Marieb Human Anatomy & Physiology Chapter 21: The Immune System

Overview of the Immune System

The immune system is a functional system, not an anatomical organ system, that provides resistance to disease-causing microorganisms (microbes) such as bacteria, fungi, and viruses.
It utilizes a diverse array of molecules and immune cells (notably lymphocytes) residing in lymphoid tissues and circulating in body fluids.
Castle Analogy: The body is like a medieval castle with multiple lines of defense acting independently and cooperatively.
Three Lines of Defense:
- First Line of Defense: Surface barriers consisting of intact skin and mucosae (structural walls and moats).
- Second Line of Defense: Innate internal defenses (inflammation, antimicrobial proteins, and phagocytes) activated when the first line is penetrated.
- Third Line of Defense: The adaptive (specific) defense system, acting like an elite force with specific weapons, though taking longer to mount a response.
Integration: Innate and adaptive systems are integrated; they recognize many of the same molecules. Innate proteins alert the adaptive system to specific foreign molecules.
Effective operations protect from microbes, cancer cells, and transplanted tissues/organs.

Innate Defenses: First Line of Defense (Surface Barriers)

Surface barriers include skin and mucous membranes along with their specific secretions.
Protective Chemicals:
- Acid: The "acid mantle" (acidity of skin, vaginal, and stomach secretions) inhibits bacterial growth.
- Enzymes: Lysozyme in saliva, respiratory mucus, and lacrimal fluid kills microbes; protein-digesting enzymes in the stomach kill many microbes.
- Mucin: A protein that, when dissolved in water, forms sticky mucus lining the digestive and respiratory tracts to trap microbes.
- Defensins: Broad-spectrum antimicrobial peptides secreted in response to inflammation or barrier breach to inhibit growth.
- Other Chemicals: Lipids in sebum and dermcidin in eccrine sweat are toxic to bacteria.
Respiratory Modifications: Mucus-coated nose hairs trap particles, and upper tract cilia sweep mucus toward the mouth.

Innate Defenses: Second Line of Defense (Internal Defenses)

Utilizes nonspecific cellular and chemical means: phagocytes, natural killer (NK) cells, antimicrobial proteins, inflammation, and fever.
Pattern Recognition Receptors: Identify pathogens by binding to specific-shaped molecules (e.g., carbohydrates) not found on human cells.
Toll-like Receptors (TLRs): Humans have $11$ types of TLRs. Each recognizes a specific class of microbe (e.g., one specifically responds to a glycolipid in the cell wall of the tuberculosis bacterium). TLRs are found on macrophages and epithelial cells lining the respiratory and gastrointestinal (GI) tracts.
Phagocytes:
- Neutrophils: Most abundant white blood cells (WBCs); phagocytize infectious material.
- Macrophages: The most voracious phagocytes.
  - Free Macrophages: Wander through tissue spaces (e.g., alveolar macrophages). Derived from monocytes.
  - Fixed Macrophages: Permanent residents (e.g., stellate macrophages in the liver, microglia in the brain).

The Process of Phagocytosis

Adherence: Phagocyte receptors bind to the pathogen.
Engulfment: Pseudopods form to engulf particles, creating a membrane-lined vesicle called a phagosome.
Fusion: The phagosome fuses with a lysosome to form a phagolysosome.
Destruction: Lysosomal enzymes (acid hydrolases) and an acidified environment destroy contents.

Respiratory Burst: For pathogens resistant to enzymes (e.g., tuberculosis), helper T cells ( $T_H$ ) stimulate the macrophage to:
- Release destructive free radicals.
- Produce oxidizing chemicals (e.g., hydrogen peroxide).
- Increase pH and osmolarity to activate protein-digesting enzymes.
Defensins: Secreted by neutrophils to pierce pathogen membranes.
Opsonization: The immune system coats pathogens with opsonins (complement proteins or antibodies) to provide "handles" for phagocytes to grab, accelerating the process.
Netosis: Neutrophils can release a net of DNA and proteins to kill extracellular pathogens, destroying themselves in the process.

