Immunology Exam Review (2) PDF

Lecture 1 Lecture 1 1. Purpose of the Immune System Definition: The immune system recognizes and destroys dangerous entities, both exogenous (e.g., viruses, bacteria) and endogenous (e.g., damaged or cancerous cells). Pathogens: Microorganisms that cause disease, including viruses, b...

Lecture 1 Lecture 1 1. Purpose of the Immune System Definition: The immune system recognizes and destroys dangerous entities, both exogenous (e.g., viruses, bacteria) and endogenous (e.g., damaged or cancerous cells). Pathogens: Microorganisms that cause disease, including viruses, bacteria, fungi, and parasites. 2. Major Categories of Human Pathogens Viruses: Examples include Rotavirus, Poliovirus, HIV, Measles virus, Influenza virus, and Ebola virus. Bacteria: Examples include Mycobacterium tuberculosis (tuberculosis), Bordetella pertussis (whooping cough), and Vibrio cholerae (cholera). Fungi: Examples include Candida albicans (thrush) and Cryptococcus neoformans (cryptococcal meningitis). Parasites: Examples include Plasmodium species (malaria) and Schistosoma mansoni (schistosomiasis). 3. Tumors Definition: Tumors are cells that have lost control of their cell cycle and divide uncontrollably. Immune Evasion: A hallmark of cancer is the ability to evade the immune system. 4. Immunity Definition: The state of protection against foreign pathogens or substances (antigens). Historical Observations: Immunity has been observed for over 2000 years, with ancient records noting that recovered individuals could safely nurse the ill. 5. Types of Immune Responses Innate Immunity: ○ Found in all organisms.  ○ Non-specific responses that do not change after repeated exposure to the same pathogen. ○ Includes barriers like skin and mucous membranes, and cells like neutrophils and macrophages. Adaptive Immunity: ○ Present only in animals with a backbone and jaw. ○ Highly specific, with memory for faster and stronger responses upon re- exposure. ○ Mediated by lymphocytes (B cells and T cells). 6. Barriers First Line of Defense: Physical and chemical barriers like skin and mucous membranes. Epithelial Tight Junctions: Prevent pathogens from crossing epithelial layers. 7. Innate Immune Cells Leukocytes: White blood cells, including monocytes, macrophages, mast cells, dendritic cells, and natural killer cells. Pattern Recognition Receptors (PRRs): Bind to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). 8. Adaptive Immune Responses Diversity and Specificity: Lymphocytes have unique receptors (BCRs and TCRs) that recognize specific antigens. Memory: Memory cells provide a faster and stronger response upon re-exposure to the same pathogen. Clonal Expansion: Activated lymphocytes undergo rapid mitosis to produce clones. 9. Phases of Adaptive Immunity Primary Immune Response: Initial response to a pathogen, taking 7-10 days. Secondary Immune Response: Faster and stronger response upon re-exposure, due to memory cells. 10. Vaccination  Purpose: To induce immunity by simulating a primary immune response without causing disease. Adjuvants: Components of vaccines that trigger innate immune responses, necessary for activating adaptive immunity. 11. Key Definitions Antigen: Any substance that induces an immune response. Antibody: A protein produced by B cells that binds to specific antigens. Memory Cells: Long-lived cells that provide immunological memory. 12. Important Concepts Cross-Reactivity: Innate immune responses can be broad-spectrum, providing protection against multiple pathogens. Conservation: Innate immune mechanisms are highly conserved across species. Tolerance: The immune system's ability to ignore self-antigens to prevent autoimmunity. 13. Methodologies Vaccine Development: Involves using killed or attenuated pathogens or pathogen components to induce immunity. Adjuvant Use: Essential for triggering the necessary innate immune signals to activate adaptive immunity. This summary encapsulates the foundational knowledge required to understand the immune system's structure, function, and response mechanisms, as outlined in the document. Lecture 2 Lecture 2 1. Immune System Cells: ○ Hematopoietic Stem Cells (HSCs): Give rise to myeloid and lymphoid progenitor cells. ○ Myeloid Cells: Include neutrophils, eosinophils, basophils, monocytes, and macrophages. ○ Lymphoid Cells: Include T cells, B cells, and Natural Killer (NK) cells. ○ Mast Cells: Play a role in allergy and asthma responses. 2. Hematopoiesis: ○ The process by which blood cells are formed. Most leukocytes mature in the bone marrow, except for mast cells and macrophages, which mature in peripheral tissues, and T cells, which mature in the thymus. 3. Polymorphonuclear Cells (PMNs): ○ Include neutrophils, eosinophils, and basophils. Neutrophils are the most common white blood cells and are rapidly recruited to sites of infection. 4. Phagocytosis: ○ Neutrophils recognize pathogens via surface receptors, engulf them into phagosomes, and kill them using cytotoxic molecules and reactive oxygen species (ROS). 5. Eosinophils and Basophils: ○ Eosinophils are involved in defense against parasites and allergies. Basophils express high-affinity receptors for IgE and release inflammatory mediators. 6. Monocytes and Macrophages: ○ Monocytes enter tissues and differentiate into macrophages, which are long-lived cells that kill pathogens by phagocytosis and produce proinflammatory cytokines. 7. Lymphocytes: ○ B Cells: Produce antibodies and usually remain in lymph nodes. ○ T Cells: Include CD4+ helper T cells and CD8+ cytotoxic T cells. They play crucial roles in activating immune responses and killing infected cells. ○ NK Cells: Innate cells that kill virus-infected or tumour cells. 8. Dendritic Cells (DCs): ○ Found at barriers and close to epithelial cells. Immature DCs internalize antigens and mature in lymph nodes, where they present antigens to T cells. 9. Cytokines:  ○ Soluble mediators essential for immune communication. Include interleukins (ILs), chemokines, and others. They can be pro-inflammatory or anti-inflammatory. 