[HS 202]-E01-T05-Fundamentals of Immunology.pdf

w hs 202: Biopsychosocial Dimension of Illness Fundamentals of Immunology Fresthel Monica M. Climacosa, MD, PhD | September 26, 2024 OUTLINE I. Introduction C. Effector Function...

w hs 202: Biopsychosocial Dimension of Illness Fundamentals of Immunology Fresthel Monica M. Climacosa, MD, PhD | September 26, 2024 OUTLINE I. Introduction C. Effector Functions of A. Immunity Adaptive Immunity B. Innate Immunity vs. D. Evasion of Adaptive Adaptive Immunity Immunity II. Innate Immunity IV. Failures of the Immune A. Anatomical Barriers System B. Chemical Barriers V. Applications of C. Activation of the Innate Immunology Immune System A. Immunization vs. D. Effector Functions of Vaccination Innate Immune System B. Vaccines E. Evasion of the Innate VI. Immunization for Public Immune System Health III. Adaptive Immunity VII. References A. Cellular Components VIII. Appendix B. Activation of Adaptive Immunity I. INTRODUCTION A. IMMUNITY Etymology: From Latin word immunis, meaning exempt → A state of exemption or protection → Resistance to infectious disease Modern redefined definition: Distinguishing self from non-self Figure 1. Coordinated and Regulated Immune Response (Enlarged in Appendix) → Defense against pathogens B. INNATE IMMUNITY VS ADAPTIVE IMMUNITY → Defense against tumors Dichotomous classification of the immune system → Recognize tissue grafts They do NOT act separately, they work hand-in-hand A regulated and coordinated process Table 1. Comparison of innate and adaptive immunity. Exposure/gaining of access to the body by pathogens leads to Adaptive infectious diseases Characteristic Innate Immunity Immunity → Main defenses are physical barriers like the skin Recognition Minutes to hours Days ▪ E.g. breach of skin integrity leads to a body response Time Defenses also has effects on own cells → Could attack indiscriminately, damaging own cells Specificity Molecules and Patterns Highly specific Associated with Pathogen (PAMPs) and Dead/Damaged cells (DAMPs) Diversity Low Very high Self/non-self Yes Yes Recognition Memory Limited Yes Response Anatomical Skin, Mucosal Epithelia, Lymphocytes, and Chemical Antimicrobial molecules, Antibodies at Complement system Epithelia Barriers Cellular Macrophages, Neutrophils, B and T Components Dendritic cells, Natural Killer Lymphocytes (NK) cells, Mast cells, Innate Lymphoid cells Trans 05 TG10B: Rivas, Rivera R., Rivera T., Robles, Rodiel, Rodriguez TH: Tubilla 1 of 26  Figure 2. Overview of B-cell and T-cell Maturation and Differentiation in Various Lymphoid Organs Figure 4. Histology of the Skin, a Mechanical Barrier II. INNATE IMMUNITY Also called natural immunity or native immunity Ready to recognize and eliminate microbes and dead cells First line of defense A. ANATOMICAL BARRIERS Skin (See Figure 4) → Good mechanical/physical barrier to infection → Sweat and sebaceous glands secrete substance with inherent antimicrobial activity Conjunctiva → Blinking Reflex: physiologic protective mechanism to ward off big foreign bodies from your eyes → Tears: contain lysozymes that are antimicrobial Gastrointestinal tract (See Figure 5) → Acidic gastric pH → Peristalsis expels ingested pathogens (e.g. diarrhea) ▪ Advised NOT to take too much antimotility drugs (i.e. loperamide) to allow clearance of the pathogen Respiratory tract (See Figure 6) → Goblet cells create mucus, trapping microbes and particulate matter → Ciliary motion expels inhaled foreign substances → Sneezing and Cough reflex Microbiota → Beneficial bacteria that are commensals (See Figure 7) → Already colonized the mucosa, epithelial surfaces, and skin Figure 5. Stomach Body Histology. Note parietal cells that produce gastric acid. ▪ Making it difficult for infectious agent to establish a colony in your body → Even lungs have been discovered to have normal microbiota Figure 6. Respiratory Epithelium. Note mucinous goblet cells and cilia. Figure 3. Anatomical Barriers HS 202 Fundamentals of Immunology 2 of 26  Surfactant Secretions of Block bacterial surface Proteins respiratory tract, other components; promote mucosal epithelia phagocytosis RegIII Proteins Intestinal epithelia Bind cell wall carbohydrates and prevent bacterial binding to epithelial cells; produce membrane pores that kill cells Antimicrobial Peptides Location Activities Disrupt membranes of Skin, mucosal epithelia bacteria, fungi, Defensins (mouth, intestine, nasal protozoan parasites, and (ɑ and β) / respiratory tract, viruses; additional toxic urogenital tract), blood effects intracellularly; kill cells and disable viruses Disrupts membranes of Mucosal epithelia Cathelicidin bacteria; additional toxic (respiratory tract, (LL-37) urogenital tract) effects intracellularly; kills cells Lectins that bind to fungal cell walls and Histatins Saliva enter the cytoplasm, where they have several Figure 7. Microbiota Composition in Different Regions of the Body harmful effects B. CHEMICAL BARRIERS Antibacterial and Skin (from sweat antifungal; produces Antimicrobial Proteins and Peptides Dermcidin glands) channels in membranes Increased levels indicate ongoing immune defense activity that disrupt ion gradients Lysozyme → Found in tears and saliva Complement System → Cleaves the glycosidic bonds of peptidoglycans in cells of wall bacteria, leading to lysis ▪ Review: Bacterial cell wall is necessary in protecting itself against osmotic lysis Surfactant proteins → Not just necessary for maintaining the lungs and preventing their collapse → Also has bactericidal properties ▪ Review: Necessary for maintaining lung surface tension Defensins → Disrupts membranes of bacteria, fungi, protozoan parasites, and viruses Table 2. Human antimicrobial proteins and peptides (Enlarged in Appendix) Antimicrobial Proteins Location Activities Lysozyme Mucosal glandular Cleaves glycosidic secretions bonds of peptidoglycans Figure 8. Complement System Cascade (tears, saliva, in cell walls of bacteria, Set of plasma proteins produced by the liver respiratory tract) leading to lysis Can be