The Immune System: Overview

General Functions and Organization

The immune system is a functional system that provides resistance to disease-causing microorganisms such as bacteria, fungi, and viruses. It utilizes a variety of molecules and immune cells, especially lymphocytes, which reside in lymphoid tissues and circulate in body fluids. The body employs three lines of defense, acting both independently and cooperatively, to resist invasion and provide immunity.

• First Line of Defense: Surface barriers (skin and mucosae)

• Second Line of Defense: Innate internal defenses (inflammation, antimicrobial proteins, phagocytes)

• Third Line of Defense: Adaptive (specific) defense system (lymphocytes and antibodies)

Innate Defenses

Surface Barriers: First Line of Defense

Surface barriers include the skin and mucous membranes, along with their secretions. These barriers are highly effective for most microbes due to the presence of keratin, which is resistant to acids, bases, bacterial enzymes, and toxins. Mucosae provide similar mechanical barriers within the body.

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

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 such as phagocytes, natural killer cells, antimicrobial proteins, inflammation, and fever.

• Pattern Recognition Receptors: Toll-like receptors (TLRs) recognize specific classes of attacking microbes and trigger immune responses.

Phagocytes

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

• Neutrophils: Most abundant phagocytes; phagocytize infectious material in tissues.

• Macrophages: Most voracious phagocytes; can be free (wandering) or fixed (resident in organs).

Phagocytosis Process

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

Natural Killer (NK) Cells

NK cells are large granular lymphocytes that police blood and lymph, targeting cells with abnormal surface proteins (e.g., lacking MHC). They kill cancer and virus-infected cells by inducing apoptosis and secrete chemicals that enhance inflammation.

Inflammation

Inflammation is a nonspecific response to tissue injury, characterized by redness, heat, swelling, pain, and sometimes impaired function. It 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, cytokines, and complement proteins are released.

• Vasodilation and Increased Permeability: Local hyperemia and exudate formation bring immune cells and chemicals to the affected area.

Phagocyte Mobilization

Four steps:

1. Leukocytosis: Increased WBCs enter blood from bone marrow.

2. Margination: Phagocytes cling to capillary walls.

3. Diapedesis: Phagocytes squeeze through capillary walls.

4. Chemotaxis: WBCs move toward injured area guided by chemicals.

Antimicrobial Proteins

• Interferons (IFNs): Proteins produced by virus-infected cells that interfere with viral replication in neighboring cells.

• Complement System: A group of plasma proteins that amplify inflammation and lyse certain bacteria and cells. Activated via classical, lectin, or alternative pathways.

Fever

Fever is a systemic response to infection, triggered by pyrogens released by leukocytes and macrophages. It increases immune cell migration, metabolic rate, and suppresses bacterial growth.

Adaptive Defenses

General Features

The adaptive immune system is a specific defense system that targets and eliminates pathogens and abnormal cells. It consists of humoral (antibody-mediated) and cellular (cell-mediated) immunity.

• Humoral Immunity: Antibodies in body fluids bind to extracellular targets.

• Cellular Immunity: Lymphocytes target infected, cancerous, or foreign cells.

Antigens

Antigens are substances that trigger adaptive defenses.

• Complete Antigens: Have immunogenicity and reactivity; include proteins, polysaccharides, lipids, and nucleic acids.

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

• Antigenic Determinants: Specific parts of an antigen that antibodies or lymphocyte receptors bind to.

Self-Antigens: MHC Proteins

MHC proteins are glycoproteins on cell surfaces that display self or foreign peptides. They are unique to each individual and are essential for T cell recognition.

Cells of the Adaptive Immune Response

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

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

• Antigen-Presenting Cells (APCs): Present antigens to T cells.

Lymphocyte Development, Maturation, and Activation

1. Origin: Hematopoietic stem cells in red bone marrow.

2. Maturation: Occurs in bone marrow (B cells) or thymus (T cells); involves immunocompetence and self-tolerance.

3. Seeding: Naive cells colonize secondary lymphoid organs.

4. Antigen Encounter and Activation: Clonal selection upon antigen challenge.

5. Proliferation and Differentiation: Formation of effector and memory cells.

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 maintain T cell activation.