10. Cytokine Receptors: ○ Cytokines bind to receptors, activating downstream proteins like JAKs and transcription factors like STATs, leading to immune responses. 11. Lymphatic System: ○ Immune cells traffic through the blood and lymphatic systems. Lymph nodes are key sites for antigen concentration and lymphocyte activation. 12. Primary and Secondary Lymphoid Organs: ○ Primary: Bone marrow and thymus, where leukocytes are produced and mature. ○ Secondary: Lymph nodes, spleen, and mucosa-associated lymphoid tissues (MALT), where leukocytes are activated. 13. T Cell Selection: ○ Occurs in the thymus. T cells undergo positive and negative selection to ensure they can recognize self-MHC and do not react against self- antigens. 14. Major Histocompatibility Complex (MHC): ○ Helps T cells recognize self and antigens. MHC class I is expressed by all nucleated cells, while MHC class II is expressed by antigen-presenting cells (APCs). 15. Secondary Lymphoid Organs: ○ Lymph Nodes: Concentrate antigens and activate lymphocytes. ○ Spleen: Filters blood and contains white pulp (lymphocytes) and red pulp (red blood cell destruction). ○ MALT: Includes tonsils, adenoids, and Peyer’s patches, providing localized immune responses in mucosal areas. Important Facts and Definitions Hematopoiesis: The formation of blood cellular components. Phagosome: A vesicle formed around a particle engulfed by a phagocyte. Reactive Oxygen Species (ROS): Molecules that can damage pathogens. Chemokines: Cytokines that cause cells to migrate in specific directions. Cluster of Differentiation (CD): Cell surface molecules used to identify cell types. Negative Selection: Process of eliminating self-reactive lymphocytes. Positive Selection: Process of selecting lymphocytes that can recognize self- MHC. Methodologies Flow Cytometry: Used to identify and sort cells based on CD markers. ELISA: Enzyme-linked immunosorbent assay used to detect cytokines. Immunohistochemistry: Used to visualize the distribution and localization of specific cellular components within tissues. Lecture 3 Lecture 3 1. Self vs. Non-Self Recognition: ○ Charles Janeway's Theory: The immune system responds to foreign entities like pathogens or transplants. ○ Danger Model (Polly Matzinger): The immune system responds to damage rather than distinguishing between self and non-self. 2. Innate Immune Cell Recognition: ○ Receptors: Cells use receptors to recognize pathogens. These receptors bind to ligands, stimulating signaling pathways. ○ Molecular Structures: Innate receptors exploit differences between host and pathogen molecular structures, such as lipopolysaccharide (LPS) in Gram-negative bacteria. 3. Pattern Recognition Receptors (PRRs): ○ Types: Scavenger receptors, C-type lectins, Toll-like receptors (TLRs), Nod- like receptors (NLRs), RIG-I-like receptors. ○ Ligands: Pathogen-Associated Molecular Patterns (PAMPs) and Danger- Associated Molecular Patterns (DAMPs). 4. Adaptive Receptors: ○ B Cell Receptors (BCRs) and T Cell Receptors (TCRs): These are randomly generated and can detect a wide range of antigens. Important Facts and Definitions 1. Innate Immune Sensors: ○ Location: Can be membrane-bound, intracellular, or secreted. ○ Function: Detect pathogens both inside and outside cells. 2. Soluble PRRs: ○ Examples: Collectins (e.g., Mannan Binding Lectin, Surfactant Protein A), Pentraxins (e.g., C-reactive protein, Serum amyloid P component). ○ Function: Bind to conserved molecular structures on pathogens, aiding in opsonization and phagocytosis. 3. Opsonization: ○ Process: Coating pathogens with host proteins to make them more visible to phagocytes. ○ Opsonizers: Complement proteins, antibodies. 4. Phagocytosis: ○ Phagocytes: Macrophages and neutrophils.  ○ Mechanism: Pathogen recognition, ingestion, formation of phagosome, fusion with lysosome, pathogen killing, and digestion. 5. Inflammation: ○ Purpose: Recruit leukocytes and mediators to the infection site, raise temperature to slow pathogen replication. ○ Types: Acute local, acute systemic, chronic inflammation. 6. Type I Interferon (IFN) Responses: ○ Function: Establish an antiviral state by increasing the expression of interferon-stimulated genes (ISGs). 7. Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS): ○ Function: Kill microorganisms through oxidative damage. Methodologies and Processes 1. Phagocytosis Mechanism: ○ Steps: Pathogen binding, ingestion, phagosome formation, fusion with lysosome, pathogen killing, and release of digestion products. 2. Inflammasome Formation: ○ Trigger: Requires two signals - PRR binding to PAMP and activation of NLRP3. ○ Outcome: Activation of caspase-1, leading to inflammation and cell death (pyroptosis). 3. Complement Activation: ○ Pathways: Lectin pathway (activated by MBL), classical pathway (activated by antibodies), alternative pathway (spontaneous activation). Key Definitions PAMPs: Pathogen-Associated Molecular Patterns - molecular structures present in pathogens but not in the host. DAMPs: Danger-Associated Molecular Patterns - host molecules released from stressed or damaged cells. Opsonization: The process of coating pathogens with host proteins to enhance phagocytosis. Phagolysosome: The vesicle formed by the fusion of a phagosome with a lysosome, where pathogens are killed and digested. Important Formulas and Pathways 1. NADPH Oxidase Pathway:  ○ Reaction: NADPH + O₂ → NADP⁺ + O₂⁻ (superoxide anion). ○ Outcome: Generation of reactive oxygen species (ROS) to kill pathogens. 2. Interferon Signaling Pathway: ○ Steps: IFN binds receptor → JAKs phosphorylate and activate STATs → STATs increase ISG expression → establishment of antiviral state. Summary The document provides a comprehensive overview of innate immunity, detailing the mechanisms by which the immune system recognizes and responds to pathogens. It covers the roles of various receptors, the process of phagocytosis, the importance of inflammation, and the generation of immune responses through signaling pathways. Key concepts such as self vs. non-self recognition, the danger model, and the function of PRRs and PAMPs are thoroughly explained, along with detailed methodologies and definitions crucial for understanding innate immunity. Lecture 4 Lecture 4 1. The Complement System The complement system is a series of plasma proteins (C1-C9) that act in a cascade to defend against pathogens. It has three main pathways: Classical, Lectin, and Alternative, all of which converge to produce similar outcomes. Key Outcomes of Complement Activation: 1. Formation of the Membrane Attack Complex (MAC): ○ Creates pores in pathogen cell walls, leading to cell lysis. ○ MAC is a polymer of C5b6789. 