activated via three pathways Lactoferrin Mucosal/glandular Binds and sequesters → Classical, Alternative, or Lectin Pathways secretions iron, limiting growth of (milk, intestinal mucus, bacteria and fungi; Formation of the Membrane Attack Complex (MAC) is the nasal / respiratory and disrupts microbial ultimate protective mechanism and effector function urogenital tracts) membranes; limits → MAC attacks the bacterial membrane causing lysis infectivity of some ▪ Bacterial cell membrane functions: viruses − Selective barrier that keeps the contents of the cell inside Secretory Skin, mucosal / Blocks epithelial infection − Respiration Leukocyte glandular secretions by bacteria, fungi, − Control movement in and out of the cell (intestines, respiratory viruses; antimicrobial Protease → The MAC attacks susceptible membranes and urogenital tracts, Inhibitor milk) ▪ Depending how thick the capsule is S100 Skin, mucosal / ▪ In general, having a capsule is an evasive advantage for a. Psoriasin glandular secretions (a) Disrupts membranes, pathogens as the MAC won’t be able to damage the (tears, saliva / tongue, killing cells membrane intestine, (b) Binds and b. Calprotectin → Complement system is implicated in some of the pathology in nasal/respiratory and sequesters divalent urogenital tracts) cations (manganese non-communicable diseases and zinc), limiting growth of bacteria and fungi HS 202 Fundamentals of Immunology 3 of 26  Cellular Components − Azurophilic granules: Myeloperoxidase, Defensins (antimicrobial peptides), Cathelicidins ▪ Phagocytic → Eosinophils ▪ Contain basic proteins, and are acid-loving (eosinophilic) ▪ Best defense against helminthic infections ▪ Produce histaminase, major basic protein, eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin ▪ Weakly phagocytic − More effective against helminths → Basophils ▪ Non-phagocytic granulocyte containing basophilic granules ▪ Implicated in allergic reactions because of their granules containing histamine → Mast cells ▪ Abundant in the skin and mucosal epithelia − As a result, they take up a very low count in the complete blood count (CBC) ▪ Release potent inflammatory mediators that defend against helminthic infections or cause symptoms of allergies − Due to histamine, it leads to sneezing, itchy throat, etc. Mononuclear Cells (Agranulocytes) → Monocytes ▪ Found in blood ▪ Once they reach the tissue and reside there, they differentiate into macrophages → Macrophages ▪ Strongest phagocytes − Phagocytose bacteria, debris, and senescent RBCs Figure 9. Hematopoiesis and Maturation of Cellular Components of the Innate Immune System (Enlarged in Appendix) ▪ Sentinel cells: survey the environment ▪ Antigen-presenting cells (APC) Immune cells originate from generative lymphoid organs: the ▪ Can promote repair of damaged tissues bone marrow and the thymus ▪ Tissue-resident macrophages (See Figure 11) → Innate cellular components all mature in the bone marrow − Brain: Microglial cells Leukocytosis: increase in the number of a particular leukocyte − Liver: Kupffer cells → The type of leukocyte that is abnormally high may give you − Lungs: Resident alveolar macrophages clues as to which type of infection is present − Heart: Myocardial macrophages → In contrast, Leukopenia is abnormally low WBC count Leukocytes White blood cells Figure 11. Tissue-resident Macrophages Cytokines Molecules that communicate among cells of the immune system Figure 10. (Left, from top to bottom) Neutrophil, Monocytes, and Macrophage; Interleukins: mediate communication between WBCs (Right, from top to bottom) Eosinophils, Basophils and Mast Cell Chemokines: chemoattractant substances Polymorphonuclear Cells (Granulocytes) C. ACTIVATION OF INNATE IMMUNE SYSTEM → Neutrophils Antigens ▪ Most abundant (50-70%) WBC in peripheral blood → Any nonself substance that can interact with immune cells ▪ Principal cell type in acute inflammatory reactions → Elicit an immune response when recognized by the body particularly against bacterial infections → Not only infectious, but also non-infectious − Dedicated that they die in the process of protection, ▪ Infectious: bacterial, viral, protozoal, helminth making up much of pus ▪ Non-infectious: ▪ First to act on immune response − Aberrant self-antigens ▪ Granules − Food antigens − Specific granules: Lysozyme (attacks cell wall), − Plant products (pollen) Collagenase, Elastase HS 202 Fundamentals of Immunology 4 of 26  − Dust − Cell surface proteins − Synthetic chemicals − Venom − Insect toxins Non-Self Recognition PAMPs, DAMPs, and PRRs are responsible for the specificity of the immune response Pathogen-Associated Molecular Pattern (PAMPs) → Structures that are shared by microbes essential for survival, that are not present on normal host cells → Unique to microbes (See Figure 12) ▪ Viruses: Glycoprotein, Viral DNA, Viral RNA ▪ Gram-negative bacteria: Lipopolysaccharide (LPS) or Endotoxin ▪ Fungi: Zymosan, Mannan, β-glucan, Ergosterol Figure 12. PAMPs that are Unique to Microbes Damage-Associated Molecular Patterns (DAMPs) → Intracellular components released from necrotic host cells Figure 14. Inflammation Pathway → Leaking out sends danger signals alerting about injury Pattern Recognition Receptors (PRRs) Inflammation Cascade (See Figure 14) → Receptors of innate immunity recognize DAMPs and PAMPs The offending agent is recognized by host cells and molecules and send signals to the body that there is a pathogen present → PRRs recognize PAMPs (See Figure 13) Leukocytes and plasma proteins are recruited from the circulation ▪ Membrane-bound (Extracellular) to the site where the offending agent is located − Detection of extracellular nonself pathogens → Recruitment of leukocytes (depends on pathogen) − E.g. TLR4 recognizes LPS in gram (-) bacteria ▪ E.g. Neutrophils for bacteria, Eosinophils for helminths ▪ Cytosolic Leukocytes and proteins are activated and work together to − Detection of pathogens which already crossed the destroy and eliminate the offending substance (See Figure 15) membrane, such as viruses → Microbe