Antibody-Mediated Immunity: Prenatal to Childhood

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Questions and Answers

Describe the course of the development of pre-natal immunity and the defining events associated with these steps.

8 weeks: B cells first appear in the fetal liver and are produced in the bone marrow beginning in the second trimester. 10-30 weeks: Small amounts of immunoglobulin may be detected and the isotopes appear in a certain order (IgM > IgD > IgG > IgA). Fetal Immunity: Protection is derived largely from the position in the womb. Active transport of maternal IgG by FcRn begins around the 16th week. More than 50% of the transfer occurs after the 34th week. Self-Recognition: Tolerance to autoantigens is being established. Intrauterine Infection: The fetus is immunodeficient and may develop varying degrees of tolerance to the infectious organism. Prenatal infection is indicated by the presence of IgM and IgA in the core blood.

Understand the changes that occur in the immune response during life beginning with neonatal immunity and continuing through geriatric immunity.

Neonatal Immunity: The neonatal immune system is present, but underdeveloped. Neonates can produce all Ig isotypes, but IgM is predominant. Maternal IgG persists for up to 6 months. Ig metabolism is slower in the neonate, and it is a major source of neonatal immunity. The mother must be immune to protect the child against a specific pathogen. There is no memory to this passive immunity. Childhood Immunity: Two common events shape the acquisition of immunity during childhood: The loss of maternal IgG around 5-6 months is associated with common acute infectious diseases (common childhood infections). Routine pediatric immunizations helps develop active immunity. The immune response is reasonably mature by 2-3 years, but a normal child is immunologically inexperienced.

Know the general trends (not specific numbers) for immunoglobulin levels during life.

Fetal Stage: IgG is the only antibody that crosses the placenta, providing passive immunity. IgM, IgA, IgE are not produced in significant amounts. Neonatal Period: High IgG levels from maternal transfer initially. Maternal IgG declines rapidly, leaving an "immunity gap" until the infant begins producing its own IgG. IgM production starts shortly after birth. IgA begins production but remains low. Infancy & Early Childhood: IgG production increases, reaching adult levels by ~4-6 years. IgA and IgM gradually increase but remain lower than adult levels. Adulthood: IgG, IgA, IgM reach stable, mature levels. IgE remains low unless influenced by allergies. Geriatric Phase: IgG levels remain stable but may decrease slightly. IgA may increase, particularly in mucosal tissues. IgM levels decline. Immune response to new infections and vaccinations weakens due to immunosenescence.

Describe the mechanisms of antibody-mediated immunity to infectious disease: neutralization, opsonization, and complement fixation.

Viral Neutralization: Analogous to toxin-neutralization. Physical binding of an antibody prevents a virus from attaching to its complementary cell receptor, stopping infection of the cell. Important mechanism of action for the influenza vaccine. Blocking of Bacterial Attachment: Disease-causing bacterial infections at the mucosal surfaces are prevented by neutralizing antibodies. Secretory IgA (SIgA) prevents bacterial attachment and penetration to mucosal surfaces and membranes. Without SigA, bacteria will bind to the cell surface, leading to infection. With SIgA, the antibody binds to the bacteria and blocks binding to the cells. SigA-antigen complex is excreted with the mucus. Toxin Neutralization: Bacterial toxins cause many common diseases. Physical binding of an antibody prevents toxin from binding to its receptor site, inhibiting the toxic activity. Signup and view all the answers

Describe and contrast the characteristics of T Cell antigens vs B Cell antigens.

B Cell Antigens: Exist in their natural, unprocessed state and can be proteins, polysaccharides, lipids, or small chemicals. B cells use their B Cell Receptors (membrane-bound antibodies), to bind directly to these antigens. Since B Cell recognition does not require antigen processing (can be recognized in their native form), B cells can interact with whole pathogens, surface-bound antigens, or free-floating molecules like toxins. T Cell Antigens: Must be processed and presented by antigen-presenting cells (APCs), such as dendritic cells, macrophages, or B cells. These antigens are typically protein-derived peptides so they must be broken down into short fragments and displayed on MHC molecules. They cannot recognize whole antigens. Can only interact with peptide-MHC complexes. Signup and view all the answers

Contrast how B Cells see antigens vs how T Cells see antigens.

