Pre Lecture: Host defense mechanisms 1

Introduction

• Speaker: Annette Hatt Sintel

• Affiliation: Veterinary immunology and parasitology in veterinary medicine and veterinary nursing programs.

• Purpose of Lectures: Provide a refresher on host defense mechanisms relevant to immune mechanisms; not comprehensive but highlights key immune responses.

• Contact Information: Questions can be posted on Brightspace or sent via email for discussion in face-to-face sessions.

Recommended Textbooks

• Cellular and Molecular Immunology by Abbas

  • Description: Despite its daunting title, it is very readable.

  • Highlight: Contains favorable introductions at the start of each chapter.

  • Availability: Accessible as an e-book through the library website.

• Textbook by Michael Day

  • Description: Concise and well-structured.

  • Availability: Only available in hard copy at the library, on short loan.

Learning Objectives

• Compare characteristics of the innate and adaptive immune responses.

• Describe how each system detects, recognizes, and responds to foreign antigens.

Definition of Immunity

• Historical Definition: Body's defense against infectious microbes.

• Current Definition: Immunity encompasses reactions to components of microbes, macromolecules, and chemicals recognized as foreign. This includes the recognition of non-infectious agents such as allergens (e.g., pollen, dust mites), environmental toxins, or even self-components in autoimmune conditions, which can provoke immune responses leading to inflammation, tissue damage, or allergic reactions.

Characteristics of the Immune Response

• Ability to distinguish self from non-self antigens, a crucial feature that prevents harmful autoimmune reactions. This self-tolerance is developed through complex mechanisms during lymphocyte maturation.

• Must differentiate between friend (e.g., beneficial commensal flora residing on mucosal surfaces, which aid in digestion and compete with pathogens) and foe (e.g., virulent pathogens that cause disease). The immune system employs various strategies to maintain this delicate balance, often involving specialized immune cells in mucosal tissues.

• Must be tightly regulated through a balance of activating and inhibitory signals to ensure efficient pathogen clearance without causing excessive tissue damage or chronic inflammation. Breakdown in this regulation can lead to autoimmune diseases or immunodeficiencies.

• Importance: Critical for survival; protects against infectious pathogens (bacteria, viruses, fungi, parasites) and removes harmful foreign substances, senescent or dead cells (via phagocytosis), and transformed (cancerous) cells through immune surveillance.

Types of Immunity

Innate Immunity

• Function: Serves as the immediate, first line of defense against a wide array of pathogens. It is evolutionarily ancient and present in all multicellular organisms.

• Components: Includes physical barriers (skin, mucous membranes), chemical barriers (antimicrobial peptides, stomach acid), and cellular components (phagocytes like macrophages and neutrophils, natural killer (NK) cells, mast cells, basophils, and eosinophils).

• Recognition: Recognizes conserved molecular patterns (pathogen-associated molecular patterns - PAMPs) unique to microbes, and damage-associated molecular patterns (DAMPs) released from damaged host cells.

• Response Time: Rapid (minutes to hours) due to pre-existing cellular and molecular components, but lacks immunological memory, meaning its effectiveness does not increase upon repeated exposure.

• Role: Crucial in containing infections early and instructing the adaptive immune response on the type of response required (e.g., T helper 1 vs. T helper 2 response), thus linking the two branches of immunity.

Adaptive Immunity

• Function: Provides a highly specific and sophisticated immune response, developing customized defenses tailored to individual pathogens. This precision allows for highly effective pathogen elimination.

• Components: Primarily mediated by lymphocytes: B cells (responsible for humoral immunity via antibody production) and T cells (responsible for cell-mediated immunity, directly killing infected cells or coordinating other immune cells).

• Response Time: Slower to develop (days to weeks) upon initial exposure because specific lymphocytes must be selected, activated, and clonally expanded.

• Memory Capability: Possesses immunological memory, leading to faster, stronger, and more efficient secondary responses upon re-exposure to the same pathogen. This is the basis for vaccination.

Mechanisms of Immune Response

Time Course of Defense Mechanisms

• Physical and Chemical Barriers: (e.g., intact skin, mucous membranes lining respiratory and gastrointestinal tracts, cilia, tears, saliva, stomach acid, antimicrobial peptides like defensins) provide immediate, continuous protection by preventing pathogen entry.