engulfed by phagocyte to form a phagosome ▪ Endosomal → Lysosomes fuse with phagosome to form a phagolysosome − Detection of phagocytized pathogens ▪ Lysosomal enzymes degrade the microbe, killing it (See Figure 15) − Oxygen-independent: Phospholipases breaks down cell membranes − Oxygen-dependent: Generates reactive oxygen species o ROS can insert in membranes, proteins, or DNA o Need for antioxidants (i.e. glutathione, vitamin C, etc.) Figure 13. Pattern Recognition Receptors (PRRs) D. EFFECTOR FUNCTIONS OF INNATE IMMUNE SYSTEM Inflammation Response of vascularized tissues to infections and tissue damage Figure 15. Oxygen-dependent vs. Oxygen-independent Mechanisms → Brings cells and molecules of host defense from the circulation → The reaction is controlled and terminated to the sites where they are needed ▪ Inflammation subsides when the offending agent is removed → To eliminate the offending agents from the body − Proves that the immune response is self-regulating ▪ However, danger signals (DAMPs) can be recognized that may lead to more damage HS 202 Fundamentals of Immunology 5 of 26  − The offending agent is not being attacked but rather the Antiviral Defense surrounding cells (collateral damage) Natural Killer (NK) Cells o E.g. Autoimmune disease, Hyperimmune response → The damaged tissue is repaired, mediated by cytokines (See Figure 16): − Interferon-γ (IFN-γ) o Promote classically activated macrophage (M1) = Enhances phagocytic and inflammatory activities − IL-13, IL-4 o Promote alternatively activated macrophage (M2) = Induces tissue repair = Reduces inflammatory activities Figure 18. Mechanism of Action of NK cells NK cells secrete the macrophage-activating cytokine IFN-𝛾 (Interferon-gamma) → This activation enhances the phagocytic ability of Figure 16. Classical vs. Alternatively Activated Macrophages macrophages Complement System → It also decreases protein synthesis and gene expression within Complement proteins infected cells, hindering their function and replication → Hepatically synthesized plasma proteins Recall: Viruses often hijack the cellular machinery of the infected → Function in innate immunity and inflammation cells to produce more virions. Complement cascade works in different ways on each stage of → NK cells help downregulate these viral activities, leading to a inflammation (See Figure 17) decrease in virion production → Recognition via chemotaxis Type 1 Interferon Table 3. Different complement proteins. Cytokine released by infected cells that are detected by Complement Function neighboring uninfected cells C3a, C5a Activate classical pathway → Serve as warning for the uninfected cells to increase their Anaphylatoxins that cause inflammation defenses C3b Opsonin Inhibit viral replication by inducing an antiviral state Tags foreign particles for phagocytosis → ↓ protein synthesis C9 Membrane attack complex (MAC) for → ↓ viral gene expression pathogen lysis → Viral RNA degradation Figure 17. Complement Cascade (Enlarged in Appendix) Figure 19. Antiviral Defense through Type 1 Interferon Release HS 202 Fundamentals of Immunology 6 of 26  E. EVASION OF INNATE IMMUNE SYSTEM Memory is an important characteristic of adaptive immunity Pathogens and microbes are able to adapt, evade, and fight the → First encounter with an antigen will elicit an immune response body’s defenses (See Table 4) → Second and subsequent exposures to the antigen will be Pathogens can evade through their structure readily recognized (See Figure 21) → E.g. glycoprotein, lipopolysaccharide could not be recognized ▪ Anamnestic response is a quicker and heightened immune due to capsule response will be elicited Destruction of any component of the complement cascade will → Exploited by vaccinations not form the Membrane Attack Complex ▪ Second exposure to antigens or infectious agents does not result in sickness due to memory Table 4. Mechanisms of innate immunity evasion by pathogens. Organism A. CELLULAR COMPONENTS Type of Evasion Mechanism (Example) B cell and T cell lymphocytes which come from the bone marrow Avoid detection by Proteobacteria Mutated flagellin not Humoral Immunity PRRs recognized by TLR5 → B lymphocytes: mature in the bone marrow Block PRR signaling West Nile virus Possess the NS1 protein Cell-mediated Immunity pathways & prevent that inhibits NF-kB & IRF → T lymphocytes: mature in thymus activation of transport into the nucleus responses When the B and T lymphocytes are ready, they circulate and Prevent killing, M. tuberculosis Blocks phagosome fusion home in the lymph nodes, spleen, and lymphoid tissues replication inhibition with lysosomes inhibits phagosome acidification Interference with Staphylococcus Antibody depletion by antibody- protein A complement interaction Removal of IgG by staphylokinase Binding and S. aureus Protein SCIN binds to and inactivation of inactivates C3cBbC3 complement proteins convertase Figure 20. Development and Fate of B and T lymphocytes Protease-mediated Pseudomonas & Elastase alkaline destruction of Streptococcus phosphatase from On additional information from Dr. Climacosa (2024): complement Pseudomonas degrade Leukocytes and Lymphocytes in Blood Circulation component C1q and C3/C3b In CBC, Neutrophils are the most abundant WBC since they are first to respond and they reside in the blood ScpA and ScpB from Lymphocytes are about >5% because they are in the Streptococcus degrade C5a secondary lymphoid organs Microbial mimicry of S. pyogenes M proteins bind C4BP and complement- factor H to the cell surface, regulatory accelerating the decay of components covertases bound to bacterial surface III. ADAPTIVE IMMUNITY Takes over or helps the innate immunity when it is overwhelmed Could take days to catch up compared to innate immunity Very specific → E.g. Can detect the ARGG peptide in a certain lipopolysaccharide, not just lipopolysaccharide in general Figure 21. Development of Memory Cells Table 5. Features and functional significance of adaptive immunity. Feature Functional Significance Specificity Ensures that distinct