B Cell Receptors (BCR) recognize whole, unprocessed antigens in soluble form. T Cell Receptors (TCR) recognize peptide fragments presented by MHC molecules Signup and view all the answers

Describe how the basic structure of T Cell receptors is compared to B Cell receptors.

B Cell Receptor: Can be membrane-bound or secreted as antibodies when B cells differentiate into plasma cells. Made of two identical heavy chains and two identical light chains that are linked by disulfide bonds. 4 polypeptide chains total. Contain a variable region (V) for antigen binding and a constant region (C) for structural support. The variable regions of the heavy and light chains form the antigen-binding site. T Cell Receptor: Always membrane-bound and are never secreted. TCRs are considered heterodimers made of one alpha chain and one beta chain, linked by disulfide bonds. Contains a V region for antigen binding and a C region for structure. The variable regions of the alpha and beta chains form the antigen-binding site. Signup and view all the answers

Define the basic identifying surface molecules (CD) on mature T Cells and their function.

TCR (100% of T Cells): Protein Heterodimer and Processed Immunogen Recognition. CD3 (100% of T Cells): 6 Protein Molecule Complex and Responsible for signal transduction. CD4 (65% of T Cells): Protein and Responsible for MHC Class II recognition. CD8 (35% of T Cells): Protein and Responsible for MHC Class I recognition. Signup and view all the answers

Summarize the process of negative selection during T Cell development.

Negative selection deletes autoreactive clones to ensure tolerance to self-antigens. They ensure that the developing T Cells don't attack itself. Eliminates the self-reactive T cells to prevent autoimmunity. Tight binding = dies. Moderate binding = lives. Occurs in the thymic medulla via interaction with self-antigens. Signup and view all the answers

List the CD markers on developing T Cells relative to their developmental stage.

Double Negative: No CD4/CD8 expression, low CD3 and Expression of T Cell Receptor begins. Double Positive: Expresses both CD4 and CD8, increases TCR and T Cell Receptor stimulation - Positive selection of cells that recognize self-MHC and failure to thrive of cells which do not and Immunogenic stimulation - Negative selection with deletion of autoreactive clones and tolerance to self antigens. Single Positive: Expresses either CD4 or CD8, becoming mature antigen-reactive T cells. Signup and view all the answers

Explain why the terms "double negative" and "double positive" are meaningful during T Cell development.

Double Negative: Early thymocyte stage with no CD4/CD8 and Marks the early phase to T cell development. Double Positive: Intermediate stage expressing both CD4/CD8 and Critical for positive selection (Process that ensures developing T cells can recognize self-MHC molecules, occurs in the thymus) and Both positive and negative selection occur here. Signup and view all the answers

Describe the basic structure of the TCR and its accessory molecules.

A T cell receptor is composed of a heterodimer of two polypeptide chains, typically an alpha and a beta chain, which are linked by a disulfide bond and function as the antigen-binding site. There is a variable and constant region in each chain. Variable alpha and Variable beta contribute to the antigen binding site. The transmembrane region keeps the T cell receptor attached to the T cell. Signup and view all the answers

Name the different Classes of TCR.

Alpha beta TCR: The majority of T Cells, Recognize peptide antigens presented on MHC molecules, and Subdivided into: CD4+ T cells (Helper T cells) → Recognize MHC-II and CD8+ T cells (Cytotoxic T cells) → Recognize MHC-I. Gamma delta TCR: Found in mucosal tissues (gut, skin, lungs), Recognize non-peptide antigens without MHC restriction like lipids, stress signals, metabolites), and Plays a role in innate-like immune responses. Signup and view all the answers

Describe in basic terms how a TCR works or transduces signal.

Antigen Recognition: The TCR on a T cell binds to a specific antigen that is presented on the MHC molecule by an APC and CD4 or CD8 helps stabilize the interaction by binding to MHC-II (CD4) or MHC-I (CD8). Signal Transmission Through CD3: The TCR itself does not have any signaling ability, so it relies on CD3 and Once the TCR binds to an antigen, the CD3 helps pass the signal into the cell, telling it that an antigen has been detected. T Cell Activation: This signal causes the T cell to become activated and respond and The T cell starts growing, dividing, and producing immune signals (cytokines). Depending on the type of T cell: CD4+ Helper T Cells → Help activate B cells, macrophages, and other immune cells and CD8+ Cytotoxic T Cells → Target and kill infected or cancerous cells. The TCR binds antigen → CD3 transmits the signal → the T cell activates and responds. Signup and view all the answers

List the cellular components involved in T Cell signal transduction.