2. Promotion of Inflammation: ○ Release of anaphylatoxins (C3a, C4a, C5a) that stimulate inflammation and attract immune cells. 3. Activation of Other Killing Mechanisms: ○ Opsonization: C3b coats pathogens, enhancing phagocytosis by macrophages and neutrophils. ○ Stimulation of Reactive Oxygen Species (ROS): Enhances the killing ability of phagocytes. Three Complement Pathways: 1. Classical Pathway: ○ Activated by antibodies bound to pathogens. ○ Not discussed in detail in this document. 2. Lectin Pathway: ○ Activated by mannan-binding lectin (MBL), which binds to sugars on pathogen cell walls. ○ MBL-associated serine proteases (MASP-1 and MASP-2) cleave C2 and C4, forming the C3 convertase (C4b2a). ○ C3 convertase cleaves C3 into C3a and C3b, leading to opsonization and the formation of the C5 convertase (C4b2a3b), which initiates the lytic pathway. 3. Alternative Pathway: ○ The most ancient pathway, initiated by spontaneous hydrolysis of C3. ○ C3 binds to Factor B, which is cleaved by Factor D, forming the C3 convertase (C3bBb).  ○ Properdin stabilizes C3b on the pathogen surface, enhancing the formation of C3 convertase and C5 convertase. ○ C5 convertase cleaves C5 into C5a and C5b, initiating the lytic pathway. Key Points: Complement proteins exist as inactive precursors until cleaved. Complement activation occurs in three phases: Initiation, Amplification, and Lysis. Anaphylatoxins (C3a, C4a, C5a) stimulate inflammation and can cause smooth muscle contraction. Complement-coated microbes are more susceptible to phagocytosis due to complement receptors (CRs) on phagocytes. 2. Regulation of Complement Activation Complement activation is tightly regulated to prevent damage to host cells. Key regulatory proteins include: C1 Inhibitor (C1INH): Inhibits the classical and lectin pathways. Decay-accelerating factor (DAF): Accelerates the dissociation of C3 convertases. Factor H: Regulates the alternative pathway by degrading C3b. CD59: Prevents the formation of the MAC on host cells. 3. Natural Killer (NK) Cells NK cells are part of the innate immune system and play a crucial role in killing virus- infected cells and tumor cells. They are activated by type I interferons (IFNs) and pro- inflammatory cytokines. NK Cell Activation: Activated by cytokines such as IL-2, IL-12, and IFN-gamma. NK cells secrete IFN-gamma, which activates macrophages and creates a positive feedback loop. NK Cell Recognition: NK cells do not have antigen-specific receptors like T cells. They recognize cells to kill based on the balance of inhibitory and activating signals:  ○ Inhibitory receptors bind to MHC class I molecules on healthy cells, preventing NK cell activation. ○ Activating receptors bind to stress-induced ligands on infected or transformed cells. Missing self: If a cell loses MHC class I (common in virus-infected cells), it becomes a target for NK cells. NK Cell Killing Mechanisms: 1. Granule Exocytosis: ○ NK cells release perforin and granzymes into the target cell, inducing apoptosis. 2. Receptor-Mediated Apoptosis: ○ NK cells express FasL and TRAIL, which bind to death receptors (Fas, TNFR-I) on target cells, triggering apoptosis. 4. Type I Interferon (IFN) Response Type I IFNs (e.g., IFN-alpha, IFN-beta) are crucial for antiviral defense. They induce an antiviral state in infected and neighboring uninfected cells by: Reducing viral replication and protein synthesis. Up-regulating MHC class I and antigen processing pathways. Triggering apoptosis in infected cells. 5. Key Definitions and Concepts: Opsonization: The process of coating pathogens with complement proteins (e.g., C3b) to enhance phagocytosis. Anaphylatoxins: Small peptides (C3a, C4a, C5a) that promote inflammation and attract immune cells. Membrane Attack Complex (MAC): A pore-forming complex (C5b6789) that lyses pathogens. Missing Self Hypothesis: NK cells kill cells that lack MHC class I molecules, a common evasion strategy used by viruses. 6. Methodologies and Pathways: Complement Pathways: The document details the steps of the alternative and lectin pathways, including the formation of C3 and C5 convertases.  NK Cell Activation and Killing: The document outlines the three-step process of NK cell activation, recognition, and killing, emphasizing the balance between inhibitory and activating signals. 7. Tables and Figures: Table 5-6: Lists proteins involved in the regulation of complement activity, including their functions and pathways affected. Figures: Illustrate the formation of the MAC, the lectin pathway, and the balance of signals in NK cell recognition. Conclusion: The document provides a comprehensive overview of the complement system and NK cells, two critical components of the innate immune system. It explains the mechanisms of pathogen recognition, inflammation, opsonization, and cell lysis, as well as the regulatory mechanisms that prevent damage to host cells. The interplay between complement proteins, cytokines, and NK cells highlights the complexity and efficiency of the innate immune response. Lecture 5 Lecture 5 Key Concepts and Theories 1. Adaptive Immunity: ○ Mediated by lymphocytes (B cells and T cells). ○ Enables specific immune responses against diverse pathogens. ○ Results in immune memory, leading to faster and stronger responses upon re-exposure to the same pathogen. 2. Lymphocyte Receptors: ○ T Cell Receptors (TCRs): Recognize peptide fragments presented by Major Histocompatibility Complex (MHC) molecules. ○ B Cell Receptors (BCRs): Bind to the three-dimensional structure of antigens. ○ Both TCRs and BCRs are highly diverse due to random DNA rearrangement during lymphocyte development. 