antigens elicit specific responses Diversity Enables immune system to respond to a large variety of antigens Memory Leads to enhanced responses to repeated exposures to the same antigens Clonal Increases number of antigen-specific Expansion lymphocytes from a small number of naive lymphocytes Specialization Generates responses that are optimal for defense against different types of microbes Contraction and Allow immune system to respond to newly Homeostasis encountered antigens Non-reactivity Prevents injury to the host during responses to Self to foreign antigens Figure 22. Summary of Humoral and Cell-mediated Immunity HS 202 Fundamentals of Immunology 7 of 26  Secondary Lymphoid Organs Dendritic cells Lymphocytes (See Figures 23 to 25) → Most efficient professional antigen-presenting cell → Found in lymph nodes, spleen, and mucosa-associated → Capture antigens in the periphery via phagocytosis, pinocytosis, lymphoid tissues (MALT) and receptor-mediated endocytosis (See Figure 27) → Present antigens in the lymph nodes → Abundant in the gut because portal of entries are located here Figure 23. Lymph Nodes in Various Organs Figure 26. Types of Professional Antigen-presenting Cells Figure 24. Histology of the Spleen Figure 27. Dendritic Cells’ Mechanism of Action Major Histocompatibility Complexes Class I MHC → Presents peptide fragments to CD8+ T cells → Peptide fragments come from cytosolic proteins Class II MHC → Presents peptide fragments to CD4+ T cells → Peptide fragments come from extracellular protein CD: Cluster of Differentiation → Surface proteins that help distinguish lymphocytes Figure 25. Mucosa-Associated Lymphoid Tissues B. ACTIVATION OF ADAPTIVE IMMUNITY B and T lymphocytes recognize different types of antigens B Lymphocytes → Recognize any kind of macromolecules (proteins, polysaccharides, lipids, nucleic acids) → Antibodies are then generated by B lymphocytes against these biomolecules T Lymphocytes → Can only recognize peptide fragments presented by Major Histocompatibility Complex (MHCs) → Peptide fragment are stretch of 7-11 amino acids MHCs are possessed by any nucleated cell Professional Antigen-Presenting Cells Possess a specific type of MHCs known as MHC Class II Composed of dendritic cells, macrophages, and B cells (See Figure 26) Figure 28. Class I and II MHC Pathways HS 202 Fundamentals of Immunology 8 of 26  C. EFFECTOR FUNCTIONS OF ADAPTIVE IMMUNITY Light Chain Types Composed of 2 major classes of constant regions of the antibody B-Cells light chains Produces antibodies, comprise humoral immunity → Kappa (κ) Chain Antibodies ▪ Derived from a single exon (IgK), meaning that they have the → Circulating proteins produced in vertebrates in response to same amino acid sequence exposure to foreign structures known as antigens ▪ Dominant form of human immunoglobulins → Mediators of humoral immunity against classes of microbes → Lambda (λ) Chain ▪ May come from several Cλ exons (λ1,λ 2, λ3, λ4) Antibody Structure ▪ Comprises 40% of human immunoglobulin and 95% of murine Has 2 heavy chains and 2 light chains connected via disulfide bonds, immunoglobulins (mlg) mediated by cysteine → Normal ratio κ:λ = 60:40 → Each chain has a variable region and a constant region ▪ Abnormal ratio may indicate blood cancer ▪ Variable region: different AA sequence − Can be used in diagnosis ▪ Constant region: same AA sequence − Higher ratio of λ - multiple myeloma Composed of: → Fragment antigen binding (Fab) ▪ Made from one variable region and one constant region, both from heavy and light chains → Fragment constant (Fc) Bulges are due to protein folding Figure 30. Light Chain Isotypes Antigen-Antibody Interaction Figure 29. Structure of Antibodies Epitope: specific part of antigen that the antibody binds to To ascertain that antibodies are proteins, it should be acted upon by Paratope: specific part of antibody that the antigen binds to an enzyme Interaction between antibody and antigen is very specific → Fab and Fc were determined due to the cuts by pepsin → Sometimes, there is cross-reactivity due to some similarities in structures (See Figure 31) Antibody Isotypes Based on the type of heavy chain → Alpha (ɑ), Delta (δ), Epsilon (ε), Mu (μ), Gamma (γ) Table 6. Antibody isotypes Isotype Description IgA (ɑ) Mucosal immunity → Secretion of IgA into lumen of GIT and respiratory tracts Activation of complement by the lectin pathway or by the alternative pathway IgD (δ) Relatively unknown function Found at B-cell as a membrane-bound antibody Known role as an antigen receptor, but it is not secreted IgE (ε) Defense against helminths and protozoa Mast cell degranulation (immediate hypersensitivity reactions) Figure 31. Interaction and Specificity of Antibodies IgM (μ) Characteristically a pentamer Most effective complement activator Because antibodies can exist as monomers, dimers, or pentamers, IgG (γ) Monomeric we have the concept of affinity and avidity Neonatal immunity → Affinity: strength of binding between antibody and antigen → Transfer of maternal antibody across placenta and ▪ More valuable in detection gut → Avidity: totality of binding Activation of classical pathway of the complement ▪ More valuable in therapeutics system Functions: opsonization, complement activation, antibody-dependent cell-mediated cytotoxicity, neonatal immunity, feedback inhibition of B-cells *See Appendix for Isotypes Summary HS 202 Fundamentals of Immunology 9 of 26 B-Cell Activation [2027 Trans] Figure 35. Antibody Secretion (Differentiation to Plasma Cell) Affinity Maturation (See Figure 36) → B-cells activated by the antigen are selected and undergo clonal expansion ▪ Very fast cell division → Some mutations may occur in the variable region during cell division ▪ May lead to low affinity or high affinity antibodies Figure 32. Overview of B-Cell Activation ▪ Thus, some antibodies may have weaker or stronger T Cell-Independent Pathway binding to the antigens B-cells can be activated via T-independent pathway ▪ Even at low concentrations of antigen, high affinity → Found among antigens