• Innate Immune Mechanisms: Activated within minutes to hours if pathogens breach the physical barriers. These include phagocytosis, inflammation, and the action of NK cells, effectively providing additional defense until adaptive immunity becomes robust.

• Adaptive Immunity: Takes longer to become effective, typically days to weeks for a primary response. Once successfully established, it offers highly specific and long-lasting protection, generating memory cells for future encounters.

Recognition of Invaders by Innate Immune Response

• Innate immunity uniquely recognizes evolutionarily conserved Pathogen-Associated Molecular Patterns (PAMPs), which are essential microbial components not found in host cells. Examples include:

  • Lipopolysaccharides (LPS): A major component of the outer membrane of gram-negative bacteria, acting as a potent endotoxin.

  • Peptidoglycans: A primary component of the cell wall of both gram-positive and gram-negative bacteria.

  • Flagellin: The protein subunit of bacterial flagella, important for motility.

  • Unmethylated CpG DNA: Bacterial and viral DNA often contains unmethylated CpG dinucleotides, unlike mammalian DNA which is typically methylated.

  • Double-stranded RNA (dsRNA): A common replication intermediate in the life cycle of many viruses, typically absent in mammalian cells.

• Significance: These PAMPs are fundamental for pathogen viability and pathogenicity, making them indispensable targets for immune recognition. There are approximately $1,000$ different molecular patterns recognized by the innate immune system, reflecting a broad but finite detection capability.

• Damage-Associated Molecular Patterns (DAMPs): These are intracellular molecules released or displayed by host cells undergoing stress or necrotic cell death, signaling tissue damage or danger to the immune system. Examples include ATP, uric acid, and heat shock proteins.

• Pattern Recognition Receptors (PRRs): These are germline-encoded cellular receptors expressed on or in innate immune cells (macrophages, dendritic cells, neutrophils) that specifically detect PAMPs and DAMPs. Engagement of PRRs initiates diverse innate immune responses, including:

  • Cytokine and chemokine release: Leading to inflammation and recruitment of more immune cells.

  • Phagocytosis: Engulfment and destruction of pathogens.

  • Antigen presentation: Bridging to adaptive immunity.
    Major classes of PRRs include toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and C-type lectin receptors (CLRs).

Pattern Recognition Receptors (PRRs)

• Toll-Like Receptors (TLRs):

  • Location: Strategically positioned either on the plasma membrane of immune cells (e.g., TLR1, TLR2, TLR4, TLR5, TLR6, TLR10) to detect extracellular microbial components, or within the endosomal membranes (e.g., TLR3, TLR7, TLR8, TLR9) to detect microbial nucleic acids from internalized pathogens.

  • Function: Upon binding their specific PAMPs (e.g., TLR4 binds LPS, TLR3 binds dsRNA, TLR9 binds unmethylated CpG DNA), TLRs initiate intracellular signaling cascades (often involving MyD88 or TRIF pathways) that lead to the activation of transcription factors like NF-κB and IRFs, resulting in the production of pro-inflammatory cytokines, type I interferons, and chemokines.

• NOD-like Receptors (NLRs): Cytoplasmic receptors that detect intracellular PAMPs (e.g., bacterial peptidoglycans) and DAMPs. Activation of certain NLRs (e.g., NLRP3) can lead to the formation of inflammasomes, multi-protein complexes that activate caspase-1, leading to the processing and secretion of potent inflammatory cytokines like IL-1β and IL-18, and pyroptosis (an inflammatory form of programmed cell death).

• RIG-like Receptors (RLRs): Also cytoplasmic receptors (e.g., RIG-I, MDA5) specialized in recognizing viral RNA (dsRNA or specific ssRNA structures) within the cytosol. Their activation triggers signaling pathways that induce the production of type I interferons, which are crucial for antiviral defense.

• Lectin-like Receptors (C-type Lectin Receptors - CLRs): A diverse family of receptors (e.g., Dectin-1, Mannose Receptor) found on the cell surface, primarily recognizing carbohydrate structures (polysaccharides) present on microbial (especially fungal) surfaces. Upon ligand binding, they can mediate phagocytosis, modulate inflammatory responses, and facilitate antigen presentation.

Adaptive Immune Response

• Lymphocyte Specificity and Diversity: The hallmark of adaptive immunity is its exquisite specificity. Each individual T cell or B cell possesses a unique antigen receptor (TCR or BCR) that is specific for a single, distinct antigenic epitope. This enormous diversity allows the immune system to recognize an estimated $10^7$ to $10^9$ different antigenic determinants.

