BIOL 3404 Final Exam - Comprehensive Study Guide

Chapter 1: Foundations of the Immune Response

• Vocabulary Review: Comprehensive review of all Chapter 1 terminology is essential for the exam.

• Physical Barriers against Infection:     * These constitute the "Fixed" defenses of the body, providing the first line of resistance against pathogens.

• Commensal Microbes:     * Refers to the diverse community of microorganisms that live on or within the human body without causing harm, often providing competitive inhibition against pathogens.

• Innate Immunity:     * Defense Mechanisms: Includes pre-existing mechanisms such as the Complement system and Pattern Recognition Receptors (PRRs).     * Cells: Specialized cells that mediate the immediate response to infection.     * Hallmarks: Inflammation is a primary characteristic of the innate immune response.

• Adaptive Immunity:     * Involves specialized cells that provide a tailored response to specific pathogens and establish long-term memory.

• Principal Characteristics (Fig 1.8):     * Comparison of innate and adaptive immunity regarding speed, specificity, and memory.

• Hematopoiesis (Fig 1.13):     * The process of blood cell development and differentiation from hematopoietic stem cells into various lineages (myeloid, lymphoid, erythroid).

• Antibody-Mediated Destruction:     * Antibodies facilitate the destruction of pathogens through mechanisms such as neutralization, opsonization, and activation of the complement system.

• Lymphoid Tissues:     * Primary Lymphoid Tissues: Sites where lymphocytes develop and mature (e.g., Bone Marrow and Thymus).     * Secondary Lymphoid Tissues: Sites where mature lymphocytes are stimulated by antigens (e.g., Lymph nodes, Spleen, Peyer's patches).

Chapter 2: Innate Immunity and the Complement System

• Barriers to Infection:     * Mechanical, Chemical, and Physical Barriers: Specific examples include protective mechanisms in the eyes (tears/lysozyme), nose (mucus/cilia), and oral cavity (saliva/antimicrobial peptides).

• First Line of Cellular Defense: The initial cellular entities that encounter and attempt to neutralize invading pathogens upon barrier breach.

• The Complement System:     * Activation and Fixation: There are three pathways of activation. The central event is the cleavage and fixation of Complement component $C3$.     * Cleavage Mechanism (Fig 2.4):         * Cleavage of $C3$ leads to the production of $C3a$ and $C3b$.         * The process results in solubility changes and the attachment of $C3b$ to the pathogen surface.         * Thioester Bond: The nucleophilic attack on the thioester bond is critical for the covalent attachment of $C3b$ to the pathogen surface.     * C3 Convertases:         * Alternative Pathway: Includes the $C3bBb$ complex.         * Classical Pathway: Involves specific components leading to the production of the convertase.     * The Alternative Pathway:         * Components: Involves $C3$, which yields $C3a$ and $C3b$.         * Factors: Factors $B$ and $D$ are required for the formation of the alternative convertase.         * Properdin: A regulatory protein that stabilizes the $C3$ convertase on the pathogen surface.     * Complement Control Proteins (Regulatory):         * Factors H and I: Determine where and how the complement cascade is inhibited to prevent depletion of $C3$ and damage to host cells.         * DAF (Decay-Accelerating Factor) and MCP (Membrane Cofactor Protein): Specific membrane-bound proteins that protect human cells from complement-mediated attack.     * C5 Convertase: The enzyme complex that cleaves $C5$ into $C5a$ and $C5b$, initiating the late stages of the complement cascade.     * Membrane Attack Complex (MAC):         * Definition: A pore-forming structure that disrupts the integrity of the pathogen's membrane.         * Components: Consists of proteins $C5b$, $C6$, $C7$, $C8$, and multiple units of $C9$.     * Regulatory Factors of MAC:         * Includes Factor J, HRF (Homologous Restriction Factor), and CD59 (Protectin), which prevent the assembly of the MAC on human cell membranes.

Chapter 2 Continued: Pathways and Deficiencies

• Classical Pathway:     * C3 Convertase: Formed by $C4b$ and $C2b$.     * C5 Convertase Complex: Formed by the addition of $C3b$ to the classical $C3$ convertase ($C4b2b3b$).

• Complement Deficiencies:     * Pathogenic Consequences: Investigating the result of losing the first step in the activation pathway.     * Specific Deficits: Limitations or diseases arising from the lack of $C1$, $C2$, and $C4$ proteins.     * Regulatory Deficits: The clinical outcome of deficiencies in CD59 and DAF (e.g., paroxysmal nocturnal hemoglobinuria).