Natural Killer (NK) Cells

NK cells are large granular lymphocytes that are nonphagocytic.
They scan blood and lymph for general abnormalities, such as the lack of "self" cell-surface proteins known as MHC (Major Histocompatibility Complex).
They kill cancer and virus-infected cells by inducing apoptosis (programmed cell death) before the adaptive system activates.

Inflammation: Tissue Response to Injury

Inflammation is a nonspecific response triggered by trauma, heat, chemicals, or infection.
Benefits: Prevents pathogen spread, disposes of debris, alerts adaptive immunity, and sets the stage for repair.
Four Cardinal Signs: Redness, Heat, Swelling, and Pain (Impaired function is sometimes the fifth sign).
Step-by-Step Mechanisms:
- Chemical Release: Injured/stressed tissues release histamine (from mast cells), kinins, prostaglandins, and cytokines.
- Vasodilation and Permeability: Local arterioles dilate, causing hyperemia (increased blood flow), resulting in redness and heat. Capillaries become leakier, allowing exudate (fluid with clotting factors and antibodies) to seep into tissues, causing edema (swelling) and pain.
- Phagocyte Mobilization:
  1. Leukocytosis: Neutrophils enter blood from red marrow ( $↑$ within hours).
  2. Margination: Neutrophils use cell adhesion molecules (CAMs) to cling to capillary walls.
  3. Diapedesis: Neutrophils flatten and squeeze between endothelial cells.
  4. Chemotaxis: WBCs follow a chemical trail to the injury site.
Monocytes: Arrive within $12$ hours, transform into macrophages, and provide final disposal of debris.
Pus: A yellow mixture of dead/dying neutrophils, broken-down tissue, and pathogens. If not cleared, it can be walled off as an abscess. Granulomas are tumor-like growths containing resistant bacteria (e.g., tuberculosis) surrounded by macrophages and a capsule.

Antimicrobial Proteins: Interferons and Complement

Interferons (IFNs): Immune-modulating proteins.
- Virus-infected cells secrete IFNs to protect neighbors.
- IFNs stimulate neighboring cells to block protein synthesis and degrade viral RNA.
- They activate NK cells and macrophages to fight cancer cells.
- Clinical use: Treatment for hepatitis C, genital warts, and multiple sclerosis.
Complement System: Consists of at least $20$ plasma proteins circulating in an inactive state.
- Activation Pathways:
  1. Classical: Activated by antibodies.
  2. Lectin: Activated by lectins binding to microbial sugars.
  3. Alternative: Activated spontaneously on microbial surfaces lacking inhibitors.
- Outcomes (The "PLAN" of Action):
  - Lysis: $C3b$ triggers the insertion of a Membrane Attack Complex (MAC), creating pores that cause a massive influx of water.
  - Opsonization: $C3b$ coats pathogens to enhance phagocytosis.
  - Inflammation: $C3a$ and other products stimulate histamine release and attract cells.

Fever

A systemic response to microbes involving an abnormally high body temperature.
Pyrogens: Secreted by leukocytes/macrophages to act on the hypothalamus (the body's thermostat).
Benefits:
- Increases T lymphocyte and monocyte migration into lymph nodes.
- Increages metabolic rate for faster repair and T cell production.
- Suppresses bacterial growth by reducing available metal ions (like iron).

Adaptive Defenses: Third Line of Defense

Specific: Targets identified antigens.
Systemic: Not restricted to the infection site.
Memory: Mounts stronger attacks on subsequent encounters.
Two Arms:
1. Humoral Immunity (Antibody-mediated): Antibodies in fluids (blood/lymph) target extracellular bacteria, toxins, and viruses.
2. Cellular Immunity (Cell-mediated): Lymphocytes target infected body cells, cancer cells, or foreign cells directly or indirectly.

Antigens and MHC Proteins

Antigens: Contraction of "antibody-generating"; substances provoking an immune response. Most are large, complex, nonself molecules.
Complete Antigens: Feature Immunogenicity (stimulation of lymphocyte proliferation) and Reactivity (ability to react with activated cells/antibodies).
Haptens (Incomplete Antigens): Small molecules (e.g., poison ivy, dander, cosmetics) that are not immunogenic unless attached to a body protein carrier.
Antigenic Determinants: The specific immunogenic parts of an antigen that antibodies or receptors bind to.
Self-Antigens (MHC Proteins): Glycoproteins unique to individuals.
- Class I MHC: Found on all nucleated body cells (not RBCs); display endogenous antigens (pieces of proteins made inside the cell).
- Class II MHC: Found only on APCs; display exogenous antigens (pieces of engulfed pathogens).