• Development of Diversity: This vast repertoire is generated through somatic recombination of gene segments (V(D)J recombination) during the embryonic development and maturation of lymphocytes in primary lymphoid tissues (bone marrow for B cells, thymus for T cells), occurring before any exposure to foreign antigens. This random process ensures a wide range of specificities.

• Clonal Selection and Expansion Hypothesis: When a specific antigen enters the body, it selectively binds to and activates those rare lymphocytes that express receptors specific for that antigen. This activation event triggers these selected lymphocytes to rapidly proliferate (clonal expansion) and differentiate into:

  • Effector cells: Highly specialized cells that actively eliminate the pathogen (e.g., plasma cells producing antibodies from B cells, cytotoxic T lymphocytes from T cells).

  • Memory cells: Long-lived, quiescent cells that persist after the infection is cleared, capable of mounting a faster and stronger secondary immune response upon subsequent encounters with the same pathogen.

Antigen Recognition and Lymphocyte Activation

• Pathogen Entry Points and Dissemination: Pathogens can enter the body through various routes:

  • Epithelial surfaces: (e.g., skin, gastrointestinal, respiratory, urogenital tracts), where they are often met by local innate immune cells and antigen-presenting cells (APCs) like dendritic cells.

  • Bloodstream entry: Often via insect bites (e.g., mosquitoes or ticks) or intravenous access, leading to transport of pathogens and antigens to the spleen.

  • Following entry, antigens are captured by Antigen-Presenting Cells (APCs), primarily dendritic cells, which then migrate to draining lymph nodes.

• Activation of Naive Lymphocytes: Naive T cells and B cells continuously circulate through the blood and secondary lymphoid organs (lymph nodes, spleen, mucosal-associated lymphoid tissue). Upon encountering their specific antigen presented by APCs in the context of MHC molecules (for T cells) or directly (for B cells), these lymphocytes become activated, initiating the primary adaptive immune response. This activation requires multiple signals (antigen binding, co-stimulation, cytokines) to ensure a robust and appropriate response.

Cell Lineage and Development

• All immune cells originate from pluripotent hematopoietic stem cells (HSCs) located in the bone marrow, which possess the capacity to differentiate into all types of blood cells. These HSCs differentiate into two main types of progenitor cells:

  • Common Lymphoid Progenitor Cells: These give rise to lymphocytes, the key players in adaptive immunity, and natural killer (NK) cells, important in innate immunity.

    • B lymphocytes (B cells): Mature primarily in the bone marrow, responsible for humoral immunity (antibody production).

    • T lymphocytes (T cells): Migrate from the bone marrow to the thymus for maturation, undergoing stringent selection processes. They mediate cell-mediated immunity (e.g., cytotoxic T cells, helper T cells).

    • Natural Killer (NK) cells: Innate lymphoid cells that can directly kill virus-infected or tumor cells without prior sensitization.

  • Common Myeloid Progenitor Cells: These differentiate into myeloid cells, which are crucial components of the innate immune system and also include blood-forming elements.

    • Granulocytes: Neutrophils (phagocytosis, inflammation), eosinophils (anti-parasitic immunity, allergy), basophils (allergy, inflammation).

    • Monocytes/Macrophages: Monocytes circulate in blood and differentiate into macrophages in tissues (phagocytosis, antigen presentation).

    • Dendritic cells: Highly efficient antigen-presenting cells that bridge innate and adaptive immunity.

    • Mast cells: Important in allergic reactions and defense against parasites, located in tissues.

    • Platelets: Involved in hemostasis and inflammation.

    • Erythrocytes (red blood cells): Responsible for oxygen transport.

• Collaboration of Innate and Adaptive Cells: The adaptive immune response does not function in isolation; it critically relies on and collaborates with innate immune cells. Innate cells (especially dendritic cells) often initiate and shape the adaptive response by presenting antigens and providing co-stimulatory signals, thereby enhancing overall effectiveness in combating pathogens.

Introduction

• Overview of host defense mechanisms against infectious diseases, which are crucial for maintaining organismal integrity and health.

• Distinction between innate and adaptive immune systems was made in the previous lecture, highlighting their complementary roles: innate provides immediate, non-specific defense, while adaptive offers specific, memory-driven protection.

• Encouragement to attend a module on pathobiology for a deeper understanding of disease processes and immune responses at the cellular and molecular level.