with carbohydrate molecules antibodies can bind them effectively ▪ E.g. Bacteria has repeating structures of peptidoglycans → repetitive structure is enough for secretion of IgM antibodies → IgM is always the antibody being produced in this pathway ▪ Default gene expression: gamma chain T Cell-Dependent Pathway Figure 36. Affinity Maturation (Enlarged in Appendix) Formation of Memory B-cells → Some plasma cells differentiate into memory B-cells → Classified as long-lived cells → Activated when there is secondary exposure to the antigen Figure 33. T-Cell Dependent B-Cell Activation Neutralization If the antigen is a protein, B-cells need Helper T-cells May occur via: → Helper T-cells have effects that are more favorable than → Steric hindrance T-independent activation → Aggregation or agglutination ▪ Helper T-cells secrete cytokines → Conformational changes − Isotype switching occurs: depending on the cytokine Antibodies can neutralize the pathogen, form agglutination via Fab released, different isotypes are secreted (See Figure 34) Fc region → In T-cell dependent B-cell response, plasma cells secrete → Responsible for opsonization, complement activation, antibodies (See Figure 35) Ab-dependent cell-mediated cytotoxicity, and degranulation ▪ Plasma cells have very prominent RER and golgi apparatus Antibodies can block the following: − Responsible for protein synthesis → Entry of the pathogen, Infection of the cell, Toxins Figure 34. Isotype Switching Figure 37. Methods for Neutralization of Pathogens HS 202 Fundamentals of Immunology 10 of 26  Opsonization and Phagocytosis Opsonization marks the antigen for killing via phagocytosis (See Figure 38) Antibodies can serve as opsonins when they bind the pathogen and facilitate phagocytosis Figure 38. Opsonization and Phagocytosis Antibody-Dependent Cell-Mediated Mechanisms Figure 41. Complement Activation Monoclonal Antibodies Used in diagnostics → Pregnancy tests → COVID-19 lateral flow tests → SARS-CoV-2 rapid antigen tests Used in therapeutics → Monoclonal antibody treatments (MABs) Used in prophylaxis for certain diseases Figure 39. Antibody-Dependent, Cell-mediated Cytotoxicity → Administration of monoclonal antibodies against Rabies in patients NK cells possess the Fc receptor, but instead of triggering with dog or cat bites phagocytosis, they trigger killing through the release of enzymes → Administration of preformed antibodies against Hepatitis in infants (degranulation) with mothers who test positive for Hepatitis B → Degranulation occurs when antibody is bound to the pathogen Once they recognize the Fc regions of the bound antibodies, these cells will perform their effector functions to kill the pathogen → Neutrophils and macrophages → phagocytosis → Eosinophils → release enzymes → NK cells → release perforin and granzyme Figure 40. Summary of Effector functions of Fc Receptors Complement Activation Requires antibody to be activated The most important effector function of complement activation is membrane attack complex (MAC) C3a and C5a are inflammatory mediators, and C3b is an opsonin for phagocytosis Figure 42. Monoclonal Antibodies HS 202 Fundamentals of Immunology 11 of 26  T-Cells Naive T Cell Meet with dendritic cells (professional antigen-presenting cells) at lymphoid organs, becoming activated when they are presented with the appropriate MHC molecule. → Naive CD4+ T Cells interact with MHC Class II → Naive CD8+ T Cells interact with MHC Class I Figure 44. Further Differentiation of Helper T Cells (Enlarged in Appendix) Th1 Cell (See Figure 45) → Releases IFN-γ in response to antigens, which in turn then classically activates macrophages → Macrophages turn to hyperphagocytic killing when they recognize IFN-γ → This is more favorable against bacteria compared to Th2 Figure 43. Maturation of Naive T Cells Helpful Tip from from Dr. Climacosa (2024): The product of the two numbers in MHC_ and CD_+ is equal to 8: [MHC]1 x [CD]8[+] = 8 [MHC]2 x [CD]4[+] = 8 Helper T Lymphocytes Naive CD4+ T cell → They can differentiate into many types of Helper T Cells → Previously, only Th1 and Th2 were known, but more subsets have been discovered with their own unique effectors, functions, and roles in diseases Table 7. Types of Helper T Cells. (See Figure 44) Effector Roles in Types Effector Functions Cytokines Disease IFN-γ, TNF Combats intracellular Tissue Th1 pathogens Inflammation Activates macrophages IL-4, IL-5, Combats helminth Allergy Th2 IL-13 infection Figure 45. Action of Th1 Cells Th2 Cell (See Figure 46) Activates eosinophils → Releases IL-4 and IL-13, activating the alternative complement IL-9 Combats extracellular Autoimmunity Th9 pathway pathogens, including worms ▪ Macrophages become non-phagocytic ▪ Isotype switching: B Cells produce IgE, which may induce IL-17A, Combats extracellular Autoimmunity Th17 IL-17F, pathogens in barrier Tissue mast cell degranulation IL-22 tissues Inflammation − Makes Th2 more favorable against helminths ▪ Increases secretion and peristalsis, improving turnaround IL-22 Combats extracellular Inflammatory time to expel pathogens Th22 pathogens, specifically skin disease → Releases IL-5 skin ▪ Activates eosinophils which are anthelmintic IL-4,IL-21 Regulates affinity - TFH maturation of germinal center B cells IL-10, Suppresses immune Inhibits Peripheral TGF-B responses antitumor TREG response HS 202 Fundamentals of Immunology 12 of 26  Figure 48. Action of Th17 Cells Figure 46. Action of Th2 Cells B Cell - T Cell Cytokine Interactions (Refer to Figure 34) Individual, genetic, and external factors can alter the body’s → Release of IL-4 cytokine promotes IgE formation response to pathogens and infections. This makes knowing a → Release of TGF-β cytokine promotes IgA formation patient’s immune status essential in clinical practice → Human Immunodeficiency Virus Cytotoxic T Lymphocytes → Tuberculosis Naive CD8+ T cell → Leprosy → Functions similarly to a Natural Killer (NK) Cell in that it also kills intracellular pathogens On additional information: → Responds to MHC Class I Immune