• Role of Defensins: Antimicrobial peptides that penetrate microbial membranes to induce lysis.

Chapter 3: Induced Innate Immunity

• Time Frame: The induced innate response typically occurs within hours to days (4 hours to 4 days) after the initial infection starts.

• Phases of the Human Immune Response: Transition from immediate innate to induced innate, and finally to the adaptive response.

• Receptors: Crucial in distinguishing self from non-self and initiating the inflammatory response.     * Mannose and C-type Lectin Receptors: Bind to specific carbohydrate patterns on pathogens.     * Scavenger Receptors: Involved in the recognition and phagocytosis of various negatively charged ligands from pathogens.     * Toll-like Receptors (TLRs):         * TLR4: Specifically senses Lipopolysaccharide (LPS) from Gram-negative bacteria (Fig. 3.7).         * Mechanism: Recognition of LPS by TLR4 induces signal transduction that changes macrophage gene expression, leading to the production of inflammatory cytokines.

• Inflammatory Cytokines:     * Major cytokines include: $IL-1\beta$, $IL-6$, $CXCL8$, $IL-12$, and TNF- ext{̑}.

• NOD-like Receptors (NLRs):     * Intracellular sensors of bacterial components.     * CARD Domain: Caspase Recruitment Domain, used to recruit other signaling proteins.

• Inflammasomes:     * Multi-protein complexes that amplify the innate response by increasing the processing and production of active $IL-1\beta$.     * NLRP3: Activated by various cellular stressors resulting from infection or injury.

• Neutrophils: Professional phagocytes that are the first cells recruited to the site of inflammation; they form pus upon death.

• Adhesion Molecules: Facilitate the rolling, activation, and extravasation (diapedesis) of leukocytes into infected tissues.

• Acute Phase Response:     * A systemic response to infection involving the liver's production of proteins like C-reactive protein (CRP) and Mannose-Binding Lectin (MBL).     * Mannose Binding Lectin (MBL): A secreted Pattern Recognition Receptor (PRR).

• NK Cell Activation: Natural Killer cells are activated by cytokines (like IFN- ext{̑} and IFN- ext{̒} or $IL-12$) to kill virally infected cells.

Chapter 4: Immunoglobulins and B-Cell Diversity

• Immunoglobulins (Ig):     * Association: Produced by B cells and plasma cells.     * Structure: Composed of two identical heavy chains and two identical light chains.     * Recombination: Begins at the DNA level where gene segments ($V$, $D$, and $J$) are rearranged.

• Antibodies:     * Structure: Variable ($V$) and Constant ($C$) regions. Variability is concentrated in the Hypervariable regions (CDRs).     * Proteolytic Cleavage: Occurs at the hinge region, historically using enzymes like Papain or Pepsin to produce $Fab$ and $Fc$ fragments.     * Classes: Determined by the heavy chain constant region (̓, ̒, ̑, ̔, or ̕).

• Antigen-Binding Site: Formed by the juxtaposition of the hypervariable regions ($CDRs$) of one heavy-chain $V$ domain and one light-chain $V$ domain.

• Monoclonal Antibodies: Produced using hybridoma technology (fusing a B cell with a myeloma cell) to create a line of cells producing identical antibodies.

• Germline Expression vs. Somatic Recombination:     * Before encountering an antigen, B cells undergo somatic recombination to create a functional Ig gene.     * RSS (Recombination Signal Sequences): Directed sequences that help the RAG complex identify where to cut DNA.     * RAG (Recombination-Activating Genes): The enzyme complex essential for mediating the recombination of $V$, $D$, and $J$ segments.

• Junctional Diversity: The random addition of P-nucleotides and N-nucleotides at the junctions between gene segments ($V-D$ or $D-J$), greatly increasing diversity.

• Somatic Hypermutation:     * Timing: Occurs after the B cell has encountered its specific antigen.     * Outcome: Leads to Affinity Maturation, where B cells with higher-affinity receptors are selected for.     * Class Switching: A process that changes the constant region of the heavy chain to produce different antibody classes (e.g., from $IgM$ to $IgG$) while maintaining antigen specificity.

Chapter 5: T Cell Receptors and MHC

• T Cell Receptors (TCRs):     * Association: Found exclusively on the surface of T cells.     * Structure: A heterodimer consisting of an ext{̑} and a ext{̒} chain (mostly).     * Recombination: Similar to B cells, utilizing $V$, $D$, and $J$ segments to generate diversity.

