Immunity: An Overview

Understanding Immunity: An Overview of the Immune System

• The lecture aims to explain the triggers of immune responses, how the immune system handles different antigens, and the differences between innate and adaptive immunity.
• The lecture also covers antigen specificity, roles of immune cells, antibody structure and function, and immune system disorders.

Definition of Immunity

• Immunity is the body's ability to recognize foreign substances.
• Immunity can neutralize, eliminate, or metabolize foreign susbstances.
• Immunity can minimize damage to the body's own tissues.
• Key components of immunity are pathogens and toxins.

Anatomy of the Immune System

• Lymphoid organs are specialized structures where immune cells develop, mature, and respond to pathogens.
• Lymphoid organs are crucial in both innate and adaptive immune responses.
• The immune system is localized in several parts of the body.
• Primary lymphoid organs are where immune cells develop; these include bone marrow and thymus.
• Secondary lymphoid organs are where immune responses occur, such as lymph nodes and spleen.

Primary Lymphoid Organs

• Bone marrow is the site of hematopoiesis and produces all blood cells, including B and T cells; B cells mature here.
• Thymus, located near the heart, is essential for T cells maturation, teaching T cells to distinguish between self and non-self.

Secondary Lymphoid Organs

• Spleen filters blood, removes old or damaged red blood cells, and activates lymphocytes in response to pathogens.
• Lymph nodes filter lymph fluid, trap pathogens, and present antigens to lymphocytes.
• Lymphatic vessels collect excess fluid (lymph) that has leaked from blood vessels into tissues, returning it to circulation.

Triggers of an Immune Response

• Pathogens such as bacteria (E. coli, Streptococcus), viruses (influenza, HIV), fungi (Candida), and parasites (Plasmodium) can trigger an immune response.
• Antigens, which are foreign substances that provoke an immune response, such as pollen, venom, and certain food proteins can also trigger an immune response.

Exogenous vs Endogenous Antigens

• Exogenous antigens originate from outside the body (e.g., pathogens).
• Exogenous antigens are processed by antigen-presenting cells (APCs) and presented on Major Histocompatibility Complex (MHC) Class II to CD4+ T cells, signaling for an coordinated immune response.
• Endogenous antigens are produced within the body (e.g., infected or cancerous cells).
• Endogenous antigens are presented on MHC Class I molecules to CD8+ T cells, signaling for the cell to be killed.

Immune System Overview

• The human immune system is divided into innate and adaptive (acquired) immunity.
• Innate immunity involves recognition of traits shared by broad ranges of pathogens, using a small set of receptors, and a rapid response.
• Adaptive (Acquired) immunity involves recognition of traits specific to particular pathogens, using a vast array of receptors, and a slower response.
• Innate immunity is the first line of defense with barrier defenses like physical and chemical barriers, and normal flora.
• Internal defenses such as inflammatory response, phagocytic cells, NK cells, cytokines, and soluble factors are part of the second line of defense.
• Adaptive immunity has humoral response, where antibodies defend against infection in body fluids, and cell-mediated response, where cytotoxic lymphocytes defend against infection in body cells.

Innate Immunity

• Innate immunity is the body's natural, non-specific defense mechanisms present from birth.
• In innate immunity, recognition and response depend on shared traits of pathogens.

First Line of Defense: Preventing Entry & Colonization

• Physical barriers prevent pathogen entry: intact skin forms a nearly impermeable barrier.
• Mucous membranes line the respiratory, digestive, and genitourinary tracts, trapping pathogens; cilia sweep mucus and trapped pathogens away.
• Tears/Saliva wash away pathogens from epithelial surfaces.
• Mechanical actions like coughing, sneezing, vomiting, and diarrhea expel pathogens.

First Line of Defense: Preventing Entry & Colonization - Chemical Barriers

• Chemical barriers neutralize or destroy pathogens.
• Sweat glands lower the pH of the skin to 3-5, creating an acidic environment that inhibits pathogen growth.
• Hydrolytic enzymes (lysozyme) in tears/saliva break down bacterial cell walls, neutralizing them and preventing infections.
• HCl in the stomach (pH 1.5 to 3.5) destroys most ingested pathogens, defending against foodborne illnesses.
• Proteolytic enzymes in the small intestine further digest proteins and can also degrade microbial proteins.
• The naturally acidic environment in the adult vagina helps maintain a healthy microbiota and inhibits harmful pathogens.