3. MHC Molecules: ○ Class I MHC: Present intracellular peptides to CD8+ T cells. ○ Class II MHC: Present extracellular peptides to CD4+ T cells. ○ MHC molecules are polymorphic, leading to a wide variety of peptide- binding capabilities. 4. Somatic Recombination: ○ Random rearrangement of gene segments (V, D, J) generates diverse TCRs and BCRs. ○ This process occurs in the thymus for T cells and in the bone marrow for B cells. 5. Thymic Selection: ○ Positive Selection: Ensures TCRs can bind self-MHC with low affinity. ○ Negative Selection: Eliminates self-reactive TCRs with high affinity for self-MHC. ○ Approximately 95% of thymocytes die during this process, establishing central tolerance. 6. T Cell Activation: ○ Requires three signals: 1. TCR binding to antigen-MHC complex. 2. Co-stimulation (CD28 on T cells binding to CD80/86 on APCs). 3. Cytokines that drive proliferation and differentiation. 7. T Helper Cell Subsets:  ○ Th1: Promotes cell-mediated immunity against intracellular pathogens. ○ Th2: Promotes humoral immunity against extracellular parasites. ○ Th17: Involved in inflammatory responses and autoimmunity. ○ Treg: Suppresses immune responses and maintains tolerance. 8. Cytotoxic T Lymphocytes (CTLs): ○ Recognize and kill virus-infected cells. ○ Activation involves cross-presentation of antigens by dendritic cells and help from Th1 cells. ○ Killing mechanisms include granule exocytosis (perforin and granzymes) and receptor-mediated apoptosis (Fas/FasL). Important Facts and Definitions Immunoglobulin Superfamily: Includes TCRs and BCRs, which are randomly generated and highly diverse. Somatic Recombination: Process by which lymphocyte receptor diversity is generated through random rearrangement of gene segments. MHC Restriction: T cells only recognize antigens presented by self-MHC molecules. Co-stimulation: Essential for T cell activation, involving CD28 on T cells and CD80/86 on APCs. Cytokines: Signaling molecules that influence T cell differentiation and function (e.g., IL-2 for proliferation, IL-12 for Th1 differentiation). Memory T Cells: Long-lived cells that provide rapid and robust responses upon re-exposure to the same pathogen. Methodologies Somatic Recombination: Describes the random rearrangement of V, D, and J gene segments to generate diverse TCRs and BCRs. Thymic Selection: Process by which T cells are selected for their ability to recognize self-MHC without being self-reactive. Cross-Presentation: Mechanism by which dendritic cells present extracellular antigens on MHC class I to activate CD8+ T cells. CTL Killing Mechanisms: Includes granule exocytosis and receptor-mediated apoptosis, both leading to target cell death. Formulas and Key Terms TCR Diversity: Generated by random combination of V, D, and J segments.  ○ Example: TCR beta chain diversity involves 52 V, 2 D, and 13 J segments. MHC Haplotype: Combination of HLA alleles inherited from parents, influencing antigen presentation. Cytokine Signaling Pathways: Involve transcription factors like T-bet (Th1), GATA-3 (Th2), and RORγt (Th17). Summary The document provides a comprehensive overview of the adaptive immune system, emphasizing the roles of T cells and B cells, the mechanisms of antigen recognition, and the processes of lymphocyte activation and differentiation. Key concepts include the diversity of lymphocyte receptors, the importance of MHC molecules in antigen presentation, and the critical role of co-stimulation and cytokines in T cell activation. The document also details the mechanisms by which cytotoxic T lymphocytes eliminate infected cells and the generation of memory T cells for long-term immunity. Lecture 6 Lecture 6 Key Concepts and Theories 1. Adaptive Immune Response: ○ The adaptive immune response involves lymphocytes, specifically B cells and T cells, which recognize and respond to pathogens. ○ B cells produce antibodies, while T cells have various roles, including helping B cells (helper T cells) and killing infected cells (cytotoxic T cells). 2. B Cell Receptors (BCRs): ○ BCRs are surface immunoglobulins (e.g., mIgM) that recognize the three- dimensional structure of antigens. ○ BCRs are complexed with Igα and Igβ chains, which have ITAMs (Immunoreceptor Tyrosine-based Activation Motifs) for intracellular signaling. 3. Somatic Recombination and Diversity: ○ BCR diversity is generated through somatic recombination of V(D)J gene segments during B cell development in the bone marrow. ○ This random process results in a vast and unique repertoire of BCRs. 4. B Cell Activation: ○ B cells require three signals for activation: antigen binding to BCR, co- stimulation (e.g., CD40-CD40L interaction with T cells), and cytokines from helper T cells. ○ B cells can also be activated in a T cell-independent manner by multivalent antigens. 5. Somatic Hypermutation and Affinity Maturation: ○ During an immune response, BCR genes in activated B cells undergo somatic hypermutation, introducing point mutations to increase diversity. ○ Affinity maturation occurs in germinal centers, where B cells with higher affinity BCRs are selected for survival and differentiation into plasma cells. 6. Class Switching: ○ B cells can switch the class of antibodies they produce (e.g., from IgM to IgG, IgA, or IgE) through class switching, mediated by AID (Activation- Induced Cytidine Deaminase). ○ Class switching involves genomic deletions and is influenced by cytokines. 7. Memory B Cells and Plasma Cells:  ○ Memory B cells are long-lived and provide a faster and stronger response upon re-exposure to the same antigen. ○ Plasma cells produce large amounts of antibodies and can reside in the bone marrow or mucosal tissues for long periods. 