Immunology Lecture Notes PDF

DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY RENZ BLANCO, MD Everyday our body encounters several pathogens, but only a O...

DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY RENZ BLANCO, MD Everyday our body encounters several pathogens, but only a OUTLINE few results to diseases TOPIC PAGE o Our body releases antibodies against these pathogens I. Historical Background 1 and protects us against diseases II. Immunity 1 Involves exposure to pathogens → our body will initiate an A. Immune Defense System 1 immune mechanism → release of cellular or humoral III. Cellular Natural/Innate 2 components that will trigger several mechanisms to produce A. Dendritic Cells 2 protection. B. Macrophages 2 C. Natural Killer Cells 2 D. Cellular Receptors for microbes 3 IMMUNE DEFENSE SYSTEM IV. Humoral Natural/Innate 4 V. Cellular Adaptive (Cellular Component) 4 A. Lymphocytes 4 Table 2. Immune defense system B. T-Lymphocytes 4 External Internal C. Major Histocompatibility Complex 6 D. B-Cells 6 Inflammation VI. Cellular Adaptive (Humoral Component) 7 Vascular response A. Antigen 7 Barriers (skin) (HYPEREMIA) B. Antibodies 7 Cellular response VII. Immunity cont. 9 (WBCs/Macrophages) VIII. Complement Pathway 9 A. Classic Pathway 9 Secretions (lactic acid from B. Alternative Pathway 9 sweat) C. Mannose-Binding Lectin (MBL) Pathway 10 pH (Acidity/Alkalinity of D. Regulators Of Complement Pathway 10 stomach, vagina, GIT) E. Deficiency Of Complement Activity 10 IX. Hypersensitivity 10 X. Immunodeficiencies 11 Table 3. Lymphoid Organs A. Phagocytic Cell Deficiencies 11 Primary Lymphoid Organ Secondary Lymphoid Organ B. B-Lymphocyte Deficiencies 11 Bone Marrow Spleen C. T-Lymphocyte Deficiencies 12 D. Combined B/T-Lymphocyte Thymus Lymph Nodes Deficiencies 12 Tonsils XI. Post Lecture and Laboratory Quiz 12 XII. References 12 Appendix XIII. Appendix 12 Peyer’s patches (small intestine) Mucosal-associated lymphoid tissues Must Know Good To Know Book (MALT) Primary lymphoid organs o This is the origin of the cellular component of immune cells HISTORICAL BACKGROUND Secondary lymphoid organs o Area of deposition of lymphocytes Table 1. Historic figures on immunology o Storage Author Contributions Edward Jenner Smallpox Table 4. Types of Immunity Louis Pasteur First attenuated vaccine Natural/Innate Adaptive/Acquired/Specific Elle Metchnikoff Cellular theory of immunity through Normally present from birth Activated after an exposure phagocytosis Non-adaptive, non-specific Specific (remember a prior exposure) Von Behring Humoral theory No prior exposure needed Increase response upon repeated Koch Delayed type Hypersensitivity; studies exposure of anthrax and pulmonary tuberculosis Jules Bordet Complement Natural/Innate immunity is the first response which is usually Portier Immediate Hypersensitivity / faster that adaptive Anaphylaxis Antibody produced on 1st exposure = IgM Silk and Sabin Polio vaccine Antibody produced on 2nd exposure = IgG Rosalyn Yallow Radioimmunoassay Epithelial Barriers Susumu Tonegawa Antibody diversity o Epithelia of the skin, GI and respiratory tracts provide mechanical barriers Louis Pasteur is considered the Father of Immunology o Epithelial cells also produce antimicrobial molecules such o He initiated the studies toward infections caused by as defensins microbes o Lymphocytes located in the epithelia combat microbes at o His studies proved that microorganisms are the ones these sites causing the diseases and not supernatural causes. o His also initiated studies that shows when microbes are Table 5. Acquired/Adaptive/Specific Immunity weakened, they can be used in vaccines to stimulate the Type Acquisition Antibody Duration of immune system Produced immune by host response IMMUNITY Active Normal Infection YES LONG Artificial Vaccination, YES LONG The ability of the body to defend itself against disease-causing toxins, organisms toxoids WEEK 2 | 26 SEP 2024 | 1ST SEM A.Y. 2024-2025 CLUSTER 5 : LANDINGIN, MABILIN, MARQUINA, MENDOZA, MORALES, MOYA Page 1 of 13 DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY Passive Normal Transfer in NO SHORT o Immature dendritic cells within the epidermis are called vivo or Langerhans cells. colostrum Express many receptors for capturing and responding to Artificial Anti-sera or NO SHORT microbes (and other antigens), including TLRs and