The Immune System: Innate and Adaptive Body Defenses

Introduction to the Immune System

The immune system is a functional system that provides resistance to disease-causing microorganisms such as bacteria, fungi, and viruses. It is not an anatomical organ system but consists of a variety of molecules and immune cells, especially lymphocytes, that reside in lymphoid tissues and circulate in body fluids. The immune system is often compared to a medieval castle with multiple lines of defense that act both independently and cooperatively to resist invasion.

• Three lines of defense: Surface barriers (first line), innate internal defenses (second line), and adaptive (specific) defenses (third line).

Part 1—Innate Defenses

Surface Barriers: The First Line of Defense

Surface barriers include the skin and mucous membranes, along with their secretions. These barriers are in place at birth and are the body's first defense against invading pathogens.

• Keratinized epidermis: Highly effective against most microbes; keratin is resistant to weak acids, bases, bacterial enzymes, and toxins.

• Mucosae: Provide mechanical barriers within the body, lining the tracts.

• Protective chemicals:

  • Acid: Acid mantle 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 destroy pathogens.

  • Mucin: Sticky mucus traps microbes in the digestive and respiratory tracts.

  • Defensins: Broad-spectrum antimicrobial peptides secreted in response to barrier breach and inflammation.

  • Other chemicals: Sebum and dermcidin in sweat are toxic to bacteria.

• Respiratory tract modifications: Mucus-coated hairs in the nose trap particles; cilia sweep mucus toward the mouth.

Innate Internal Defenses: The Second Line of Defense

If microbes breach the first line, the second line of defense is activated. This includes nonspecific cellular and chemical means to protect the body, such as phagocytes, natural killer cells, antimicrobial proteins, inflammation, and fever.

• Pattern recognition receptors: Identify potential pathogens by recognizing specific-shaped molecules (e.g., carbohydrates) found on them but not on normal human cells.

• Toll-like receptors (TLRs): A class of pattern recognition receptors that play a central role in triggering immune responses. Humans have 11 TLRs, each recognizing a particular class of microbe.

Phagocytes

Phagocytes are white blood cells that ingest and digest foreign invaders and cellular debris.

• Neutrophils: Most abundant phagocytes; first responders to infection.

• Macrophages: Most voracious phagocytes; derived from monocytes or formed in the embryo (fixed macrophages).

Phagocytosis

Phagocytosis begins when phagocyte receptors bind to a particle, which is then engulfed and enclosed within a vesicle (phagosome). The phagosome fuses with a lysosome to form a phagolysosome, where enzymes digest the contents. Some pathogens resist digestion and require additional mechanisms, such as the respiratory burst or defensins.

Natural Killer (NK) Cells

Natural Killer (NK) cells are large granular lymphocytes that police blood and lymph, targeting cells that lack "self" cell-surface proteins (MHC). They can kill cancer and virus-infected cells before the adaptive immune system is activated by inducing apoptosis and secreting chemicals that enhance inflammation.

Inflammation: Tissue Response to Injury

Inflammation is a nonspecific response to tissue injury caused by trauma, heat, chemicals, or infection. The four cardinal signs are redness, heat, swelling, and pain. Inflammation prevents the spread of pathogens, disposes of debris, alerts the adaptive immune system, and sets the stage for repair.

• Inflammatory chemical release: Histamine, kinins, prostaglandins, and cytokines are released by injured cells and immune cells.

• Vasodilation and increased permeability: Leads to redness, heat, and exudate formation.

• Phagocyte mobilization: Involves leukocytosis, margination, diapedesis, and chemotaxis.

Antimicrobial Proteins: Interferons and Complement

• Interferons (IFNs): Proteins produced by virus-infected cells that help protect neighboring cells by blocking viral replication and degrading viral RNA.

• Complement system: A group of at least 20 plasma proteins that, when activated, amplify inflammation and lyse certain bacteria and other cells. Activation occurs via three pathways: classical (antibody-dependent), lectin (sugar-binding), and alternative (spontaneous on microbe surfaces).

Fever

Fever is a systemic response to infection, mediated by pyrogens that reset the hypothalamic thermostat. Fever enhances immune response, increases metabolic rate, and suppresses bacterial growth by limiting access to iron.

Part 2—Adaptive Defenses

Overview of Adaptive Immunity

The adaptive immune system is a specific defense system that targets and eliminates almost any pathogen. It consists of two overlapping arms:

• Humoral immunity: Antibody-mediated; targets extracellular pathogens.

• Cellular immunity: Cell-mediated; targets infected or abnormal cells.

Antigens

Antigens are substances that trigger adaptive immune responses. Most are large, complex molecules not normally found in the body (nonself).

• Complete antigens: Have immunogenicity and reactivity.