8. Antibody Effector Functions: ○ Antibodies neutralize pathogens and toxins, agglutinate pathogens, opsonize for phagocytosis, activate the complement system, and mediate antibody-dependent cellular cytotoxicity (ADCC). ○ Different antibody classes (IgG, IgA, IgM, IgD, IgE) have distinct effector functions and distributions in the body. Important Facts and Definitions BCR Structure: Composed of heavy and light chains, with variable (V) domains that bind antigens and constant (C) domains that determine the antibody class. ITAMs: Immunoreceptor Tyrosine-based Activation Motifs are crucial for intracellular signaling upon antigen binding. Germinal Centers: Sites in lymph nodes where B cells undergo somatic hypermutation and affinity maturation. AID: Activation-Induced Cytidine Deaminase is an enzyme that mediates both somatic hypermutation and class switching. Fc Receptors (FcRs): Receptors on immune cells that bind the Fc region of antibodies, triggering various immune responses such as phagocytosis, ADCC, and degranulation. Methodologies Somatic Recombination: The process by which V(D)J gene segments are rearranged to generate diverse BCRs. Somatic Hypermutation: Introduction of point mutations in the variable regions of BCR genes to increase antibody affinity. Class Switching: Genomic rearrangement that changes the constant region of the antibody, altering its class and effector function. Affinity Maturation: Selection of B cells with higher affinity BCRs in germinal centers, leading to the production of high-affinity antibodies. Summary The document provides a detailed explanation of B cell biology, from receptor diversity and activation to effector functions and memory formation. Key processes such as somatic recombination, somatic hypermutation, affinity maturation, and class switching are crucial for generating a diverse and effective antibody response. The roles of different antibody classes and their interactions with Fc receptors are also highlighted, emphasizing the complexity and specificity of the adaptive immune response. Lecture 7 Lecture 7 Key Concepts and Theories 1. Immune System Function: ○ The immune system should recognize and destroy harmful entities (pathogens, tumors) while ignoring harmless ones (commensal bacteria, food). ○ Barriers like lungs, gastrointestinal tract, and skin are crucial for interacting with the environment and maintaining anti-inflammatory states unless danger signals (DAMP or PAMP) are present. 2. Immune Response and Disease: ○ The document discusses four examples of how immune responses can lead to disease: 1. Immunodeficiency 2. Autoimmunity 3. Hypersensitivities 4. Tumor immunity 3. Immunodeficiency: ○ Primary Immunodeficiency: Caused by genetic mutations, present at birth, and can affect innate or adaptive immune responses. Examples include Severe Combined Immunodeficiency (SCID) and X-linked hyper-IgM syndrome. ○ Secondary Immunodeficiency: Caused by external agents like drugs, radiation, or infections (e.g., HIV). 4. Severe Combined Immunodeficiency (SCID): ○ A severe, life-limiting condition characterized by a lack of functional T and B cells. ○ Symptoms include repeated infections, diarrhea, failure to thrive, and lung failure. ○ Treatment involves bone marrow or hematopoietic stem cell transplants. 5. Categories of SCID Defects: ○ Reticular dysgenesis (RD) ○ Defective purine metabolism (ADA deficiency) ○ Defects in receptor rearrangement (e.g., RAG mutation) ○ Mutations in cytokine receptor signaling ○ Defects in T cell signaling (e.g., ZAP-70 deficiency) 6. Agammaglobulinemias:  ○ Severe antibody deficiencies due to B lymphocyte defects. ○ Similar presentation to SCID and also requires bone marrow transplants. 7. Innate Immune Deficiencies: ○ Defects in phagocytes or complement systems. ○ Example: Chronic Granulomatous Disease (CGD), which affects NADPH oxidase, leading to ineffective pathogen killing and granuloma formation. 8. Immune Regulation Deficiencies: ○ Mutations affecting T cell tolerance mechanisms can lead to autoimmunity. ○ Example: Immune dysregulation, polyendocrinopathy, enteropathy, X- linked (IPEX), caused by a defect in FoxP3, leading to unchecked autoreactive T cells. 9. Secondary Immunodeficiencies: ○ Acquired immunodeficiencies, such as those caused by HIV, immunosuppressive drugs, metabolic diseases, or malnutrition. ○ AIDS is the most studied example, characterized by heightened susceptibility to infections and certain cancers. 10. HIV and AIDS: ○ HIV is an RNA retrovirus that integrates into the host genome. ○ It preferentially infects CD4+ T cells, leading to a progressive decline in immune function. ○ HIV transmission occurs through sexual contact, with the virus infecting CD4+ T cells in the genital tract. ○ HIV has a high mutation rate, leading to the generation of escape mutants and complicating treatment. 11. HIV Infection Phases: ○ Acute Phase: High viral load, rapid CD4+ T cell decline, and seroconversion. ○ Chronic Phase: Asymptomatic with partial immune control, stable viral load, and ongoing CD4+ T cell decline. ○ Symptomatic Phase (AIDS): Increased viral load, CD4+ T cell count below 200 cells/mm³, and susceptibility to opportunistic infections and cancers. 12. HIV Treatment: ○ Antiretroviral therapy (ART) suppresses viral load and can keep individuals in the asymptomatic phase for years. ○ ART involves a combination of drugs targeting different parts of the HIV replication cycle. ○ Monitoring viral load and CD4+ T cell counts is crucial for managing HIV. 13. Immune Evasion:  ○ HIV can mutate to evade immune detection, such as altering epitopes presented by MHC class I to avoid CTL recognition. 