First Line of Defense: Preventing Entry & Colonization - Normal Flora

• Normal flora are beneficial microorganisms that colonize the body's surfaces, preventing pathogen colonization.
• Competition occurs as normal flora compete with pathogens for nutrients and space.
• Antimicrobial substances are produced by normal flora to inhibit pathogen growth, such as bacteriocins and lactic acid.
• Examples of normal flora include Staphylococcus epidermidis on the skin and Streptococcus salivarius and Lactobacillus species in the oral cavity.

Second Line of Defense: Internal Defenses

• Internal defenses are activated when pathogens breach the first line of defense.
• These defenses act quickly but are non-specific.
• Internal defenses include the inflammatory response, phagocytic cells, natural killer (NK) cells, complement system, cytokines, and soluble factors.

Inflammatory Response

• Triggered by tissue damage, either from wounds or pathogen invasion.
• Three components to the basic acute inflammatory response: vasodilation, increased vascular permeability, and migration of leukocytes to the affected tissues.

Key Steps in the Inflammatory Response

• Release of chemical mediators occurs by leukocytes, releasing substances such as histamine (causes vasodilation and increases blood flow), fibrin (aids in clot formation), kinins (promote vasodilation and enhance capillary permeability), and cytokines (facilitate communication and amplify the inflammatory response).

Physiological Changes (Effects on Tissue)

• Redness (rubor) is due to increased blood flow from vasodilation.
• Heat (calor) is elevated temperature from increased metabolic activity and blood flow.
• Swelling (tumor) is caused by increased vascular permeability, leading to fluid accumulation in tissues.
• Pain (dolor) is triggered by chemical mediators stimulating nerve endings and pressure from swelling.

Phagocytic Cells

• Phagocytic cells derive from stem cells in the bone marrow.
• Monocytes differentiate into dendritic cells and macrophages.
• Granulocytes (neutrophils, eosinophils, and basophils) are distinct lineages of phagocytic cells.
• Mature monocytes contain granules, but are not technically considered granulocytes.

Types of Phagocytic Cells

• Neutrophils are first responders that engulf pathogens and release enzymes.
• Mast cells have toll-like receptors that trigger inflammatory responses, participate in antigen presentation, and can consume, kill, and process antigens.
• Macrophages clear debris and present antigens to T cells.
• Dendritic cells have long outgrowths called dendrites which help engulf microbes and present antigens to T cells.

Phagocytic Process

• Phagocytosis is the engulfment and destruction of microorganisms by phagocytes.
• Chemotaxis and attachment involve attraction to pathogens via chemotactic substances and attachment through receptors on phagocytes.
• Ingestion and killing involves the formation of a phagosome.
• Oxygen-dependent killing requires oxygen to generate reactive oxygen species (ROS) which are toxic to the microbe.
• Oxygen-independent mechanisms rely on enzymes and other antimicrobial substances already present in the phagocyte's granules.

Neutrophil Migration to Infected Sites

• Neutrophils travel through the bloodstream to reach sites of infection.
• Rolling and Adhesion occur as neutrophils roll along the vascular endothelium, adhering to it through specific interactions with adhesion molecules.
• Transmigration occurs as neutrophils slip through small gaps between endothelial cells into the surrounding tissues.

Natural Killer (NK) Cells

• Large granular lymphocytes play a crucial role in the innate immune response.
• NK cells eliminate the body's own cells that have become infected by viruses, bacteria, fungi, parasites, or transformed by cancer (tumor cells).

Mechanism of Action of Natural Killer (NK) Cells

• Target recognition: NK cells identify and bind to infected or abnormal body cells with receptors, often forming an antibody "bridge."
• Cytotoxic action: Upon binding, NK cells release perforin, which creates pores in the target cell membrane.
• Cell death induction: The formation of multiple pores allows water to enter the target cell, leading to osmotic swelling.
• An influx of calcium ions may trigger apoptosis, resulting in cell death.

Cytokines

• Cytokines are signaling proteins released by immune cells that mediate and regulate immunity and inflammation.
• They promote communication between immune cells.
• They enhance the inflammatory response by recruiting additional cells to sites of infection.

Soluble Factors

• Soluble factors consist of proteins and molecules that circulate in body fluids and contribute to the innate immune response.
• Acute phase proteins, such as C-reactive protein (CRP) and fibrinogen, increase in concentration during inflammation.
• Complement proteins are a group of proteins that enhance the ability of antibodies and phagocytic cells to clear pathogens.
• Interferons are proteins produced by virus-infected cells that help protect neighboring cells from viral infection.
• Properdin stabilizes the complement system for activation.
• Beta-lysine is an antibacterial protein derived from platelets.
• Lactoferrin and transferrin are iron-binding proteins that limit bacterial growth by sequestering iron.
• Lactoperoxidase is an enzyme present in milk and saliva with antimicrobial properties.
• Lysozyme hydrolyses cell wall.