Response in Leprosy (See Figure 47) ▪ Unlike MHC Class II which is expressed only by In some people, Th2 can be more heavily activated instead of Professional Antigen-Presenting Cells, MHC Class I is Th1 during bacterial invasions. expressed in all nucleated cells due to their propensity for ▪ Th2-heavy reactions an intracellular infection − Inhibition of phagocytic activity of macrophages Mechanism of Action (See Figure 49) o Because Th2 activation inhibits Th1 → Upon recognition of an intracellular infection, the CD8+ T cell − Allows Mycobacterium leprae to proliferate releases granzymes and perforin to trigger destruction of − Leads to more extreme facial disfiguration pathogen membranes and trigger apoptosis Figure 47. Differences in Immune Response to Mycobacterium leprae Yielding Different Manifestations Th17 Cell (See Figure 48) → Relatively newer → Releases IL-17 ▪ Recruits neutrophils ▪ Leads to the release of antimicrobial peptides → Release of IL-22 ▪ Leads to increased barrier function ▪ Leads to the release of antimicrobial peptides Figure 49. Cytotoxic T-Lymphocyte Killing Mechanisms HS 202 Fundamentals of Immunology 13 of 26  Pathogen Types (See Figure 50) When the adaptive immune cells are unused, apoptosis occurs → Intracellular pathogen for remaining cells ▪ Immune cells that operate on PRR are not able to recognize However, surviving memory cells may persist and produce a infection more rapid and more powerful anamnestic response on further ▪ Broken down cytosolic proteins of infected cells are thus exposures to the same antigen presented in the form of MHC Class I C. EVASION OF ADAPTIVE IMMUNITY ▪ CD8+ T cells are then activated for the adaptive immune Usually due to errors in presentation response. → Many viruses interrupt the processing of antigen-reporting → Extracellular pathogen substances so that they are not associated with the MHC ▪ Phagocytosis of microbes can only be executed by macrophages through Helper T Cells of the MHC Class II pathway ▪ Therefore, CD8+ T cells are not activated Figure 52. Viral Mechanisms for Evading the Adaptive Immune System Figure 50. MHC Pathways for Adaptive Immunity (Enlarged in Appendix) Summary: Timeline of the Adaptive Immune Response IV. FAILURES OF THE IMMUNE SYSTEM When antigens are eliminated, the immune response should halt. However, the immune system may still fail. → Autoimmunity: hyperactivity of the immune system → Immunodeficiency: Insufficiency of immune cells, or incompetency of cellular receptors → Self-tolerance: Excessive response to a non-immunogenic antigen (e.g. pollen) Figure 51. Adaptive Immune Response Naive T and B lymphocytes mature in the thymus or bone marrow respectively Once activated by a dendritic cell, clonal expansion occurs, Figure 53. Spectrum of Immune Responsiveness yielding more lymphocytes of the same receptor They differentiate into effector lymphocytes → B cells become plasma cells for antibody production → T cells become helper or cytotoxic T cells HS 202 Fundamentals of Immunology 14 of 26  V. APPLICATIONS OF IMMUNOLOGY Naive B cells can differentiate into antibody-producing plasma cells or memory B cells after a primary immune response → More powerful responses are facilitated by memory B cells for secondary exposures to the same pathogen Figure 56. Natural Immunity vs. Artificial Immunity Natural immunity is the immunity mounted through infection → Transplacental immunity, maternal IgA, IgG transfer through breast milk Artificial immunity is the synthetic immune response → Synthetic antibodies against hepatitis, rabies B. VACCINES Preparation of immunogenic material used to induce immunity against a pathogenic organism When you give it to an individual, you induce the favorable immune response, and mount an appropriate and stronger Figure 54. Anamnestic Response of Adaptive Immunity immune response at the second exposure. On additional information: Anamnestic Response of Adaptive Immunity (Figure 54) The secondary anti-X response should be even faster than the primary anti-X and anti-Y responses Antibody production encompasses the first two weeks following exposure to a pathogen. This is why it is important to explain to patients that they are not yet fully immune immediately after vaccination. A. IMMUNIZATION VS. VACCINATION Immunization Process of inducing immunity naturally or artificially (vaccination or administration of antibody) An outcome; the goal is immunity Vaccination Intentional administration of a nonpathogenic form of a pathogen To induce a specific adaptive immune response that protects the individual against later exposure to a related pathogen Vaccination may not lead to an outcome of immunization all the time (failure of immunity) Individuals have different abilities to make memory cells Figure 57. Common Commercially Available Vaccines Common Examples of Vaccines and Their Type Live Attenuated vaccines → MMR, BCG, Polio (OPV or Sabin) Deactivated/Killed vaccines → Sinovac (deactivated using Propionic acid; the acid damages the envelope and renders the virus incapable of replication) → Rabies → Influenza → Polio (IPV or Salk) Figure 55. Active Immunity vs. Passive Immunity Active immunity is the body’s ability to produce the immune response (e.g. natural infection, vaccines) Passive immunity is where you receive the effector functions (e.g. receive antibodies which are effector functions of B-cells, T-cells as effector functions) HS 202 Fundamentals of Immunology 15 of 26 Table 8. Vaccine types by generation. Mimic an actual infection Requires special storage Types Description facilities Mimic the whole pathogen Activates both humoral and Can replicate and be First Generation Weaken or kill the pathogen cellular immune response transmitted Able to pinpoint which part of the Long lasting immunity Can revert to virulent strain Second pathogen is most associated with a Fewer doses and boosters Associated (rare) with similar Generation protective response complications Can be parts of the pathogen; Contraindicated for E.g. Hepatitis B vaccine that