14. Vaccination: ○ HIV vaccination is challenging due to high mutation rates and variability in strains. ○ No effective vaccine currently exists, but mRNA technology is being explored. Important Facts and Definitions Primary Immunodeficiency Disorders (PIDs): Over 300 genetic mutations identified, affecting various immune response genes. X-linked Hyper-IgM Syndrome: Defective CD40L or CD40 leads to impaired B cell activation, class switching, and memory cell production. Selective IgA Deficiency: The most common antibody deficiency, often asymptomatic but can lead to increased susceptibility to infections. Chronic Granulomatous Disease (CGD): Defect in NADPH oxidase leads to ineffective pathogen killing and granuloma formation. IPEX Syndrome: Caused by a defect in FoxP3, leading to systemic autoimmune disease due to unchecked autoreactive T cells. HIV Transmission: Primarily through sexual contact, with the virus infecting CD4+ T cells in the genital tract. HIV Replication: High replicative capacity and error-prone replication lead to a high mutation rate and escape mutants. ART (Antiretroviral Therapy): Combination therapy targeting different stages of HIV replication, essential for managing HIV as a chronic disease. Methodologies Diagnosis of HIV: Detection of anti-HIV antibodies using ELISA, with seroconversion typically occurring within 2-3 weeks post-infection. Monitoring HIV: Regular monitoring of viral load and CD4+ T cell counts to evaluate disease progression and treatment efficacy. This summary encapsulates the essential elements of the document, providing a comprehensive understanding of the immune system's role in health and disease, with a particular emphasis on immunodeficiencies and HIV/AIDS. Lecture 8 Lecture 8 Key Concepts and Theories 1. Inflammation and Hypersensitivity: ○ Inflammation is a specific form of inflammatory response mediated by lymphocytes. ○ Hypersensitivity reactions are inappropriate specific immunological responses mediated by antibodies and T cells, often to antigens that pose little to no threat. 2. Types of Hypersensitivity Reactions: ○ Type I (Immediate Hypersensitivity): Mediated by IgE antibodies on mast cells and basophils. Examples: Respiratory allergens (e.g., pollen) and food allergens. Mechanism: Allergen exposure leads to IgE production, which binds to mast cells. Subsequent exposure causes degranulation and release of mediators like histamine. ○ Type II (Antibody-Mediated Hypersensitivity): Mediated by IgG or IgM antibodies targeting host cells. Examples: Blood type mismatches and hemolytic anemias. Mechanism: Antibodies bind to cell surface antigens, leading to cell destruction via complement activation or antibody-dependent cellular cytotoxicity (ADCC). ○ Type III (Immune Complex-Mediated Hypersensitivity): Mediated by antigen-antibody complexes that trigger complement and granulocyte activation. Examples: Serum sickness and lupus. Mechanism: Immune complexes deposit in tissues, causing inflammation and tissue damage. ○ Type IV (Delayed-Type Hypersensitivity, DTH): Mediated by T cells, particularly TH1 cells. Examples: Poison ivy, tuberculosis. Mechanism: Sensitized T cells release cytokines that recruit and activate macrophages, leading to tissue damage. 3. Allergies: ○ Allergic reactions are immunological responses to antigens that cause damage instead of protection. ○ Type I hypersensitivity is most commonly associated with allergies.  ○ Common allergens include plant pollens, dust mites, and certain foods. 4. Diagnosis and Treatment: ○ Diagnosis: Skin tests and ELISA can detect specific allergens. ○ Treatment: Avoidance of allergens. Immunotherapy (e.g., anti-IgE antibodies like omalizumab). Anti-histamines, adrenalin, and corticosteroids for symptom management. 5. Environmental Susceptibility: ○ The hygiene hypothesis suggests that low exposure to microorganisms is associated with increased hypersensitivity reactions. 6. Specific Conditions: ○ Peanut Allergies: Sensitization often occurs through the skin, especially in individuals with eczema. The process involves dendritic cells, TH2 cells, and IgE production. ○ Blood Transfusion Reactions: Caused by mismatched blood types, leading to complement activation and hemolysis. ○ Hemolytic Disease of the Newborn: Occurs when maternal IgG antibodies against fetal Rh antigens cross the placenta and destroy fetal red blood cells. 7. Immunotherapy: ○ Desensitization: Repeated exposure to increasing amounts of allergen to reduce sensitivity. ○ Oral Immunotherapy (OIT): Used for food allergies, involving gradual exposure to allergens to induce tolerance. Important Facts and Methodologies 1. Mast Cell Degranulation: ○ First exposure to an allergen triggers IgE production. Subsequent exposure causes mast cell degranulation, releasing mediators like histamine, heparin, and proteases. 2. Cytokines and Chemokines: ○ Play crucial roles in recruiting and activating immune cells during hypersensitivity reactions. ○ Examples: IFN-γ, TNF-α, IL-4, IL-13. 3. Tuberculin Skin Test: ○ Used to detect past infection with Mycobacterium tuberculosis or vaccination.  ○ Involves injecting purified protein derivative (PPD) and observing for a delayed hypersensitivity reaction. 4. RhoGAM: ○ Administered to Rh-negative mothers to prevent hemolytic disease of the newborn by binding to fetal Rh-positive red blood cells and preventing maternal immune response. Summary The document comprehensively covers the mechanisms, types, and treatments of hypersensitivity reactions. It emphasizes the role of immune cells, antibodies, and cytokines in mediating these reactions and highlights specific conditions like allergies, blood transfusion reactions, and hemolytic disease of the newborn. Diagnostic methods and therapeutic strategies, including immunotherapy, are also discussed in detail. Lecture 9 Lecture 9 The document covers two main topics: Water Urticaria (Aquagenic Urticaria) and Transplantation. Below is a comprehensive summary of the key concepts, theories, and important facts from the document: 1. Water Urticaria (Aquagenic Urticaria) Definition: A rare form of physical urticaria (hives) triggered by contact with water of any temperature. Symptoms: Red, itchy hives, burning sensations, and wheals appear within minutes of water exposure. Prevalence: Only 100-250 people worldwide are affected. Pathophysiology: ○ Type I Hypersensitivity: Water interacts with something on the skin to create an antigen, leading to mast cell activation and the release of histamine and other inflammatory mediators. ○ Non-IgE Mediated: The reaction is not mediated by IgE antibodies. ○ Possible Causes: Abnormalities in water channels in skin cells or altered sensitivity. Treatment: ○ Reduced water exposure. ○ Antihistamines. ○ Barrier creams. 