TCR recognizes antigens presented on MHC molecules. CD3 complex- made up of gamma, delta, epsilon, and zeta chains that are the signaling partners of the TCR. CD4 and CD8 coreceptors that stabilize the interaction between TCR and MHC. Signup and view all the answers

Describe Co-stimulation and why it is important.

Co-stimulation is a secondary signal required for full T cell activation. It occurs in addition to TCR signaling and ensures that T cells only respond to genuine threats rather than harmless antigens. It ensures that T cells activate only when it is truly needed. It is important because it can prevent accidental activation and promotes a stronger immune response. Can also prevent autoimmunity by regulating the immune tolerance. Signup and view all the answers

Describe antigen processing relative to MHC class and its relation to binding to the TCR.

MHC Class I: All nucleated cells present MHC Class I and Presents intracellular antigens (viruses, cancerous cells, intracellular bacteria) to CD8+ cytotoxic T cells, leading to the killing of infected or cancerous cells. MHC Class II: Only APCs can present MHC Class II and Presents extracellular pathogens (bacteria, fungi, toxins) to CD4+ helper T cells, coordinating immune responses. Signup and view all the answers

Define what a Superantigen is.

A superantigen is a type of antigen that causes excessive and non-specific activation of T cells by directly binding to MHC-II molecules and T cell receptors, bypassing normal antigen processing and specificity. Signup and view all the answers

Describe what a Superantigen does to T Cells and APC.

Normally, APCs process antigens and present them to T cells using MHC-II, however, a superantigen will bypass this by binding directly to both MHC-II on APCs and TCRs on T cells. Signup and view all the answers

Define two stages of pathology associated with Superantigen exposure.

Profound Immunostimulation: Superantigens bind non-specifically to MHC-II and TCRs, activating a massive number of T cells and leading to an early cytokine release and The overproduction of cytokines can cause a cytokine storm that could lead to fever, toxic shock syndrome, and multi-organ failure and Improper costimulation prevents normal immune regulation, worsening the cytokine storm. Profound Paradoxical Immunosuppression: Following the massive activation, T cells become unresponsive, with many of them undergoing apoptosis due to a lack of proper costimulatory signals, leading to profound immunosuppression and This could increase the risk of secondary infections and weakened immune response. Signup and view all the answers

Define and contrast the MHC molecules involved in the interaction of T helper versus killer cells with APC.

MHC Class I (For CD8+ T Cells - Killer T Cells): Type of Antigen: Intracellular (e.g., viruses, cancer), Expression: All nucleated cells, T Cell Interaction: Recognized by CD8+ T cells, Immune Response: Cytotoxic (cell killing), and Molecular Type: MHC I + intracellular peptide. MHC Class II (For CD4+ T Cells - Helper T Cells): Type of Antigen: Extracellular (e.g., bacteria, fungi). Expression: APCs (macrophages, dendritic cells, B cells). T Cell Interaction: Recognized by CD4+ T cells. Immune Response: Helper (cytokine release). Molecular Type: MHC II + extracellular peptide. Signup and view all the answers

Describe how T killer cell antigen processing differs from T helper cell antigen processing.

MHC Class I Presentation: Intracellular antigen is chopped up into peptides via the proteasome, Peptides are transported through the endoplasmic reticulum (ER), The Golgi apparatus creates MHC, Peptide associates with MHC Class I molecule, and Peptide-MHC complex is transported to present peptide at the cell surface. MHC Class II Presentation: Extracellular antigen is endocytosed, Antigen is chopped up into peptides, The Golgi apparatus creates MHC, Peptide associates with MHC Class II molecules, and Peptide-MHC complex is transported to present peptide at the cell surface. Signup and view all the answers

List the basic processes required for an APC to activate a T Cell (ie, what has to happen?)