targets the immunocompromised hepatitis B surface antigen (HBSAg) and individuals HPV envelope targeted by the vaccine Make use of nucleic acids Killed / Inactivated Vaccines[2027 Trans] Third Whole organism Body will produce the desired pathogenic Generation Cultured organisms killed by heat, UV, phenol, formalin, or protein to elicit the desired immune response propionic acid) Includes viral vectors (attenuated viral → Can be inactivated through chemical or physical means vector with genetic material that is needed Table 10. Advantages and disadvantages of killed / inactivated vaccines. to make immunogens) Examples of Killed / Inactivated Vaccines Cholera On additional information: Influenza Live Attenuated Vaccines [2027 Trans] Hepatitis A Microorganisms are attenuated (disabled) so that they lose Plague their ability to cause significant pathogenicity (disease) but Inactivated polio vaccine (Salk vaccine) retain their capacity for slow and transient growth within an Rabies inoculated host Zika Attenuation produces a modified organism that mimics the Advanta natural behavior of the original microbe without causing Advantages Disadvantages significant disease Stable Weaker immune response than Reduces virulence of the pathogen through the following live vaccines (predominant mechanisms: humoral/antibody response) → Identification of heterologous strains avirulent to humans Safer than live vaccines Repeated booster shots → Growth in modified/abnormal culture conditions for usually required prolonged periods Ease of storage and transport → Repeated subculturing → Manipulating microbial genes Table 11. Mechanisms of innate immunity evasion by pathogens. Characteristic Attenuated Vaccine Inactivated Vaccine Production Selection for avirulent Virulent pathogen is organisms; virulent inactivated by pathogen is grown under chemicals or adverse culture irradiation with conditions or prolonged gamma rays passage of a virulent human pathogen through different hosts Booster Generally requires Requires multiple requirement only a single booster boosters– some – despite the antigens antigens might have being weakened, the been destroyed by antigens are still intact the physical or chemical treatment Relative Less stable More stable stability (has to be potent (advantageous for when injected) developing countries where refrigeration Figure 58. Commercially Available Vaccines (Enlarged in Appendix) is limited) Type of Produces humoral Produces mainly immunity and cell-mediated humoral immunity Table 9. Advantages and disadvantages of live-attenuated vaccines. immunity induced Examples of Live Attenuated Vaccines Measles Reversion May revert to virulent Cannot revert to tendency form– reason why virulent form Mumps these vaccines are not Oral Polio vaccine (Sabin vaccine) given to Rotavirus immunocompromised Rubella Tuberculosis (bacillus Calmette Guérin – attenuated strain Mycobacterium bovis) On additional information: Varicella Subunit Vaccines [2027 Trans] Yellow fever Antigens are isolated from infectious agents Advantages Disadvantages HS 202 Fundamentals of Immunology 16 of 26  Contain some part or product of microorganisms that can → COVID-19 vaccine using adenovirus induce an immune response Attenuated vectors known not to cause disease anymore Purification or fractionation of the components of the pathogen → Vaccinia virus to isolate the fragment responsible for the induction of immune → Canarypox virus response → Attenuated poliovirus → Not the whole organism, just a subunit or part of it → Adenovirus → The component derived is the best antigen to elicit a proper → Attenuated strains of Salmonella immune response → BCG strain of M. bovis Subunit: Toxoid → Certain strains of Streptococci → Detoxified/inactivated pathogen exotoxin Nucleic Acid-based Vaccine → Induces formation of protective antibodies, which neutralize Potential to be safe, effective, and cost-effective the toxin by stereochemically blocking the active site, and Induce immune response to target the selected antigen in encourage removal by phagocytic cells pathogen → Soluble exotoxins of bacteria modified and rendered less DNA Vaccine toxic by adding formalin or by gentle heating → Direct introduction of a plasmid containing the DNA ▪ Adding chemical or physical treatment sequence encoding the antigen/s against which an immune → E.g. Diphtheria, Tetanus response is sought into appropriate tissues Subunit: Recombinant Protein Antigen → For it to be a good vaccine candidate, it has to traverse the → Specific antigens lower the chance of adverse reactions cell membrane and nuclear membrane Table 12. Advantages and disadvantages of DNA vaccines. Advantages Disadvantages Simple construction Relatively low immunogenicity profiles Non-living, non-replicating, and Ensuring delivery non-transmitting Induce local expression of Risk for autoimmune disease target antigens and (anti-DNA antibody) subsequently trigger antigen-specific T and B cell responses Good safety profile Potential risk of integration into host genome Easy storage On additional information: RNA Vaccine [2027 Trans] Has to get into the cytosol and will already be recognized by Figure 59. Production of Recombinant HB Vaccine the ribosomes Insert the gene encoding the HB surface antigen and produce Table 13. Advantages and disadvantages of RNA vaccines. it in a recombinant cell Advantages Disadvantages Extract and purify the surface antigen Only encode the gene of Relatively low inherent → This is already the vaccine interest immunogenicity E.g. → Hepatitis B Can easily and inexpensively Challenges in delivery → Pertussis mass-produced RNAse-mediated → Streptococcal pneumonia No risks of genome integration degradation → Secreted toxins high molecular weight No need to design expression → Diphtheria electrostatic repulsion vectors → Tetanus resulting from the Potential safety benefit Conjugated Vaccines Avoiding nuclear membrane interaction between the Primes infant immune systems to recognize certain bacteria barriers negatively-charged mRNA T cell independent