lectins. immune Recruited to the T-cell zones of lymphoid organs, where they sera are ideally located to present antigens to T cells (adaptive immunity) Blood typing of neonate does not use serum Express high levels of MHC and other molecules. What type of antibody in blood does an adult have? = IgM FOLLICULAR DENDRITIC CELL Table 6. Components of Natural and Acquired Immunity Present in the germinal centers of lymphoid follicles in the Cellular Humoral spleen and lymph nodes Natural Neutrophils TNF Can trap antigen bound to antibodies or complement proteins Eosinophils Interleukins Basophils Complement Monocytes Lysozymes MACROPHAGES Dendritic cells Properdin NK cells Macrophages that have phagocytosed microbes and protein antigens process the antigens and present peptide Acquired T-lymphocytes B-lymphocytes or plasma fragments to T cells B-lymphocytes cells (Immunoglobulins) Macrophages are key effector cells in certain forms of cell-mediated immunity Innate immunity functions in stages (occurs in inflammation): o T cells activate macrophages and enhance their ability to o recognition of microbes and damaged cells kill ingested microbes o activation of various mechanisms Macrophages efficiently phagocytose and destroy microbes o elimination of the unwanted substances that are opsonized (coated) by IgG or C3b Table 7. Natural immunity and its cellular components NATURAL KILLER CELLS Cell Cellular Neutrophils - Aka. PMN (Polymorphonuclear) cells - Responds to BACTERIAL infections - Phagocytosis - Killing through MPO (myeloperoxidase), lysozymes, lactoferrin Eosinophils - Responds to PARASITIC Infections and ALLERGIES - Killing through MBP (Major Basic Protein) - Lessens Hypersensitivity by releasing amine oxidase, neutralizes histamine (released by mast cells) Basophils - Responds to ALLERGIC Reactions - Releases HISTAMINE - MAST CELLS - Tissue Basophils Monocyte - Becomes MACROPHAGES (tissue) - microbial killing, tumoricidal, parasite eradication, phagocytosis, secretion of mediators and antigen presentation - Alveolar Macrophages: Lungs - Kupffer cells: Liver - Microglial cells: Brain - Histiocytes: Connective tissue Dendritic - Has long membranous extensions cells - Phagocytosis, antigen presentation All are capable in phagocytosis Phagocytosis o First functions of WBCs to control an infection o Phagocytes engulfs pathogen → forms phagosome → phagosome fuses with lysosome Figure 1. NK cell activation requiring differential engagement of cell-surface receptors in combination with stimulation by proinflammatory cytokines2 CELLULAR NATURAL/INNATE destroy irreversibly stressed and abnormal cells (e.g. virus DENDRITIC CELLS infected cells and tumor cells) 5% to 10% of peripheral blood lymphocytes Sometimes called interdigitating dendritic cells. do not express TCRs or Ig The most important antigen-presenting cells for initiating T-cell ability to kill a variety of virus-infected cells and tumor cells, responses against antigens. without prior exposure to or activation by these microbes or Located under epithelia and in the interstitia of all tissues. tumors also secrete cytokines WEEK 2 | 26 SEP 2024 | 1ST SEM A.Y. 2024-2025 CLUSTER 5 : LANDINGIN, MABILIN, MARQUINA, MENDOZA, MORALES, MOYA Page 2 of 13 DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY o e.g. interferon-γ (IFN-γ) : macrophage activation o products of necrotic cells (e.g., uric acid and released Two cell surface molecules CD16 and CD56: ATP) o CD16: NK cells ability to lyse IgG-coated target cells o ion disturbances (e.g., loss of K+) (antibody-mediated cell-mediated cytotoxicity) o some microbial products Issues on the NK cell function may cause autoimmune Several of the NLRs signal via a cytosolic multiprotein complex diseases called inflammasome CELLULAR RECEPTORS FOR MICROBES, PRODUCTS OF DAMAGED CELLS AND FOREIGN SUBSTANCES Figure 2. Cellular receptors2 Figure 3. Inflammasome2 Cells that participate in innate immunity a protein complex that recognizes products of dead cells and o capable of recognizing certain microbial components that some microbes are shared among related microbes induces the secretion of biologically active interleukin 1 o often essential for infectivity through o activates an enzyme (caspase-1) that cleaves a precursor pathogen-associated molecular patterns (PAMPs) form of the cytokine interleukin-1 (IL-1) to generate the Damage-associated