Lymphocyte Life Cycle and Education

Origin: Hematopoietic stem cells in red bone marrow.
Maturation: A $2$ to $3$ day process. B cells mature in red bone marrow; T cells mature in the thymus.
- Immunocompetence: Ability to recognize one specific antigen; cells display approximately $10^4$ identical receptors.
- Self-tolerance: Unresponsiveness to self-antigens.
- T Cell Education:
  - Positive Selection: Must recognize self-MHC; those that cannot are destroyed.
  - Negative Selection: Must NOT recognize self-antigens on self-MHC; those that do are destroyed via clonal deletion. Only $2\%$ survive.
Seeding: Naive (unexposed) cells colonize secondary lymphoid organs (spleen, lymph nodes).
Antigen Encounter: Stimulates clonal selection.
Proliferation and Differentiation: Cells form clones; most become effector cells, some become memory cells.

Somatic Recombination: Gene pieces are shuffled (like a Lego set) to create up to a billion types of antigen receptors from only hundreds of genetic bits.

Antigen-Presenting Cells (APCs)

Dendritic Cells: Mobile lookouts in skin and mucosae. Phagocytize antigens and travel to lymph nodes. The most effective APC known.
Macrophages: Present antigens to activate naive T cells and maintain T cell activation. They also become insatiable phagocytes.
B Lymphocytes: Present antigens to helper T cells to assist their own (B cell) activation.

Humoral Immunity: Antibodies and Memory

B Cell Activation: Occurs when receptors bind to an antigen, followed by receptor-mediated endocytosis, proliferation, and differentiation.
Plasma Cells: Effector B cells that secrete antibodies at a rate of $2000$ per second for $4$ to $5$ days.
Memory Cells: Provide immunological memory.
Immune Responses:
- Primary Response: $3$ to $6$ day lag; peak antibody levels reached in $10$ days.
- Secondary Response: Faster and more effective. Antibody concentration (titer) peaks in $2$ to $3$ days at higher levels and with greater affinity.
Types of Humoral Immunity:
- Active Natural: Infection.
- Active Artificial: Vaccine (dead/attenuated pathogens or mRNA). 65,000 Americans die annually from preventable infections.
- Passive Natural: Antibodies via placenta or milk.
- Passive Artificial: Exogenous antibodies (gamma globulin, antivenom, antitoxin); provides immediate but short-term ( $2$ to $3$ weeks) protection.

Antibody Structure and Classes

Basic Structure: T or Y shaped monomer; four polypeptide chains linked by disulfide bonds. Two variable (V) regions form antigen-binding sites; constant (C) regions determine class.
Five Classes:
- IgM: First class secreted during primary response; pentamer structure; potent agglutinating agent; activates complement.
- IgA: Dimer; "secretory IgA" found in saliva, sweat, and milk; prevents pathogen attachment to membranes.
- IgD: Monomer; B cell surface receptor.
- IgG: Most abundant ( $75$ to $85\%$ ); main antibody of late primary and secondary responses; crosses placenta; activates complement.
- IgE: Stem binds to mast cells/basophils; triggers histamine; levels rise during allergies or parasitic worm infections.
Antibody Mechanisms (PLAN):
- Precipitation: Soluble molecules cross-linked into large complexes.
- Lysis: Via complement activation.
- Agglutination: Clumping of cell-bound antigens.
- Neutralization: Blocking sites on viruses or toxins.
Monoclonal Antibodies: Pure preparations for a single determinant; used in pregnancy tests, STI testing, and cancer treatment.