• Haptens: Incomplete antigens that become immunogenic when attached to proteins.

• Antigenic determinants: Specific parts of an antigen recognized by antibodies or lymphocyte receptors.

Self-Antigens: MHC Proteins

Self-antigens are proteins on cell surfaces that are not antigenic to self but are to others. MHC proteins (major histocompatibility complex) are glycoproteins that display peptides (self or foreign) and are essential for T cell recognition.

B and T Lymphocytes and Antigen-Presenting Cells

The adaptive immune response involves B lymphocytes (humoral immunity), T lymphocytes (cellular immunity), and antigen-presenting cells (APCs).

• Lymphocyte development: Originates in red bone marrow; B cells mature in bone marrow, T cells in thymus.

• Immunocompetence: Ability to recognize one specific antigen.

• Self-tolerance: Unresponsiveness to self-antigens.

• Clonal selection: Activation and proliferation of lymphocytes upon antigen encounter.

Antigen-Presenting Cells (APCs)

• Dendritic cells: Capture antigens and present them to T cells in lymph nodes.

• Macrophages: Present antigens to naive T cells and become activated phagocytes.

• B lymphocytes: Present antigens to helper T cells for their own activation.

Humoral Immunity

Antibody Production and Clonal Selection

Naive B cells are activated when their surface receptors bind to an antigen, leading to proliferation and differentiation into plasma cells (antibody-secreting) and memory cells.

Primary and Secondary Humoral Responses

• Primary response: Occurs after initial antigen exposure; lag period of 3–6 days.

• Secondary response: Faster and more effective due to memory cells.

Active and Passive Humoral Immunity

• Active immunity: Body produces antibodies (naturally via infection or artificially via vaccination).

• Passive immunity: Antibodies are received from another source (naturally via placenta/milk or artificially via injection).

Antibodies (Immunoglobulins)

Antibodies are proteins secreted by plasma cells that bind specifically to antigens. They have a basic Y-shaped structure composed of two heavy and two light chains, each with variable and constant regions.

Antibody Classes

• IgG: Main antibody in secondary and late primary responses; crosses placenta.

• IgA: Found in secretions; prevents pathogen entry.

• IgM: First antibody released; potent agglutinating agent.

• IgE: Involved in allergic reactions and defense against parasitic worms.

• IgD: Functions as a B cell receptor.

Antibody Roles

• Neutralization: Blocks binding sites on pathogens/toxins.

• Agglutination: Clumps antigens together.

• Precipitation: Cross-links soluble molecules for easier phagocytosis.

• Complement activation: Triggers cell lysis and enhances inflammation.

Cellular Immunity

T Lymphocytes: Types and Functions

T cells provoke cellular immune responses when presented with antigens. Major types include:

• CD4 cells: Most become helper T cells, which activate B cells, other T cells, and macrophages.

• CD8 cells: Most become cytotoxic T cells, which destroy infected or abnormal cells.

• Regulatory T cells: Moderate the immune response and prevent autoimmunity.

MHC Proteins and Antigen Presentation

MHC proteins display antigen fragments on cell surfaces for T cell recognition. Class I MHC is found on all nucleated cells and presents to CD8 cells; Class II MHC is found on APCs and presents to CD4 cells.

Activation and Differentiation of T Cells

T cells are activated by APCs through antigen binding and co-stimulation. Activated T cells proliferate and differentiate into effector and memory cells. Cytokines, such as interleukins, regulate these processes.

Roles of Specific Effector T Cells

• Helper T cells: Mobilize both humoral and cellular immunity by activating B cells, other T cells, and macrophages.

• Cytotoxic T cells: Directly attack and kill infected or abnormal cells using perforins and granzymes to induce apoptosis.

• Regulatory T cells: Suppress immune responses to prevent autoimmunity.

Clinical Aspects and Immune Disorders

Organ Transplants and Prevention of Rejection

Organ transplants require matching of ABO and MHC antigens. Immunosuppressive therapy is used to prevent rejection but increases risk of infection and cancer.

Immune System Disorders

• Immunodeficiencies: Congenital or acquired conditions that impair immune function (e.g., SCID, AIDS).

• Autoimmune diseases: Immune system attacks self-antigens (e.g., rheumatoid arthritis, type 1 diabetes, multiple sclerosis).

• Hypersensitivities: Overactive immune responses to harmless antigens (allergies, cytotoxic, immune complex, and delayed hypersensitivities).

Developmental Aspects of the Immune System

Immune system stem cells develop in the liver and spleen during early fetal life, then in bone marrow. With age, immune efficiency declines, increasing susceptibility to infections, cancer, and autoimmune diseases. The thymus atrophies after puberty, reducing production of naive T and B cells.