Antigen Uptake and Processing: The APC engulfs and internalizes an antigen and The antigen is broken down inside the APC into peptides via the proteasome (for intracellular antigens) or lysosomes (for extracellular antigens). Antigen Presentation on MHC Molecules: The processed peptides are loaded onto MHC molecules. T Cell Receptor (TCR) Recognition: The TCR on the T cell specifically binds to the MHC-antigen complex on the surface of the APC and Co-stimulation: In addition to TCR recognition, the T cell also requires a co-stimulatory signal for full activation. Cytokine Secretion (for CD4+ T Cells): The APC may secrete specific cytokines that influence the type of immune response that will occur. Full Activation and Differentiation: Once co-stimulation and cytokine signaling have occurred, the T cell becomes fully activated. Signup and view all the answers

Define what a T Cell checkpoint is and how it relates to cancer immunity.

T cell checkpoints are mechanisms that regulate immune responses by inhibiting T cell activation. Tumor cells can exploit these checkpoints to escape immune surveillance and avoid destruction by T cells. Checkpoint inhibitors (such as PD-1/PD-L1 or CTLA-4 blockers) are used in cancer immunotherapy to reactivate T cells and enhance anti-tumor immunity. Signup and view all the answers

Define the terms "mature" and "naïve" relative to T Cells.

Naive T Cells: T cells that have never encountered their specific antigen, They are naive in the sense that they haven't participated in an immune response yet, and They have to wait for antigen recognition to be activated. Mature T Cells: T cells that have undergone the full development process in the thymus and They are capable of participating in an immune response and responding to antigens. Signup and view all the answers

Contrast Th cells (T Helper cells) with T Killer (CTL) cells regarding function.

Th Cells: Th cells help other immune cells by secreting cytokines that then activate B cells, macrophages, and CTL cells, They coordinate the immune response, but they do not directly kill the infected cells, and Th cells primarily respond to extracellular pathogens. CTL Cells: CTL cells directly kill infected or abnormal cells by releasing cytotoxic molecules and CTL cells primarily target infected or cancerous cells. Signup and view all the answers

Contrast Th cells with CTL with regard to surface markers.

Th Cells: Surface marker CD4 and Th cells express CD4, thus recognizing antigens presented by MHC Class II. CRL Cells: Surface marker CD8 and CTLs express CD8, thus recognizing antigens presented by MHC Class I. Signup and view all the answers

List the different types of T helper cells.

Th1: Primary involved in cell-mediated immunity and the defense against intracellular pathogens. Th2: Play a key role in the humoral immune response, helping B cells produce antibodies, especially in response to extracellular pathogens. Th17: Involved in inflammation and immune responses to fight infections and some bacteria and Can also play a role in autoimmune diseases. Tfh: Follicular Helper T Cells and Specialized in assisting B cells to produce high-affinity antibodies, especially in response to infectious agents. Treg: Regulatory T Cells and Suppress immune responses to maintain immune tolerance and prevent autoimmunity. Signup and view all the answers

Recognize the defining cytokines each Th type produces.

Th1 cells: IL-12, IFN-γ. Th2 cells: IL-4. Th17 cells: IL-6, TGF-B, IL-23. Tfh cells: IL-6, IL-21. T reg cells: TGF-β. Signup and view all the answers

Name at least one characteristic cytokine each Th type produces.

Th1 cells: IL-2, IFN-γ. Th2 cells: IL-4, IL-5. Signup and view all the answers

Describe the principal pathogen(s) each Th cell targets.

Th1 cells: Target intracellular pathogens. viruses, and bacteria. Th2 cells: Target extracellular parasites and large extracellular pathogens. Th17 cells: Target extracellular bacteria and fungi. Tfh cells: Help B cells produce high-affinity antibodies against various pathogens (both extracellular and some intracellular). Treg cells: Suppress immune responses to prevent autoimmunity and maintain tolerance rather than targeting pathogens directly. Signup and view all the answers

Define inflammation

The response of a vascularized tissue to injury or infection. Signup and view all the answers

List the 2 causes of inflammation

2 major causes of inflammation are infection or injury. Signup and view all the answers

Describe how macrophages initiate inflammation

TLR signaling activates the transcription factor NFKB, which induces the expression of proinflammatory cytokines. Signup and view all the answers

Identify 5 proinflammatory cytokines produced by macrophages

IL-1β, TNFα, IL-6, CXCL8, IL-12. Signup and view all the answers

Identify interacting partners that allow neutrophils to enter the site of inflammation

