The Immune System: Overview

General Functions and Organization

The immune system provides resistance to disease-causing microorganisms such as bacteria, fungi, and viruses. It is a functional system, not an anatomical organ system, and utilizes 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 acting both independently and cooperatively to resist invasion.

• Three lines of defense:

  • Surface barriers (first line)

  • Innate internal defenses (second line)

  • Adaptive (specific) defense system (third line)

• Integration: Innate and adaptive defenses are integrated, always working together.

Innate Defenses

Surface Barriers: First Line of Defense

Surface barriers include the skin and mucous membranes, along with their secretions. These barriers are in place at birth and provide mechanical and chemical protection against pathogens.

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

• Mucosae: Provide similar mechanical barriers within the body.

• Protective chemicals:

  • 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 stomach kill many microbes.

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

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

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

• Respiratory tract: Mucus-coated hairs in nose trap particles; cilia sweep dust- and bacteria-laden mucus toward mouth.

Innate Internal Defenses: 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 pathogens by recognizing specific-shaped molecules found on them (not on normal human cells).

• Toll-like receptors (TLRs): Play a central role in triggering immune responses; humans have 11 TLRs, each recognizing a particular class of attacking microbe.

Phagocytes and Phagocytosis

Phagocytes are white blood cells that ingest and digest foreign invaders and cellular debris. The most abundant are neutrophils, while macrophages are the most voracious.

• Free macrophages: Wander through tissue spaces (e.g., alveolar macrophages).

• Fixed macrophages: Permanent residents of particular organs (e.g., stellate macrophages of liver).

Phagocytosis begins when phagocyte receptors bind to a particle, which is then pulled inside and enclosed within a membrane-lined vesicle (phagosome). The phagosome fuses with a lysosome to form a phagolysosome, where lysosomal enzymes digest contents.

• Respiratory burst: Helper T cells stimulate macrophages to produce destructive free radicals and oxidizing chemicals to kill resistant pathogens.

• Opsonization: Pathogens are coated with opsonins (complement proteins or antibodies) to accelerate phagocytosis.

• Netosis: Neutrophils release sticky nets of DNA and proteins to trap and kill extracellular pathogens.

Natural Killer (NK) Cells

NK cells are large granular lymphocytes that police blood and lymph, looking for general abnormalities such as lack of "self" cell-surface proteins (MHC). They can kill cancer and virus-infected cells before the adaptive immune system is activated, primarily by inducing apoptosis.

Inflammation: Tissue Response to Injury

Inflammation is a nonspecific response to any tissue injury, with benefits including prevention of pathogen spread, disposal of debris, alerting the adaptive immune system, and setting the stage for repair. The four cardinal signs are redness, heat, swelling, and pain.

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

• Vasodilation and increased vascular permeability: Local hyperemia brings more immune cells; exudate seeps into tissue, causing swelling and pain.

• Phagocyte mobilization: Neutrophils and monocytes flood damaged tissue in four steps: leukocytosis, margination, diapedesis, and chemotaxis.

Antimicrobial Proteins

Antimicrobial proteins enhance innate defenses by attacking microbes directly or hindering their ability to reproduce. The most important are interferons and complement proteins.

• Interferons (IFNs): Immune-modulating proteins produced by virus-infected cells; stimulate production of proteins that block viral replication in neighboring cells.

• Complement system: At least 20 plasma proteins that circulate in inactive state; activated complement amplifies inflammation and lyses certain bacteria and other cell types.

Fever

Fever is a systemic response to invading microbes. Pyrogens secreted by leukocytes and macrophages act on the hypothalamus to raise body temperature, enhancing immune response and suppressing bacterial growth.

Adaptive Defenses

General Features

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

• Humoral immunity: Provided by antibodies in body fluids; targets extracellular pathogens.

• Cellular immunity: Provided by lymphocytes; targets infected body cells, cancer cells, and foreign cells.

Antigens

Antigens are substances that can mobilize the adaptive defenses and provoke an immune response. Most are large, complex molecules that are foreign to the body.

• Complete antigens: Have immunogenicity and reactivity.

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

• Antigenic determinants: Parts of antigen that antibodies or lymphocyte receptors bind to; most antigens have several determinants.

Self-Antigens: MHC Proteins

MHC proteins are glycoproteins coded by the major histocompatibility complex and unique to each individual. They display peptides (self or foreign antigens) and are essential for T lymphocyte recognition.