Cellular Immunity: T Lymphocyte Activation and Types

T cells require Double Recognition: They must bind both the MHC protein and the foreign antigen it displays.
CD4 Cells: Usually become Helper T cells ( $T_H$ ) or Regulatory T cells ( $T_{Reg}$ ). Restricted to Class II MHC.
CD8 Cells: Become Cytotoxic T cells ( $T_C$ ). Restricted to Class I MHC.
Two-Step Activation:
1. Antigen Binding: TCR binds to antigen-MHC complex.
2. Co-stimulation: T cell binds co-stimulatory signals on APCs. Without this, the cell enters anergy (unresponsiveness).
Cytokines: Chemical messengers like Interleukin 1 (IL-1) and Interleukin 2 (IL-2). IL-2 is a key growth factor for T cell division.

Specific Effector T Cell Roles

Helper T Cells ( $T_H$ ): Central role. Without $T_H$ , there is NO adaptive response. They activate B cells (via cytokines), signal dendritic cells to activate CD8 cells, and amplify innate defenses.
Cytotoxic T Cells ( $T_C$ ): Directly attack cells. Mechanism: Release perforins (to create pores) and granzymes (to enter and induce apoptosis). They perform immune surveillance.
Regulatory T Cells ( $T_{Reg}$ ): Dampen the response to prevent autoimmune reactions via inhibitory cytokines like IL-10.
Organ Transplants: Most are allografts (same species). Require matching ABO/MHC antigens and lifelong immunosuppressive therapy. Infections and cancers are major death causes for recipients.

Disorders of the Immune System

Immunodeficiencies:
- Severe Combined Immunodeficiency (SCID): Genetic defect; deficit in B and T cells.
- Hodgkin’s Lymphoma: Cancer of B cells.
- AIDS: Caused by HIV (Human Immunodeficiency Virus). Destroys $T_H$ cells. HIV uses reverse transcriptase to produce DNA from viral RNA (a provirus). No cure, but "anti-HIV cocktails" exist.
Autoimmune Diseases: Failure of self-distinction (autoimmunity). Affects $5\%$ of North American adults ( $2/3$ female). Examples: Rheumatoid arthritis, Multiple sclerosis, Type 1 diabetes, Systemic lupus erythematosus (SLE).
- Causes: Cross-reactivity (e.g., rheumatic fever) or appearance of new self-antigens via mutation or trauma.
Hypersensitivities:
- Immediate (Type I): Allergies; IgE binds to mast cells; flood of histamine. Anaphylactic shock is a systemic response treated with epinephrine.
- Subacute: IgM/IgG mediated. Slower onset ( $1$ to $3$ hours); lasts $10$ to $15$ hours (e.g., mismatched blood transfusion).
- Delayed: T cell mediated. Onset in $1$ to $3$ days (e.g., poison ivy/contact dermatitis, TB skin tests).

Developmental and Aging Aspects

Stem cells develop in liver/spleen (weeks $1$ to $9$ ) before bone marrow takes over.
Newborn immunity depends on antibodies and $T_H$ cells. Lack of exposure to microbes may teeter the system toward allergies.
Impact of Aging: Thymus atrophies after puberty; production of naive cells declines. Older adults move into a state of sustained low-grade inflammation, contributing to atherosclerosis and Alzheimer’s disease. Dietary Vitamin D is essential for activating CD8 cells.

Cytotoxic T cells (Tc cells) are a type of T lymphocyte responsible for directly attacking and destroying infected cells, cancer cells, or foreign cells.

Targets of Cytotoxic T Cells

Infected Cells: Primarily, Tc cells target cells infected by viruses or intracellular pathogens.
Cancer Cells: They can also recognize and eliminate cells that have undergone malignant transformation.
Foreign Cells: Tc cells may target transplanted tissues or organs that are recognized as non-self.

Mechanism of Killing

Cytotoxic T cells utilize specific mechanisms to kill their targets:

Recognition: Tc cells recognize specific antigens presented on the surface of infected or abnormal cells via the MHC Class I molecules.
Release of Cytotoxic Granules: Upon activation, Tc cells release cytotoxic granules containing perforins and granzymes.
- Perforins: These create pores in the target cell's membrane, leading to an influx of water and ions.
- Granzymes: These serine proteases enter the target cell through the pores and induce apoptosis (programmed cell death) by activating apoptotic pathways.
Induction of Apoptosis: The combined action of perforins and granzymes leads to the destruction of the target cells, thereby eliminating the threat without harming adjacent healthy cells.