• TCR vs. BCR (Comparison):     * BCRs can be secreted (as antibodies), whereas TCRs are always membrane-bound.     * After antigenic stimulation, BCRs undergo somatic hypermutation and class switching; TCRs do not undergo these processes.

• T Cell Receptor Complex:     * Consists of the TCR heterodimer and the signaling apparatus including the $CD3$ complex and ̖ chains.

• Co-receptors:     * CD4: Associated with helper T cells; binds to MHC Class II.     * CD8: Associated with cytotoxic T cells; binds to MHC Class I.

• MHC Molecules:     * MHC I: Found on every nucleated cell; presents intracellularly derived peptides.     * MHC II: Found on specialized Antigen-Presenting Cells (APCs) (dendritic cells, macrophages, B cells); presents extracellularly derived peptides.

• Pathways of Antigen Presentation:     * Intracellular Pathway (MHC I): Proteins are degraded by the Proteasome in the cytosol. Peptides are transported into the Endoplasmic Reticulum (ER) by TAP proteins where they meet and bind to MHC I molecules.     * Extracellular Pathway (MHC II): Proteins are taken up into endocytic vesicles, degraded in lysosomal compartments (phagolysosome), and MHC II molecules meet the peptides in specialized vesicles after the invariant chain is degraded.

Chapter 7: T Cell Development and the Thymus

• The Thymus:     * Organized into an outer Cortex and an inner Medulla.     * Contains thymocytes (developing T cells), cortical epithelial cells, medullary epithelial cells, dendritic cells, and macrophages.

• Developmental Migration:     * Progenitor T cells originate in the Bone Marrow and travel to the Thymus for development.     * After maturation, they migrate to Secondary Lymphoid Organs to encounter antigens.

• Marker Expression: Involves specific transcription factors (e.g., Notch1) that drive the T cell lineage commitment.

• Positive Selection:     * Location: Thymic Cortex.     * Function: Ensures T cells can recognize the host's MHC molecules (MHC restriction).

• Negative Selection:     * Location: Thymic Medulla (mostly) and at the corticomedullary junction.     * Function: Eliminates T cells that react too strongly to self-antigens (Self-tolerance).

Chapter 9: B Cell Activation and Antibody Functions

• Signal Transduction:     * Initiation: B cell binds to a pathogen via its surface Immunoglobulin (BCR).     * Mechanism: Tyrosine kinases (e.g., Blk, Fyn, Lck) bind to ITAMs (Immunoreceptor Tyrosine-based Activation Motifs) on $-$ and $-$ subunits of the BCR, leading to phosphorylation.     * Lyn: A kinase that binds to doubly phosphorylated ITAMs, triggering a signaling cascade that activates transcription factors for B cell division and differentiation.

• T-Independent (TI) Activation:     * TI-1 Antigens: Involve TLR signaling in addition to BCR signaling. No memory is produced; mostly produces $IgM$.     * CD19: Acts as a critical co-receptor and marker for B cells.     * TI-2 Antigens: Have highly repetitive epitopes that cross-link BCRs extensively on the surface. No additional signals needed; thought to be an evolutionarily older pathway.

• T-Dependent (TD) Activation:     * Requires interaction between B cells and Helper T cells ($T_H$ cells) in the lymphoid follicle.     * Germinal Centers: Where B cells undergo Somatic Hypermutation and Class Switching. Somatic hypermutation is greatest in the Variable ($V$) regions of the BCR.

• Antibody Functions:     * IgM: Pentameric structure; the first response antibody; highly effective in complement activation.     * IgG: Monomeric; dominant in the late primary and secondary immune responses; provide long-term memory; the only class that crosses the placenta.     * IgA: Can be monomeric (blood) or dimeric (mucosal surfaces/secretions like breast milk).     * IgE: Involved in strong inflammatory responses; binds to mast cells and basophils; critical for defense against parasites and involved in allergic reactions.     * IgD: Found on the surface of mature, naive B cells; important for signaling B cell activation.

Questions & Discussion (Exam Format)

• Question count: The final exam may include between 30 and 100 questions.

• Question types:     * Multiple Choice     * Short Answer     * Essay     * True or False     * Fill-in-the-Blank

• Key Consideration for Deficiencies: If there is an issue making complement proteins $C1$, $C2$, or $C4$, the classical pathway cannot initiate, leading to increased susceptibility to infections and potential autoimmune issues (like Lupus).