Learning Objectives

• Describe the main innate and adaptive defense mechanisms, detailing their components and functions.

• Understand the specific immune cells (e.g., phagocytes, lymphocytes, NK cells) and molecules (e.g., complement proteins, antibodies, cytokines) involved in these intricate defense mechanisms.

Defense Mechanisms Overview

• The lecture will cover various types of defense mechanisms utilized by host organisms against invaders. These mechanisms operate in a coordinated fashion to detect, eliminate, and remember pathogens, including:

  • Barriers: Physical, chemical, and biological layers that prevent initial entry of pathogens.

  • Complement System: A cascade of plasma proteins that directly kill pathogens and enhance other immune functions.

  • Phagocytosis: The process by which specialized cells engulf and destroy pathogens.

  • Inflammation: A localized protective response to infection or injury, designed to remove harmful stimuli and initiate healing.

  • Direct Killing of Infected Host Cells: Mechanisms employed by immune cells to eliminate pathogen-reservoir cells.

  • Antibody Production (Humoral Immunity): The generation of specific proteins (antibodies) that neutralize and eliminate extracellular pathogens.

  • Role of T Helper Cells: Central orchestrators of the immune response, coordinating the activities of various immune cells.

Barriers to Infection

• Barriers prevent infections from occurring by blocking pathogen entry and colonization:

  • Physiological Barriers: Internal processes that help eliminate toxins and pathogens.

  • Include: vomiting, which expels harmful substances from the stomach; coughing and sneezing, which remove respiratory irritants and microbes; diarrhea, which flushes pathogens from the intestines; flushing action of the urinary tract, mammary glands, and tear ducts, which wash away microbes. The acidic pH of the stomach and vagina also serves as a potent chemical barrier.

  • Anatomical Barriers: Physical structures lining internal and external surfaces.

  • Examples include the skin, a robust, multi-layered organ composed of keratinocytes, forming a tough physical shield. Epithelia of the gastrointestinal tract, urogenital tract, and respiratory tree, characterized by tight junctions between cells that restrict pathogen passage. The mucociliary escalator in the respiratory tract uses mucus to trap pathogens and cilia to sweep them out.

  • Chemical Barriers: Secreted substances that inhibit microbial growth or directly destroy pathogens.

  • Include antimicrobial enzymes and peptides (e.g., lysozyme in tears and saliva, which breaks down bacterial cell walls; defensins and cathelicidins, small peptides secreted by epithelial cells and phagocytes that directly disrupt microbial membranes); low pH environments (e.g., stomach acid, vaginal acidity); and other substances like lactoferrin (sequesters iron, limiting bacterial growth).

  • Biological Barriers: The normal commensal bacterial flora that colonize various body surfaces.

  • These normal flora compete with pathogens for space and essential nutrients, and produce their own antimicrobial substances (e.g., bacteriocins, short-chain fatty acids), thereby preventing pathogen colonization.

Overview of Mechanical, Chemical, and Microbiological Barriers

• Mechanical: Physical mechanisms that physically impede or remove pathogens.

  • Examples: Tight junctions between epithelial cells creating a sealed barrier, cell sloughing (desquamation) of epithelial cells which removes attached microbes, and continuous mucus secretion by goblet cells (e.g., in respiratory and GI tracts) which traps microbes that are then removed by ciliary action or peristalsis.

• Chemical: Soluble molecules with antimicrobial properties.

  • Examples: Antimicrobial enzymes like lysozymes, which cleave peptidoglycan in bacterial cell walls; defensins and other antimicrobial peptides that create pores in microbial membranes; a variety of complement proteins which can directly lyse pathogens or enhance phagocytosis; stomach acid (HCl).

• Microbiological: The beneficial resident microbiota.

  • This normal flora exerts a protective effect by competitive exclusion (outcompeting harmful pathogens for attachment sites and nutrients) and by producing antimicrobial compounds, thus bolstering host defense.

Complement System

• Discovery: Initially identified by Jules Bordet, who highlighted its crucial role in enhancing antibody efficacy, demonstrating that a heat-labile serum component was necessary for antibodies to effectively lyse bacteria.

• Structure: A collection of over 30 distinct proteins found in blood plasma and on cell surfaces. Most circulate in inactive forms as proenzymes (zymogens) to prevent auto-activation and damage to host cells.