Selectins Mediate Neutrophil Capture and Rolling Along an Activated Endothelium: Activated endothelium upregulates E-selectin and P-selectin and Neutrophils express sialyl-LewisX (s-LeX), which binds to both E-selectin and P-selectin. Integrins Mediate Stronger Neutrophil Interaction with the Activated Endothelium: Activated endothelium expresses ICAM-1 and ICAM-2 (intercellular adhesion molecules) and These molecules bind to LFA-1 and CR3 integrins expressed on neutrophils. CXCL8 strengthens neutrophil adhesion, while CD31 mediates diapedesis. Signup and view all the answers

Identify 3 mechanisms of action of corticosteroids

Inhibition of NFKB. Corticosteroids block PLA2 activity. Corticosteroids induce anti-inflammatory gene expression and formation of Annexin A1. Signup and view all the answers

List at least 5 side effects of corticosteroids

Hypertension, Immunosuppression, Mood changes, Glaucoma, Growth retardation. Signup and view all the answers

List the 5 monoclonal antibody targets in inflammation

Proinflammatory cytokines and their binding receptors, JAK proteins, Integrins used by T cells to enter inflamed tissues, Th2 response cytokines and their binding receptors, and IgE. Signup and view all the answers

Identify targets for NSAIDs, 5-LOX inhibitors, and LTRAS

NSAIDs (Nonsteroidal Anti-Inflammatory Drugs): Target: Cyclooxygenase (COX) enzymes. 5-LOX Inhibitors (5-Lipoxygenase Inhibitors): Target: 5-Lipoxygenase (5-LOX). LTRAS (Leukotriene Receptor Antagonists): Target: Leukotriene receptors. Signup and view all the answers

Describe the polarization of M1 versus M2 microglia

M1 Microglia (Classical Activation) – Pro-inflammatory: Function: Pathogen defense, tissue damage and Cytokine Production: Pro-inflammatory: IL-1β, IL-6, TNF-α, CCL2 and Reactive molecules: ROS (Reactive Oxygen Species), NO (Nitric Oxide) and Activation Stimuli: Pro-inflammatory cytokines (e.g., IFN-γ) and Pathogen-Associated Molecular Patterns (PAMPs) (e.g., Lipopolysaccharide (LPS)). M2 Microglia (Alternative Activation) – Anti-inflammatory & Pro-Resolving: Function: Tissue repair, neuroprotection and Cytokine Production: Anti-inflammatory: IL-10 and Activation Stimuli: Anti-inflammatory cytokines (IL-4, IL-13). Signup and view all the answers

Describe the different effects of engagement of CB1 and CB2 receptors

CB1 Receptor: Location: Primarily in the CNS (central nervous system) and Functions: Mediates the psychoactive effects of cannabinoids, including: Altered perception, Mood changes, and Cognitive effects; Influences motor control, appetite, memory, and pain perception; and Plays a role in regulating neurotransmitter release. CB2 Receptor: Location: Primarily in the immune system (macrophages, T cells, B cells) and Also found in peripheral tissues and to a lesser extent in the CNS and Functions: Modulates immune responses, including inflammation and immune cell function and Plays a role in pain modulation, particularly in inflammatory and neuropathic pain. Signup and view all the answers

Describe the anti-inflammatory mechanism of selective cannabinoid 2 receptor agonists

Selective CB2 receptor agonists reduce inflammation by: Decreasing pro-inflammatory cytokine production (IL-1β, TNF-α), Modulating immune cell migration and activation, Potentially increasing anti-inflammatory cytokine production (IL-10), Impacting intracellular signaling pathways (NF-kB inhibition), Modulating microglial phenotypes (shifting from M1 (pro-inflammatory) to M2 (anti-inflammatory)). Signup and view all the answers

Describe the anatomy and specific cells of the mucosal immune system.