2. Transplantation Transplantation is a clinical treatment for end-stage organ failure, offering life-saving benefits. However, recipients must take immunosuppressive drugs for life to prevent rejection. Types of Transplants: 1. Autograft: Transplanting tissue from one part of the body to another (within the same individual). 2. Isograft: Transplanting tissue between identical twins. 3. Allograft: Transplanting tissue between different members of the same species (most common in clinical practice).  4. Xenograft: Transplanting tissue between members of different species. Laws of Transplantation: Inbred Mouse Strains: Used to study transplantation. ○ Transplants within the same inbred strain (e.g., Strain A to Strain A) succeed. ○ Transplants between different inbred strains (e.g., Strain A to Strain B) are rejected. ○ Transplants from an inbred strain to an F1 hybrid (e.g., Strain A to Strain A/B) succeed, but not vice versa. ○ Immunodeficient mice (e.g., SCID or nude mice) can accept any graft, but adoptive transfer of T cells can enable rejection. T Cells and MHC in Transplant Rejection: First Set Rejection: Initial exposure to a transplant takes 10-14 days to reject. Second Set Rejection: Subsequent exposure to the same transplant leads to faster rejection (3-7 days). T Cell Depletion Studies: ○ Depletion of CD4 T cells reduces rejection time. ○ Depletion of both CD4 and CD8 T cells further extends the time to rejection. Allorecognition: Direct Allorecognition: Donor APCs in the transplanted tissue present antigens to recipient T cells, which recognize non-self MHC and mount an immune response. Indirect Allorecognition: Donor MHC shed during transplantation is taken up by recipient APCs, which present donor MHC peptides to recipient T cells. Matching Donor and Recipient: 1. Blood Type: Must match blood group antigens between donor and recipient to prevent hyperacute rejection. 2. HLA Type: Matching HLA haplotypes (especially HLA-A, B, and DR) is crucial, particularly for bone marrow transplants. 3. Cross-Matching: Tests for pre-existing antibodies in the recipient against donor HLA antigens. Skipping this step can lead to hyperacute rejection. Transplant Rejection Types: 1. Hyperacute Rejection (HAR): ○ Caused by pre-formed antibodies and complement activation. ○ Occurs within hours to days.  ○ Rare due to blood typing and cross-matching. 2. Acute Rejection (AR): ○ Cell-mediated rejection involving Th1/Th17 responses and pro- inflammatory cytokines. ○ CD4+ T cells produce cytokines (IFN-γ, TNF-α, IL-2) that increase MHC expression, promote macrophage activation, and T cell proliferation. ○ CD8+ T cells directly lyse donor cells. ○ Occurs within 10 days and can be reversed with immunosuppressive drugs. 3. Chronic Rejection: ○ Less understood, likely involves Th2 responses. ○ Results in irreversible graft damage, fibrosis, and tissue remodeling. ○ Common, with 40% of kidney transplants lost due to chronic rejection. ○ No effective treatment; occurs over months to years. Immunotherapies: General Immunosuppressive Drugs: Target all T and B cells (e.g., azathioprine, which inhibits cell proliferation). Specific Immunosuppressive Drugs: Monoclonal antibodies that target specific immune responses, reducing side effects. Key Definitions: Autograft: Transplant within the same individual. Isograft: Transplant between identical twins. Allograft: Transplant between members of the same species. Xenograft: Transplant between different species. Hyperacute Rejection: Rapid rejection due to pre-formed antibodies. Acute Rejection: Cell-mediated rejection occurring within days. Chronic Rejection: Long-term, irreversible graft damage. Key Concepts: T Cell Role: CD4+ and CD8+ T cells are central to transplant rejection. MHC Matching: Critical for reducing rejection, especially in bone marrow transplants. Immunosuppression: Lifelong requirement for transplant recipients to prevent rejection. This summary encapsulates the essential information from the document, providing a clear understanding of water urticaria and the complexities of transplantation, including the immunological mechanisms involved in graft rejection and the strategies used to mitigate it. Lecture 10 Lecture 10 The document provides an in-depth overview of tumor immunity, focusing on the interaction between the immune system and cancer cells. Here is a comprehensive summary of the key concepts, theories, and important facts presented in the document: 1. Normal vs. Transformed Cells Normal Cells: Have a finite life span, differentiate, function, and undergo apoptosis when old. Macrophages take up apoptotic bodies. Transformed (Cancerous) Cells: Undergo mutations, lose control of the cell cycle, and proliferate uncontrollably, leading to tumor formation. 2. Tumor Immunity Tumor Cells: Are healthy body cells that express self-molecules. Malignant tumors can metastasize and are often immunosuppressive, with high levels of Treg CD4+ helper T cells and anti-inflammatory cytokines like TGF-β and IL-10. 3. Immune Evasion by Tumor Cells Mechanisms: ○ Avoid recognition by down-regulating MHC class I molecules. ○ Resist destruction by up-regulating anti-apoptotic molecules. ○ Actively suppress the immune response by activating anti-inflammatory cells and mediators. Main Immune Effectors: NK cells and cytotoxic T lymphocytes (CTLs). 4. Tumor Antigens Types: ○ Tumor-Specific Antigens (TSA): Unique to tumor cells, not expressed by normal cells. ○ Tumor-Associated Antigens (TAA): Expressed at higher levels on tumor cells compared to normal cells, or expressed during fetal development but not in adult cells. Examples: HER-2 (Human Epidermal Growth Factor Receptor 2), involved in 20- 30% of breast cancers, targeted by Herceptin. 5. Immunoediting of Tumor Cells  Three Ways the Immune System Controls Cancer: 1. Identify and destroy cancer-causing viruses. 2. Remove pathogens quickly to reduce chronic inflammation, which can support cancer development. 3. Identify and eliminate tumor cells through immunosurveillance. 6. Tumor Vaccines Types: Whole tumor cells, peptides from tumor cells, tumor-specific antigen- defined vaccines, and vaccines aiming to increase dendritic cells (DCs) to activate T cell responses. Challenges: Tumors evade immune responses, and antigenic variation between individuals complicates vaccine development. 