• Activation:

  • A proteolytic cascade is triggered upon pathogen detection. This involves a precisely regulated sequence where an activated enzyme cleaves and activates the next proenzyme in the series, leading to an amplification effect characteristic of cascades.

  • This cascade generates potent effector molecules with diverse immune functions.

Pathways of Activation

1. Alternative Pathway: Considered part of the innate immune response, it is constantly active at a low level (tick-over) and is rapidly triggered by detecting pathogen-associated molecular patterns (PAMPs) directly on microbial surfaces (e.g., bacterial endotoxins, fungal cell walls), particularly via unstable $C3b$ binding.

   • A key aspect of innate immune response, providing rapid, antibody-independent activation.

2. Lectin Pathway: Also an innate pathway, triggered by specific lectins, particularly mannose-binding lectin (MBL), which bind to carbohydrate structures (e.g., mannose) present on bacterial, fungal, or viral surfaces (PAMPs) but largely absent on host cells.

3. Classical Pathway: The primary adaptive immune pathway for complement activation, triggered by antibodies (specifically IgM or certain subclasses of IgG) that are bound to antigens on pathogen surfaces. It can also be activated by direct binding of $C1q$ to certain bacterial components.

Functions of the Complement System

• Facilitates Phagocytosis (Opsonization): The deposition of complement proteins, especially $C3b$ and its cleavage product $iC3b$, directly onto pathogen surfaces. These act as opsonins, tagging pathogens for efficient recognition and engulfment by phagocytic cells that express specific complement receptors (e.g., $CR1$).

  • Opsonins: Molecules such as antibodies (e.g., IgG) and complement proteins (e.g., $C3b$) that coat pathogens, enhancing their uptake by phagocytes.

• Direct Killing of Pathogens (Cell Lysis): The terminal pathway of the complement cascade leads to the assembly of the Membrane Attack Complex (MAC), a pore-forming structure composed of complement proteins (C5b, C6, C7, C8, and multiple C9 molecules). The MAC inserts into the pathogen's cell membrane, creating transmembrane channels that disrupt osmotic balance, leading to osmotic lysis and pathogen death.

• Induces Inflammation (Chemotaxis and Vasodilation): Some complement proteins, particularly the small cleavage products $C3a$ and $C5a$ (anaphylatoxins), act as vasoactive agents and potent chemotactic factors. They bind to receptors on mast cells and basophils, triggering histamine release (leading to vasodilation and increased vascular permeability), and attract other immune cells (e.g., neutrophils, monocytes) to the site of infection.

Phagocytosis

• Process: Phagocytosis is a critical cellular process where specialized phagocytic cells engulf and internalize pathogens, cellular debris, and foreign particles. This process involves several steps:

  • Chemotaxis: Phagocytes are attracted to the site of infection by chemical signals (chemokines, complement proteins like $C5a$).

  • Adherence: Phagocytes bind to pathogens directly via Pattern Recognition Receptors (PRRs) or indirectly via opsonins (e.g., antibodies, $C3b$) on the pathogen surface.

  • Engulfment: The phagocyte extends pseudopods to encircle the pathogen, forming a membrane-bound vesicle called a phagosome.

  • Fusion: The phagosome then fuses with enzyme-rich lysosomes, creating a phagolysosome.

  • Killing: Inside the phagolysosome, a highly toxic environment is generated, employing mechanisms such as reactive oxygen species (ROS) (e.g., superoxide, hydrogen peroxide), reactive nitrogen species (RNS) (e.g., nitric oxide), and hydrolytic enzymes (e.g., lysozyme, proteases, acid hydrolases) to efficiently digest and kill pathogens.

• Main Phagocytic Cells:

  • Neutrophils: These are the first responders and most abundant granulocytes (40-70% of white blood cells) in the bloodstream. They are highly mobile, possess multi-lobed nuclei, and are specialized for rapid engulfment and killing of bacteria and fungi during acute inflammation. Neutrophils are short-lived, typically dying after a single burst of phagocytic activity, contributing to the formation of pus upon their death.

  • Macrophages: These are professional phagocytes that differentiate from monocytes (which have characteristic kidney-shaped nuclei) once monocytes leave the bloodstream and enter tissues. Macrophages are longer-lived and larger than neutrophils, capable of sustained phagocytosis, antigen presentation, and cytokine production. They play a crucial role in chronic inflammation and tissue repair.

