.     2. Platelets: Essential for blood clotting.     3. Leukocytes (White Blood Cells): Involved in defending the body against invaders.

Leukocytes (White Blood Cells)

Leukocytes are classified into two groups based on the presence of visible granules in their cytoplasm.

Granulocytes

1. Neutrophils (Polymorphonuclear PMNs):     * The most abundant WBC ($60-70\%$).     * Primary component of pus (whitish appearance).     * First responders (arriving within $1$ hour).     * Involved in acute inflammation.
2. Basophils:     * The least common WBC ($0.5-1\%$).     * Release histamine and other chemical mediators of inflammation.
3. Eosinophils:     * Represent $2-4\%$ of WBCs.     * Fight viral infections and helminth (worm) colonizations.     * Play a significant role in allergic reactions.

Agranulocytes

1. Lymphocytes:     * Represent $20-25\%$ of WBCs.     * Includes T-cells, B-cells, and Natural Killer (NK) cells.     * Primarily involved in specific (adaptive) immunity.
2. Monocytes:     * Represent $3-8\%$ of WBCs.     * Leave the blood and mature into Macrophages, which are highly phagocytic.

Clinical Analysis of Leukocytes

A differential white blood cell count is a diagnostic tool used to identify disease:

• Increase in Eosinophils: May indicate an allergic reaction or parasitic worm infection.
• Increase in total Leukocytes: May suggest bacterial/viral infection or cancer.

Phagocytosis and Immune Signaling

Phagocytosis means "eating by cell." It is the process by which cells obtain nutrients and rid the body of pathogens.

The Six Steps of Phagocytosis

1. Chemotaxis: Movement toward (positive chemotaxis) or away from (negative chemotaxis) a chemical stimulus. Phagocytes use pseudopods to crawl toward infection sites, attracted by microbial components, secretions, damaged tissues, white blood cells, chemokines, and cytokines.
2. Adherence: The phagocyte attaches to the microorganism via glycoproteins. This is enhanced by opsonization, where pathogens are coated with complement proteins to provide more binding sites.
3. Ingestion: The phagocyte extends pseudopods to surround and engulf the pathogen.
4. Maturation: Membranous organelles fuse with the newly formed phagosome to create a phagolysosome.
5. Killing: The phagolysosome uses antimicrobial substances, toxic oxygen forms, a very acidic environment, and enzymes to destroy the microbe, resulting in a residual body.
6. Elimination: Incomplete digestion remnants are released via exocytosis. These processed pieces may later serve adaptive immunity or recruit other cells (leukocytes, lymphocytes) to the site.

Chemical Signaling: Cytokines and Chemokines

• Cytokines: Soluble proteins acting as communication signals. They regulate proliferation, differentiation, and inhibition.     * Autocrine: Stimulates the cell that secreted it.     * Paracrine: Stimulates nearby cells.     * Endocrine: Travels through the bloodstream to stimulate distant cells.
• Chemokines: Specific chemotactic factors that recruit leukocytes to sites of infection, damage, or inflammation.

Nonphagocytic Killing

Some cells kill microbes without engulfing them:

• Eosinophils: Attach to parasitic worms and inject toxic extracellular proteins (including mitochondrial DNA) to weaken or kill the worm.
• NK Lymphocytes: Secrete toxins onto the surface of virally infected cells and tumors to induce cell death.
• Neutrophils (PMNs): Create super toxic, reactive oxygen radicals ($O_2^-$) to kill nearby invaders. They also form NETs (Neutrophil Extracellular Traps)—a form of cellular suicide that traps and kills pathogens.

The Complement System

The complement system consists of over $30$ proteins (mostly produced by the liver) circulating in inactive forms. It enhances antibodies and phagocytic cells.

Key Components and Activation

• C3 Convertase: Cleaves C3 into C3a (inflammation) and C3b (opsonization).
• C5 Convertase: Cleaves C5 into C5a (inflammation) and C5b (initiates MAC).
• Membrane Attack Complex (MAC): Formed by proteins C5b, C6, C7, C8, and C9. It creates a pore in pathogen membranes, leading to lysis (primarily affecting Gram-negative bacteria).

Activation Mechanisms

1. Classical Pathway: Most efficient; requires adaptive immunity (antigen-antibody complexes).
2. Alternative Pathway: Spontaneous activation of C3 ($C3 \rightarrow C3a + C3b$) on pathogenic surfaces.
3. Lectin Pathway: Requires binding of lectin (Mannose-Binding Lectin or MBL) to carbohydrates on the microbial surface.

Inflammation and Fever

Inflammation is a protective response to eliminate the cause of injury, remove damaged cells, and initiate repair.

Types of Inflammation

1. Acute Inflammation: Short-term, rapid onset (minutes/hours). Involves neutrophils, macrophages, and mast cells. Resolves when the threat is gone.
2. Chronic Inflammation: Long-term (weeks/months). Involves lymphocytes, macrophages, and fibroblasts. Can lead to autoimmune disorders, cancer, and fibrosis.

The Steps of the Inflammatory Response

1. Recognition: Pattern recognition receptors (PRRs) detect pathogens or damage.
2. Vasodilation & Permeability: Histamines and prostaglandins cause blood vessels to widen and leak, leading to edema (swelling). This allows clotting factors and phagocytes to reach the wound.
3. Cell Recruitment: Chemokines (e.g., IL-8) guide neutrophils (first) then monocytes/macrophages to the site.
4. Clearance & Repair: Phagocytes destroy debris and microbes. Cytokines like IL-1, TNF-α, and IL-6 coordinate the response. Platelets seal the area.

The Cardinal Signs (The 5 R's)

1. Redness (Rubor): Caused by increased blood flow.
2. Heat (Calor): Caused by increased metabolism and blood flow.
3. Swelling (Tumor): Accumulation of fluid (edema).
4. Pain (Dolor): Activation of receptors by inflammatory mediators.
5. Loss of Function: Result of severe inflammation.

Summary of Nonspecific Defenses

Transition to the Third Line of Defense

Specific or Acquired Immunity involves the body's ability to recognize and defend against distinct invaders. It features Specificity, Memory, and Self-tolerance. It is triggered by Antigens and divided into:

1. Humoral Immunity: B cells producing specific antibodies.
2. Cell-mediated Immunity: Activated T cells targeting intracellular pathogens, cancer cells, and tissue transplants.