7. Cancer Immunotherapies Monoclonal Antibodies: Target surface tumor cell antigens, triggering ADCC or complement-mediated cell lysis. Can be naked or toxin-conjugated. Adoptive Cell Transfer: ○ Antigen-Loaded DCs: DCs are removed, loaded with tumor-specific proteins, and reintroduced to stimulate T cells. ○ Tumor-Reactive T Cells (TILs): Isolated, expanded in vitro, and reintroduced to the patient. ○ CAR T Cells: Engineered to express a chimeric antigen receptor (CAR) specific to tumor antigens. Immune Checkpoint Inhibitors: Monoclonal antibodies that block inhibitory molecules like CTLA-4, PD-1, or PD-L1, preventing T cell deactivation. 8. Key Definitions and Concepts MHC Class I: Presents intracellular peptides to T cells. TAP (Transporter Associated with Antigen Processing): Transports peptides into the ER for MHC class I presentation. B2M (Beta-2 Microglobulin): Part of the MHC class I complex. IFN-γ: Induces MHC class I expression. 9. Methodologies Vaccine Strategies: Combining tumor vaccines with existing vaccines, adding cytokines (e.g., GM-CSF, IL-2), and using adjuvants to promote co-stimulation.  Adoptive Cell Transfer: Involves isolating, modifying, and reintroducing immune cells to enhance anti-tumor responses. 10. Figures and Illustrations Figure 19-3: Illustrates the four ways tumor antigens arise. Figure 19-8: Depicts various cancer immunotherapy strategies, including monoclonal antibodies, adoptive cell transfer, and immune checkpoint inhibitors. This summary encapsulates the essential elements of tumor immunity, providing a foundation for understanding how the immune system interacts with cancer cells and the various strategies employed to harness immunity for cancer treatment. Lecture 11 Key Concepts and Definitions 1. Autoimmunity: ○ Definition: Autoimmunity occurs when the immune system mistakenly attacks the body's own tissues, leading to a loss of self-tolerance. ○ Mechanisms: This involves the production of autoantibodies or autoreactive T cells that target self-antigens. 2. Autoimmune Disease: ○ Progression: Autoimmune diseases can manifest in various forms, ranging from mild to severe, and can involve systemic or organ-specific damage. ○ Comorbidity: Often associated with other conditions, leading to complex clinical presentations. Causes of Autoimmunity 1. Genetic Factors: ○ HLA Gene Variants: Certain human leukocyte antigen (HLA) gene variants are linked to a higher risk of autoimmune diseases. ○ Family History: A family history of autoimmune diseases increases susceptibility. 2. Environmental Triggers: ○ Infections: Microbial infections can trigger autoimmune responses. ○ Sex and Hormonal Factors: Autoimmune diseases are more common in females, suggesting a role for sex hormones. 3. Microbial and Environmental Stimuli: ○ Environmental Compounds: Exposure to certain chemicals and pollutants can contribute to the development of autoimmunity. Common Autoimmune Diseases 1. Systemic Diseases: ○ Rheumatoid Arthritis: A systemic autoimmune disease that can be influenced by environmental factors. 2. Organ-Specific Diseases: ○ Type 1 Diabetes: Targets the pancreas. ○ Multiple Sclerosis: Affects the nervous system. ○ Hashimoto's Thyroiditis: Targets the thyroid gland. Symptoms of Autoimmune Diseases 1. General Symptoms:  ○ Fatigue, joint pain/swelling, skin rashes, and recurring fevers. 2. Organ-Specific Symptoms: ○ Example: Low thyroid hormone levels in Hashimoto's thyroiditis. 3. Disease-Specific Symptoms: ○ Example: Butterfly-shaped rash on the face in lupus. Diagnosis 1. Blood Tests: ○ Autoantibodies: Detection of specific autoantibodies. ○ Inflammatory Markers: C-reactive protein, complete blood count, erythrocyte sedimentation rate (ESR), complement levels, and urinalysis. 2. Clinical Evaluation: ○ Comprehensive assessment of symptoms and medical history. Treatment 1. Medications: ○ Immunosuppressants: Such as methotrexate, to reduce overall immune system activity. ○ Biologics: Target specific immune pathways, e.g., TNF and IL-6 inhibitors. ○ Corticosteroids: Such as prednisone, to reduce inflammation. ○ NSAIDs: Such as ibuprofen, to manage pain and inflammation. 2. Lifestyle Changes: ○ Dietary Modifications: Adjustments to diet to support immune health. ○ Regular Exercise: To improve overall health and reduce stress. ○ Stress Management: Techniques to manage chronic stress, which can exacerbate autoimmune conditions. First-World Connection 1. Hygiene Hypothesis: ○ Concept: Higher levels of cleanliness and sanitation reduce childhood exposure to microbes, leading to a less trained immune system. ○ Impact: Lower rates of autoimmune diseases in regions with higher exposure to parasites and infectious diseases. 2. Lifestyle Factors: ○ Diet: Higher consumption of processed foods and reduced fiber intake disrupt gut microbiota. ○ Pollution: Increased exposure to industrial pollutants and chemicals. ○ Urbanization: Reduced contact with natural environments.  ○ Chronic Stress and Lack of Physical Activity: Contribute to the prevalence of autoimmune diseases in first-world countries. Methodologies and Formulas 1. Sed Rate Test (ESR): ○ Method: Measures how fast red blood cells fall to the bottom of a tube in one hour. Inflammation causes red blood cells to stick together and sink faster. 2. Blood Test Parameters: ○ Example Parameters: Hemoglobin (Hb), white blood cells (WBCs), platelets, ANA titer, anti-dsDNA titer, C3, C4, ESR, CRP, creatinine, 24-hour protein, urine analysis (proteinuria, RBCs, WBCs, blood cell casts), CXCL12 levels. Conclusion The document provides a comprehensive overview of autoimmunity, covering its causes, common diseases, symptoms, diagnostic methods, and treatment options. It also explores the connection between autoimmune diseases and first-world lifestyles, emphasizing the role of environmental and genetic factors. Understanding these concepts is crucial for diagnosing and managing autoimmune diseases effectively.