  • Specific Types: Macrophages are highly adaptable and are given specific names depending on their tissue location, such as Microglia (in the Central Nervous System), Kupffer cells (in the liver sinusoids), Alveolar macrophages (in the lung alveoli), and osteoclasts (in bone).

  • Dendritic Cells (DCs): While highly efficient at phagocytosis, their primary role is to capture pathogens and process their antigens. They then migrate to lymphoid organs (e.g., lymph nodes) to present antigens to naive T and B lymphocytes, effectively bridging innate and adaptive immunity.

Inflammation

• Definition: Inflammation is a fundamental, localized protective response of vascularized tissues to infection, tissue damage, or irritation. Its primary goals are to remove the initial cause of cell injury (e.g., pathogens, toxins), clear out necrotic cells and damaged tissues, and initiate the process of tissue repair.

• Cardinal Signs of Inflammation: Galen described these classic signs:

  • Redness (rubor): Due to vasodilation and increased blood flow to the injured area.

  • Heat (calor): Also a result of increased blood flow.

  • Pain (dolor): Caused by the release of inflammatory mediators (e.g., prostaglandins, bradykinin) that stimulate nerve endings.

  • Swelling (tumor): Results from increased vascular permeability, allowing fluid (exudate) and immune cells to leak from blood vessels into interstitial tissues.

  • Loss of function (functio laesa): A consequence of pain, swelling, and tissue damage.

• Steps in Inflammation:

  1. Delivery of immune cells and molecules (e.g., neutrophils, monocytes, complement proteins, antibodies, acute-phase proteins) from the circulation to the infection site to combat pathogens and clear debris.

  2. Local blood clotting occurs at the site of injury or infection, forming a fibrin meshwork that prevents the spread of infection to adjacent tissues and aids in wound healing.

  3. Promotion of tissue repair: After the clearance of pathogens and debris, inflammatory processes initiate the repair phase, involving proliferation of fibroblasts and synthesis of extracellular matrix components.

Mechanism of Inflammation Initiation

• Recognition: Inflammation is initiated when resident immune cells (e.g., macrophages, mast cells, dendritic cells) in tissues recognize PAMPs (Pathogen-Associated Molecular Patterns) derived from microbes or DAMPs (Damage-Associated Molecular Patterns) released from distressed or dying host cells. This recognition occurs via Pattern Recognition Receptors (PRRs) like Toll-like Receptors (TLRs) and NOD-like Receptors (NLRs), leading to alarm signaling.

• Cytokine/Chemokine Release: Upon recognition, resident cells rapidly release pro-inflammatory cytokines (e.g., TNF-$\alpha$, IL-1, IL-6) and chemokines (e.g., IL-8). These mediators trigger localized vasodilation (causing redness and heat) and dramatically increase endothelial permeability (leading to swelling) in nearby blood vessels.

• Cell Migration: The altered vascular endothelium expresses adhesion molecules, facilitating the sequential process of margination (leukocytes adhere to vessel walls), rolling, adhesion, and diapedesis (emigration of leukocytes through the vessel wall into the inflamed tissue). Neutrophils are typically the first cells to leave circulation and arrive at the site, followed by monocytes (which differentiate into macrophages), and later lymphocytes for a more sustained response.

Direct Killing of Infected Cells

• This mechanism is crucial for eliminating intracellular pathogens (e.g., viruses, some bacteria) by destroying the host cells they infect.

• Cell Types: The primary cells involved are Natural Killer (NK) cells (innate immunity) and Cytotoxic T lymphocytes (CTLs or CD8+ T cells) (adaptive immunity).

• Natural Killer Cells (NK): Part of the innate immune response and represent a crucial early defense against viral infections and tumor cells. They are activated based on a delicate balance of inhibitory signals (from MHC Class I molecules expressed on healthy cells) and activating signals (from stress ligands on infected or cancerous cells, or absence of MHC I, a phenomenon known as "missing self"). NK cells kill infected cells using directly injected perforins (pore-forming proteins) and granzymes (proteases that induce apoptosis).

• Cytotoxic T Cells (CD8): Part of the adaptive immune response, these cells specifically recognize and kill host cells that display pathogen-derived antigens on their surface via MHC Class I molecules. CD8+ T cells are activated through complex interactions with antigen-presenting cells (APCs) and T helper cells. Once activated, they become CTLs and employ a similar mechanism to NK cells, using perforins to create pores in the target cell membrane and injecting granzymes to induce programmed cell death (apoptosis) in the infected cells.