antigens can activate B cells even in the molecules and the absence of T cells (See Figure 32) negative charge of the → IgM proteoglycan-coated cell → Short-lived plasma cells membrane → Do not have memory cells E.g. → Haemophilus influenzae type → Streptococcal pneumonia Vector-based Vaccines Uses attenuated viral or bacterial vectors to introduce genes that encode key antigens of target pathogen Maintain advantages of live attenuated vaccine approach while avoiding risk for reversion E.g. → Ebola vaccine using vesicular stomatitis virus HS 202 Fundamentals of Immunology 17 of 26  Figure 60. Vaccine-delivered Immune Response Vaccines can now be directed towards tumors Tumor antigens → These antigens are more expressed in tumors, and so they are effective targets for vaccine production → Different from HPV and Hepatitis vaccines because they are oncolytic viruses Figure 61. DOH Sample Immunization Record for a 1 year old baby VI. IMMUNIZATION FOR PUBLIC HEALTH Primary health care (PHC) is essential health care based on VII. REFERENCES practical, scientifically sound and socially acceptable methods Abbas, A. K., Lichtman, A. H., Pillai, S., & Baker, D. L. (2022). Cellular and and technology made universally accessible to individuals. molecular immunology (10th ed.). Elsevier. PHC Includes at least: Climacosa, F. M. M. (2024). Powerpoint Presentation. Punt, Jenni, Stranford, Sharon A, Jones, Patricia P, Owen, Judith A. (2019). Kuby → Education concerning prevailing health problems and the Immunology (8th). New York: Macmillan Learning. methods of preventing and controlling them UPCM 2026 Trans. (2022). Fundamentals of Immunology. → Promotion of food supply and proper nutrition UPCM 2027 Trans. (September 21, 2023). Fundamentals of Immunology. → Adequate supply of safe water and basic sanitation → Maternal and child health care, including family planning; → Immunization against the major infectious diseases → Prevention and control of locally endemic diseases; → Appropriate treatment of common diseases and injuries → Provision of essential drugs. Overall goal: To reduce the morbidity and mortality among children against the most common vaccine-preventable diseases → Vaccine hesitancy is a challenge in achieving this goal ▪ It is the delay or total refusal of vaccine acquisition Covered vaccination against: → Tuberculosis → Poliomyelitis → Diphtheria → Tetanus → Pertussis → Measles On additional information: Fully Immunized Child at 12 Months [2027 Trans] 1 dose BCG Vaccine at birth 1 dose Hepatitis B Vaccine at birth 3 doses Pentavalent Vaccine (DPT-Hib-Hepa B) 3 doses of OPV or 1 dose of IPV 1 dose of Measles or MMR vaccine HS 202 Fundamentals of Immunology 18 of 26  APPENDIX Figure 1. Coordinated and Regulated Immune Response HS 202 Fundamentals of Immunology 19 of 26  Figure 9. Hematopoiesis and Maturation of Cellular Components of the Innate Immune System HS 202 Fundamentals of Immunology 20 of 26  Figure 17. Complement Cascade Figure 36. Affinity Maturation HS 202 Fundamentals of Immunology 21 of 26  Figure 44. Further Differentiation of Helper T Cells HS 202 Fundamentals of Immunology 22 of 26  Figure 52. Viral Mechanisms for Evading the Adaptive Immune System HS 202 Fundamentals of Immunology 23 of 26  Figure 58. Commercially available vaccines HS 202 Fundamentals of Immunology 24 of 26 Table 2. Human antimicrobial proteins and peptides Proteins Location Antimicrobial Activities Lysozyme Mucosal glandular secretions Cleaves glycosidic bonds of peptidoglycans in (tears, saliva, respiratory tract) cell walls of bacteria, leading to lysis Lactoferrin Mucosal/glandular secretions Binds and sequesters iron, limiting growth of (milk, intestinal mucus, nasal / respiratory and bacteria and fungi; disrupts microbial urogenital tracts) membranes; limits infectivity of some viruses Secretory leukocyte protease inhibitor Skin, mucosal / glandular secretions Blocks epithelial infection by bacteria, fungi, (intestines, respiratory and urogenital tracts, viruses; antimicrobial milk) S100 Skin, mucosal / glandular secretions (tears, (c) Disrupts membranes, killing cells a. Psoriasin saliva / tongue, intestine, nasal/respiratory (d) Binds and sequesters divalent cations and urogenital tracts) (manganese and zinc), limiting growth of b. Calprotectin bacteria and fungi Surfactant proteins Secretions of respiratory tract, other mucosal Block bacterial surface components; promote epithelia phagocytosis RegIII proteins Intestinal epithelia Bind cell wall carbohydrates and prevent bacterial binding to epithelial cells; produce membrane pores that kill cells Peptides Location Antimicrobial Activities Disrupt membranes of bacteria, fungi, Skin, mucosal epithelia (mouth, intestine, Defensins protozoan parasites, and viruses; additional nasal / respiratory tract, urogenital tract), (ɑ and β) toxic effects intracellularly; kill cells and blood disable viruses Mucosal epithelia (respiratory tract, urogenital Disrupts membranes of bacteria; additional Cathelicidin (LL-37) tract) toxic effects intracellularly; kills cells Lectins that bind to fungal cell walls and enter Histatins Saliva the cytoplasm, where they have several harmful effects Antibacterial and antifungal; produces Dermcidin Skin (from sweat glands) channels in membranes that disrupt ion gradients HS 202 Fundamentals of Immunology 25 of 26 Table 6. Summary of antibody Isotypes. Plasma Isotype of Subtypes (H Half Life Secreted Concentration Structure Functions Antibody Chain) (days) Form (mg/mL) Mainly dimer; IgA1,2 (ɑ1 IgA 3.5 6 also Mucosal immunity or ɑ2) monomer, trimer B cell antigen IgD None Trace 3 Monomer receptor Defense against helminthic parasites, IgE None (ε) 0.05 2 Monomer immediate hypersensitivity Opsonization, complement activation, IgG1-4 (ɣ1, antibody-dependent IgG ɣ2, ɣ3, or 13.5 23 Monomer cell-mediated ɣ4) cytotoxicity, neonatal immunity, feedback inhibition of B-cells Naive B cell antigen receptor (monomeric IgM None (μ) 1.5 5 Pentamer form), complement activation HS 202 Fundamentals of Immunology 26 of 26