Organized Mucosal Follicles: GALT (Gut-Associated Lymphoid Tissue) and BALT (Bronchus-Associated Lymphoid Tissue). Key Structures: Waldeyer's Ring: Tonsils and adenoids form a lymphoid tissue ring around the entrance of the airways and gut; Peyer's Patches: Secondary lymphoid follicles found under the mucosal epithelium of the small intestine; contain T and B cells and follicular dendritic cells; Isolated Lymphoid Follicles: Found in the small and large intestines, containing mostly B cells; and Lamina Propria: Beneath the basement membrane; contains many immune cells, including macrophages, dendritic cells, T cells, and B cells. Intraepithelial Lymphocytes: Located between epithelial cells beneath tight junctions; specialized CD8 T cells with cytotoxic granules. Special Cells: Innate Lymphoid Cells (ILCs): Found in the lamina propria; involved in inflammatory responses; M Cells: Specialized epithelial cells that transport material from the lumen to mucosal follicles; and Intraepithelial Dendritic Cells: Capture antigens from the gut lumen and present them to T cells. Signup and view all the answers

Explain how non-specific and specific factors work in concert to provide protection from harmful pathogens in this system.

Non-specific Factors: Mechanical: Motor activity for mucus movement (peristalsis, ciliary action) and tight junctions providing a physical barrier; Chemical: Lysozyme, gastric acid, bile salts, etc.; and Microbiological: Normal flora in the nose, mouth, and gut that prevent pathogen overgrowth. Specific Factors: Immune Cells: The mucosal system employs immune cells such as macrophages, T cells, B cells, dendritic cells, etc., to respond to pathogens and Antibodies: Produce immune responses tailored to specific pathogens while preventing inflammatory damage. Signup and view all the answers

Describe how the mucosal immune system differs from the rest of the immune system.

Immunogen Reception: The mucosal immune system receives antigens via the epithelium (from gut, airways, etc.), while the systemic immune system gets them via lymph or blood. Antibodies: Predominantly sIgA (secretory IgA) in the mucosal immune system, with slgM being less common. T Cells: Specialized mechanisms for mucosal immune responses and regulation. Homing System: Mucosal immune cells selectively home to diffuse lymphoid tissue underlying mucosal surfaces. Anti-inflammatory Bias: Mechanisms such as IgA and Tregs minimize inflammatory damage during immune responses. Signup and view all the answers

Describe how innate lymphoid cells target specific infections

Innate Lymphoid Cells (ILCs): Found in the lamina propria, they secrete cytokines and can either promote or inhibit inflammation and While ILCs don't express T or B cell receptors, they play an important role in modulating immune responses during infection. While they lack the antigen-specific receptors of T and B cells, ILCs target specific infections through a combination of mechanisms: Expressing pattern recognition receptors (PRRs) that recognize PAMPs and DAMPs. Signup and view all the answers

Detail the mechanisms by which specific immunoglobulins under the regulation of T cells are produced and mediate mucosal immunity.

IgA Production: T cell activation by dendritic cells, T cell interaction with IgM-expressing B cells at the T cell/B cell zone interface, TGF-ẞ and T cell interactions with B cells induce class switching to IgA, and B cells migrate to the lamina propria via mesenteric lymph nodes. Activated B cells interact with T cells expressing CD40L and cytokines (IL-5, IL-6) to drive IgA plasma cell differentiation. IgA's Role in Mucosal Immunity: Prevents colonization without promoting inflammation, as slgA is non-complement activating and inhibits phagocyte binding and IgA can neutralize pathogens by preventing their attachment to mucosal surfaces. Signup and view all the answers

Describe how IgA is transported across epithelium and how slgA stays bound to mucous.

Transcytosis of IgA: IgA dimers are transported across the epithelium through the poly-lg receptor. Part of the poly-lg receptor remains bound to IgA when it is released into the mucus, holding IgA to the mucosal surfaces, and This process ensures IgA remains in place on mucosal surfaces, aiding in pathogen neutralization. Signup and view all the answers

Describe how passive transfer of immunity protects infants from infection, including the mechanisms and the timing of exposure to IgG and IgA.

Passive transfer of immunity provides early protection for infants through the transfer of maternal antibodies, both during pregnancy and through breast milk. During fetal development: IgG is transferred from the mother to the fetus via the placenta, This transfer occurs through the FcRn receptor, which binds to maternal IgG and transports it into the fetal circulation, and The neonate is born with high levels of IgG, providing significant protection against infections. Signup and view all the answers

Flashcards

8 weeks

B cells appear in the fetal liver, and are produced in the bone marrow.

10-30 weeks

IgM > IgD > IgG > IgA. Small amounts of immunoglobulin may be detected in this order.

Fetal Immunity

Protection derived largely from the position in the womb. Active transport of maternal IgG by FcRn begins.