Antibody Production (Humoral Immune Response)

• Structure: Antibodies, also known as immunoglobulins (Ig), are Y-shaped glycoproteins produced by plasma cells (differentiated B lymphocytes). They are composed of four interconnected peptide chains: two identical light chains and two identical heavy chains. Each chain has variable regions (Fab), which form the antigen-binding sites, giving antibodies their specificity, and constant regions (Fc), which mediate effector functions by binding to specific receptors on immune cells or complement proteins.

• Functions of Antibodies:

  • Neutralization: Antibodies bind directly to pathogens (e.g., viruses, bacteria) or their toxins, preventing them from attaching to or entering host cells, thereby blocking their pathogenic effects.

  • Opsonization: Antibodies (especially IgG) coat pathogen surfaces, making them more recognizable and palatable for phagocytic cells that express Fc receptors, thus enhancing phagocytosis.

  • ADCC (Antibody-Dependent Cell-mediated Cytotoxicity): Antibodies bind to antigens on the surface of infected cells or tumor cells. The Fc region of these antibodies is then recognized by Fc receptors on immune effector cells (e.g., NK cells), leading to the lysis of the target cell.

  • Complement Activation: When antibodies (IgG or IgM) bind to antigens on a pathogen surface, their Fc regions undergo a conformational change, allowing them to bind and activate the $C1q$ component of the classical complement pathway, thereby triggering the complement cascade.

Antibody Isotypes

1. IgG: The most abundant immunoglobulin in blood plasma ($75-80\%$ of total Ig). It is a monomer, an efficient opsonin, and crucial for the memory immune response (secondary response). IgG is the only antibody isotype that can cross the placenta, providing passive immunity to the fetus. It also plays a significant role in agglutination (clumping of particulate antigens).

2. IgM: A large pentameric (five Y-shaped units) antibody found predominantly in the bloodstream; it is the primary antibody produced during the initial (primary) immune response. Its pentameric structure makes it highly efficient at complement activation (via the classical pathway) and agglutination, despite having a lower affinity than IgG.

3. IgA: Primarily found in mucosal secretions (e.g., tears, saliva, breast milk, gastrointestinal, respiratory, and urogenital tracts), where it often exists as a dimer linked by a J chain and protected by a secretory component. Its main function is to prevent pathogen adherence to epithelial surfaces and provide mucosal immunity, including important neonatal immunity through breast milk.

4. IgE: Present in minimal amounts in serum but plays a critical role in responses to parasitic infections (e.g., helminths) and allergic reactions. It binds strongly to Fc receptors on mast cells and basophils, triggering the release of inflammatory mediators (e.g., histamine) upon subsequent encounters with allergens or parasites.

Role of T Helper Cells (CD4)

• Function: T helper cells (CD4+ T cells) are central to the adaptive immune response, acting as coordinators and enhancers for almost all other immune responses. They do not directly kill infected cells or pathogens but activate and regulate other immune cells, including B cells, macrophages, and cytotoxic T cells.

• Activation: T helper cells are activated when their T cell receptor recognizes antigens presented on MHC Class II molecules by professional Antigen Presenting Cells (APCs) (e.g., dendritic cells, macrophages, B cells). Upon activation, they proliferate and differentiate into various subsets, each specialized to produce different sets of cytokines.

• Th1 (T Helper 1): Primarily activated by intracellular pathogens (e.g., viruses, intracellular bacteria). Th1 cells release cytokines like interferon-gamma (IFN-$\gamma$), which activates macrophages for enhanced killing of intracellular microbes and promotes the differentiation of cytotoxic T cells.

• Th2 (T Helper 2): Primarily involved in combating extracellular parasitic infections (e.g., helminths) and allergic responses. Th2 cells produce cytokines such as IL-4, IL-5, IL-13, which stimulate B cells to produce IgE antibodies, promote eosinophil activation, and contribute to tissue repair and fibrosis.

Conclusion

• Recap of the lecture's main points regarding the multifaceted array of host defense mechanisms, encompassing both innate (barriers, complement, phagocytosis, NK cells, inflammation) and adaptive (T cells, B cells, antibodies) immunity.

• Encouragement to review and integrate this knowledge to understand how these systems collaboratively protect the host from a diverse range of pathogens.

Conclusion

• Wrap up of the first lecture on host defense mechanisms.

• Encouragement to ask questions and engage in further discussion during sessions.