Role of Fever

• Fever is an increase in body temperature as a systemic response to infection or inflammation.
• It is induced by cytokines acting on the hypothalamus.
• Fever inhibits pathogen growth.
• Fever enhances immune cell activity (e.g., neutrophils, macrophages).
• Fever promotes tissue repair.

Complement System

• The complement system consists of proteins that enhance the ability of antibodies and phagocytic cells to clear pathogens.
• Opsonization marks pathogens for destruction by phagocytes.
• Chemotaxis attracts immune cells to sites of infection.
• Lysis directly destroys pathogens by forming membrane attack complexes (MAC).
• The classical pathway is initiated by antibodies bound to pathogens.
• The alternative pathway is initiated by direct interaction with microbial surfaces.

Key Points to Remember About Innate Immunity

• Innate immunity has a fast and immediate response (within hours).
• Innate immunity is a generalized, non-specific response to injury, illness, or infection.
• Innate immunity causes inflammation (swelling, heat, fever) that accompanies an injury or infection.
• Innate immunity includes barrier shields like the skin and mucous membranes.
• Innate immunity includes bodily fluids that are inhospitable to pathogens, such as mucous and tears.
• The innate immune system activates the adaptive immune system.

Adaptive Immunity: Specific and Long-Lasting Protection

• Adaptive immunity is the ability of the immune system to recognize and remember specific pathogens.
• Adaptive immunity leads to an enhanced response upon subsequent exposures.
• Adaptive immunity is also called acquired immunity.
• Adaptive immunity is activated by the innate immune system, which presents antigens and signals the need for a targeted response.
• Humoral immunity and cell-mediated immunity are examples of adaptive immunity.

Adaptive Immunity: Key Characteristics

• Specificity enables this system to distinguish between different pathogens and even different strains of the same pathogen.
• Memory drives the immune system to form a chemical 'memory' of the invading microbe, leading to a rapid, strong response upon re-encounter.

Cells of Adaptive Immunity

• The primary cells involved in adaptive immunity are B lymphocytes (B cells) and T cells.
• B lymphocytes (B cells) produce antibodies, which are specialised proteins that specifically target and neutralize pathogens; this process is known as humoral immunity.
• T cells include helper T cells (CD4+) & cytotoxic T cells (CD8+) both as cell-mediated immunity.
• Helper T cells (CD4+) assist other immune cells by releasing cytokines, which help activate B cells and cytotoxic T cells, and play a crucial role in orchestrating the overall immune response.
• Cytotoxic T cells (CD8+) directly kill infected or cancerous cells by recognizing specific antigens presented on MHC molecules and are essential for controlling viral infections and eliminating tumor cells.

Humoral Immunity: Antibodies to the Rescue

• Humoral immunity defends against extracellular pathogens (bacteria, viruses) in body fluids.
• Humoral immunity is mediated by B cells.
• B cell activation process: antigen recognition occurs as B cell receptors (BCRs) bind to specific antigens.
• Further B cell activation: clonal expansion occurs when activated B cells multiply rapidly.
• B cells differentiate into: Plasma Cells (produce and secrete large quantities of antibodies) and Memory B Cells (provide long-lasting immunity and quick response upon re-exposure).

Antibodies (Immunoglobulins)

• Antibodies, also known as immunoglobulins, are glycoproteins produced by B cells in response to antigens.
• Function: crucial role in the immune response such as:Neutralization, Opsonization, and Activation of complement system.
• Neutralization refers to antibodies neutralizing toxins or block pathogens from entering cells.
• Opsonization refers to antibodies coating pathogens, making them easier targets for phagocytes.
• Activation of the complement system refers to antibody binding, which can trigger the complement system, leading to the destruction of pathogens.

Antibody Structure and Function

• The basic structure is composed of four polypeptide chains: two heavy chains and two light chains in a 'Y' formation.
• Fab Region (fragment of antigen binding) exists as the arms of the Y, contains variable regions responsible for antigen binding (paratope).
• Fc Region (fragment of crystallization) exists as the trunk of the Y, determines immunological function based on heavy chain type.
• The antibody has a unique variable region that binds to a specific epitope on an antigen.
• Binding forces involves electrostatic forces, van der Waals forces, hydrogen bonding, and hydrophobic interactions between epitope and paratope.