B and T Lymphocytes and Antigen-Presenting Cells

The adaptive immune system involves three crucial types of cells:

• B lymphocytes (B cells): Provide humoral immunity.

• T lymphocytes (T cells): Provide cellular immunity.

• Antigen-presenting cells (APCs): Present antigens to T cells; include dendritic cells, macrophages, and B lymphocytes.

Lymphocyte Development, Maturation, and Activation

T and B cells share five general steps in their life cycles: origin, maturation, seeding secondary lymphoid organs, antigen encounter and activation, and proliferation and differentiation.

• Immunocompetence: Ability to recognize a specific antigenic determinant.

• Self-tolerance: Unresponsiveness to self-antigens.

• Somatic recombination: Process by which lymphocytes generate diverse antigen receptors.

• T cell education: Positive and negative selection in the thymus ensures self-tolerance.

Humoral Immunity: Antibody Production

When a B cell encounters its antigen, it triggers a humoral immune response, leading to the production of antibodies specific for that antigen. Most clone cells become plasma cells, which secrete antibodies, while some become memory cells.

Active and Passive Humoral Immunity

Active immunity: B cells encounter antigens and produce antibodies; can be naturally acquired (infection) or artificially acquired (vaccination).

Passive immunity: Antibodies are introduced into the body; can be naturally acquired (mother to fetus/infant) or artificially acquired (injection of exogenous antibodies).

Antibodies: Structure and Classes

Antibodies (immunoglobulins, Ig) are proteins secreted by plasma cells. They have a basic structure of four polypeptide chains (two heavy, two light) forming a T or Y shape. The variable regions form antigen-binding sites, while the constant regions determine antibody class and function.

• IgG: Main antibody of secondary and late primary responses; crosses placental barrier.

• IgA: Found in secretions; helps prevent entry of pathogens.

• IgM: First antibody released during primary response; potent agglutinating agent.

• IgE: Binds to mast cells/basophils; involved in allergic responses.

• IgD: Functions as B cell surface receptor.

Antibody Targets and Functions

Antibodies inactivate and tag antigens for destruction, forming antigen-antibody complexes. Defensive mechanisms include:

• Neutralization: Antibodies block specific sites on viruses or toxins.

• Agglutination: Antibodies cause clumping of antigens.

• Precipitation: Soluble molecules cross-link into large complexes.

• Complement activation: Triggers cell lysis and amplifies inflammation.

Cellular Immunity

T Lymphocytes: Types and Functions

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

• Helper T cells (CD4): Activate B cells, other T cells, and macrophages; direct adaptive immune response.

• Regulatory T cells: Moderate immune response.

• Cytotoxic T cells (CD8): Destroy infected, abnormal, or foreign cells.

MHC Proteins and Antigen Presentation

T cells respond only to processed fragments of antigens displayed on cell surfaces by MHC proteins. MHC restriction means CD4 and CD8 cells have different requirements for the MHC protein class that presents antigens to them.

Activation and Differentiation of T Cells

T cells are activated by APCs in a two-step process involving antigen binding and co-stimulation. Activated T cells proliferate and differentiate into effector cells (helper, cytotoxic, regulatory) or memory cells.

Roles of Specific Effector T Cells

• Helper T cells: Mobilize both arms of adaptive immunity; activate B and T cells, secrete cytokines, and amplify innate defenses.

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

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

Immune System Disorders

Immunodeficiencies

Immunodeficiency is a condition that impairs function or production of immune cells or molecules. Examples include severe combined immunodeficiency (SCID) syndromes and acquired immunodeficiencies such as AIDS.

Autoimmune Diseases

Autoimmune diseases occur when the immune system fails to distinguish self from foreign antigens, leading to production of autoantibodies and self-reactive T cells. Examples include rheumatoid arthritis, multiple sclerosis, and type 1 diabetes mellitus.

Hypersensitivities

Hypersensitivities are immune responses to perceived threats that cause tissue damage. Types include:

• Immediate (acute) hypersensitivity: Allergies mediated by IgE.

• Subacute hypersensitivity: Mediated by IgM and IgG; slower onset.

• Delayed hypersensitivity: Mediated by T cells; takes longer to appear.

Developmental Aspects of the Immune System

Immune System Development and Aging

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

Summary Table: Immunoglobulin Classes

Additional info: This table summarizes the key characteristics of immunoglobulin classes, as described in the original textbook tables and images.

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