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

Humoral Immunity

B Cell Activation and Antibody Production

Naive B cells are activated by binding to their specific antigen, leading to clonal selection, proliferation, and differentiation into plasma cells (antibody-secreting) and memory cells.

Primary and Secondary Humoral Responses

• Primary Response: Occurs upon initial exposure; lag period of 3–6 days.

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

Active and Passive Humoral Immunity

• Active Immunity: B cells produce antibodies; acquired naturally (infection) or artificially (vaccination).

• Passive Immunity: Antibodies are introduced; acquired naturally (mother to fetus/infant) or artificially (injection of antibodies).

Antibodies (Immunoglobulins)

Antibodies are proteins secreted by plasma cells, grouped into five classes: IgG, IgA, IgM, IgE, and IgD.

• Structure: Four polypeptide chains (two heavy, two light) with variable and constant regions.

• Function: Bind specifically to antigens and dictate antibody class.

Antibody Classes

• IgG: Main antibody of secondary response; crosses placenta.

• IgA: Found in secretions; prevents pathogen entry.

• IgM: First antibody released; potent agglutinating agent.

• IgE: Triggers histamine release; involved in allergies.

• IgD: Functions as B cell receptor.

Antibody Roles

• Neutralization: Block sites on pathogens or toxins.

• Agglutination: Clumping of antigens.

• Precipitation: Formation of large complexes for phagocytosis.

• Complement Activation: Leads to cell lysis and enhances inflammation.

Cellular Immunity

T Lymphocytes and Their Functions

T cells provoke cellular immune responses when presented with antigens.

• CD4 Cells: Become helper T cells (activate B cells, other T cells, and macrophages) or regulatory T cells (moderate immune response).

• CD8 Cells: Become cytotoxic T cells (destroy infected, abnormal, or foreign cells).

MHC Proteins and Antigen Presentation

T cells respond only to processed fragments of antigens displayed by MHC proteins.

• MHC Class I: On all body cells except RBCs; display endogenous antigens.

• MHC Class II: On antigen-presenting cells; display exogenous antigens.

Activation and Differentiation of T Cells

T cell activation requires antigen binding and co-stimulation by APCs. Activated T cells proliferate and differentiate into effector and memory cells.

Roles of Specific Effector T Cells

• Helper T Cells: Mobilize both humoral and cellular immunity; activate B cells, other T cells, and macrophages.

• Cytotoxic T Cells: Directly attack and kill infected, cancerous, or foreign cells using perforins and granzymes to induce apoptosis.

• Regulatory T Cells: Suppress immune response and prevent autoimmunity.

Immune System Disorders

Immunodeficiencies

• SCID: Severe combined immunodeficiency; marked deficit in B and T cells.

• AIDS: Acquired immune deficiency syndrome; caused by HIV, destroys helper T cells.

Autoimmune Diseases

Autoimmunity results from failure to distinguish self from foreign antigens, leading to destruction of self tissues. Examples include rheumatoid arthritis, myasthenia gravis, multiple sclerosis, Graves’ disease, type 1 diabetes, lupus, and glomerulonephritis.

Hypersensitivities

• Immediate (Acute) Hypersensitivity: Allergies; IgE-mediated, rapid onset.

• Subacute Hypersensitivity: IgM and IgG-mediated; slower onset, longer duration.

• Delayed Hypersensitivity: T cell-mediated; takes 1–3 days to appear.

Developmental Aspects of the Immune System

Immune System Development and Aging

• Immune system stem cells develop in liver and spleen during early weeks, then bone marrow becomes primary source.

• Efficiency wanes with age, increasing susceptibility to infections, cancer, and autoimmune diseases.

• Thymus atrophies after puberty, reducing naive T and B cell production.

• Chronic low-grade inflammation may promote age-related diseases.

Summary Table: Key Differences Between Innate and Adaptive Defenses

Summary Table: Immunoglobulin Classes

Summary Table: Types of Hypersensitivity