Classes of Antibodies

• There are five main classes of antibodies, each with distinct structures and functions: IgA, IgD, IgE, IgG, and IgM.

Cell-Mediated Immunity: T Cells Take Action

• An immune response which does not involve antibodies and instead uses T cells to eliminate infected or abnormal cells after the T cells have been activated by antigen presentation.
• T cells (specifically, cytotoxic T cells and helper T cells) are the key players
• Cell mediated Immunity is effective against intracellular pathogens and cancer.
• T cells can only be activated when their receptors (TCRs) bind to antigens presented on MHC molecules (MHC I and II).

T Cell Receptors (TCRs) and MHC Presentations

• T cells cannot bind to free-floating antigens, and antigens must be presented to the TCR by MHC molecules on the surface of other cells.
• MHC Molecules:Surface receptors can be found on antigen-presenting cells (APCs) that include dendritic cells and macrophages.
• Processed antigen fragments are displayed for recognition by TCRs.
• MHC II on APCs: Signals to CD4+ helper T cells to coordinate an immune response.
• MHC I on infected cells: Signals to CD8+ cytotoxic T cells to kill cells.

Cytotoxic T Cells (CD8+): Targeting Infected Cells

• Cytotoxic T Cells (CD8+) directly kill infected or cancerous cells.
• A cytotoxic T cell's TCR must bind to a specific antigen presented on MHC Class I of an infected or cancerous cell to activate.
• When a cytotoxic T cell is activated, The release cytotoxic granules containing perforin and granzymes.
• Perforin forms pores in the target cell's membrane.
• Granzymes enter the target cell and trigger apoptosis (programmed cell death).

Helper T Cells (CD4+) - Directing the Immune Response

• Helper T Cells help activate other immune cells (B cells, cytotoxic T cells, macrophages) by releasing cytokines (that do not directly kill infected cells).
• A helper T cell's TCR must bind to a specific antigen presented on MHC Class II of an APC (dendritic cell, macrophage, or B cell) to activate the cells.
• B Cell Activation: Help B cells produce antibodies by providing co-stimulatory signals and cytokines.
• Cytotoxic T Cell Activation: Secrete cytokines (e.g., IL-2) that promote the proliferation and activation of cytotoxic T cells.
• Macrophage Activation: Secrete cytokines (e.g., IFN-gamma) that enhance the ability of macrophages to kill ingested pathogens.

Summary of Humoral and Cell-Mediated Immune Response

• Adaptive Immunity consist of a Humoral (mediated by antibodies), which Target extracellular pathogens with a B cell key player.
• Also Adaptive Immunity consists of Cell mediated which target Intracelluar pathogens through Infected cells with T cells(CD8+ and CD4+) key players;
• T cells require the MHC to activate for cell medicated Adaptive immunity.

Immunological Memory - The Foundation of Long-Term Immunity

• The ability of the immune system to mount a faster and stronger response upon repeated exposure to the same antigen.

Primary vs. Secondary Immune Response

• Primary Immune Response occurs after the first encounter with an antigen and is Slow and weak due to naïve B and T cells needing activation to lead to generating memory cells.
• Secondary Immune Response occurs upon subsequent encounters with the same antigen and is Rapid and strong through relies on pre-existing memory B and T cells in order to eliminate the pathogen before it can cause significant disease.

Memory B Cells: Long-Lived Antibody Factories

• Patrol the body, ready to respond swiftly if the same antigen returns, rapidly differentiating into plasma cells, producing large amounts of high-affinity antibodies.
• Provide Faster & more effective neutralization & clearance of said pathogen.

Memory T Cells: Ready to Defend

• Persist in the body for years, ready to act on T antigens that originally activated;
• Memory CD4+ T cells help activate other immune cells and memory CD8+ T cells that quickly become activated and mount a rapid & potent cell-mediated immune response.

Overview of Immune System Disorders

• Immunodeficiency disorders: such as severe combined immunodeficiency (SCID) and acquired immunodeficiency syndrome (AIDS), result from a weakened immune system, making individuals more susceptible to infections.
• Autoimmune disorders, such as rheumatoid arthritis, lupus, and multiple sclerosis, occur when the immune system mistakenly attacks the body's own tissues.
• Hypersensitivity reactions are exaggerated immune responses to harmless substances, such as allergies and asthma.