molecular patterns (DAMPs) biologically active form o molecules released by injured and necrotic cells that are Gain-of-function mutations in one of the NLRs result in periodic recognized by leukocytes fever syndromes called autoinflammatory syndromes Pattern recognition receptors o cellular receptors that recognize PAMPs and DAMPs C-TYPE LECTIN RECEPTORS ▪ plasma membrane receptors: extracellular microbes expressed on the plasma membrane of macrophages and ▪ endosomal receptors: ingested molecules dendritic cells ▪ cytosolic receptors: microbes in the cytoplasm detect fungal glycans and elicit inflammatory reactions to fungi TOLL-LIKE RECEPTORS RIG-LIKE RECEPTORS present in the plasma membrane and endosomal vesicles located in the cytosol of most cell types signal by a common pathway that culminates in the activation detect nucleic acids of viruses that replicate in the cytoplasm of two sets of transcription factors of infected cells o NF-kB: stimulates the synthesis and secretion of cytokines these receptors stimulate the production of antiviral cytokines and the expression of adhesion molecules o Interferon regulatory factors (IRFs): stimulate the G PROTEIN-COUPLED RECEPTORS production of the antiviral cytokine, type I interferons present on granulocytes like neutrophils, macrophages and Germline loss-of-function mutations affecting TLRs and their most other types of leukocytes signaling pathways are associated with rare but serious recognize short bacterial peptides containing immunodeficiency syndromes. N-formylmethionyl residues this receptor enables neutrophils to detect bacterial proteins NOD-LIKE RECEPTORS and stimulate chemotactic responses of the cells Cytosolic receptors o recruitment of white blood cells in the site of infection Recognize a wide variety of substances through WEEK 2 | 26 SEP 2024 | 1ST SEM A.Y. 2024-2025 CLUSTER 5 : LANDINGIN, MABILIN, MARQUINA, MENDOZA, MORALES, MOYA Page 3 of 13 DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY MANNOSE RECEPTORS IL4 key regulator in humoral immunity recognize microbial sugars transformation of Naive Helper T cell to o often contain terminal mannose residues unlike become TH2 cells mammalian glycoproteins IL6 induces acute phase response along with induce phagocytosis of the microbes IL1 and TNF Acute Phase Reactants: checked through laboratory tests if HUMORAL NATURAL/INNATE there is a severe inflammation o CRP (favorite test of clinicians) Table 8. Cells of Humoral Natural/Innate Immunity o MBP o serum amyloid A Cells Functions o alpha-1-antitrypsin Complement group of non-specific serum components that o fibrinogen enhance the effect of antibodies o haptoglobin present in the blood even without infection by o ceruloplasmin being in its inactive form; activated via o C3-complements Complement Cascade Lysozyme enzyme with antibacterial activity found in tears, saliva and other cells CELLULAR ADAPTIVE (CELLULAR COMPONENT) Properdin serum protein with bactericidal and viricidal Immune surveillance effects o Lymphocytes and other cells involved in immune Betalysin heat-stable cationic substance with responses constantly circulate among lymphoid and other bactericidal activity tissues via the blood and the lymphatic circulation Interferon glycoproteins that exert non-specific antiviral Antigen Receptor Diversity activities (interference with viral replication) o Generated by somatic recombination of the genes that Tumor protein secreted by many different cells; encode the receptor proteins Necrosis principal mediator in response to o During lymphocyte maturation (in the thymus for T cells Factor gram-negative bacteria and the bone marrow for B cells), these gene segments Interleukin group of mediators secreted by different type recombine in random sets forming many different genes of cells cause to inflammatory effects that can be transcribed and translated into functional Acute Phase plasma proteins that increase during the antigen receptors Reactants acute phase response of inflammation INTERFERON T-LYMPHOCYTES Table 9. Types of Interferons Interferon Released Functions by: IFN-α Leukocytes (alpha) antiviral IFN-β Fibroblasts, ↑ in MHC Class I expression (beta) Epithelial cells IFN-γ T cells, major macrophage activator (gamma) NK cells induces MHC Class II antagonist to IL-4 TUMOR NECROSIS FACTOR (TNF) Table 10. Types of TNF TNF Released by: Functions TNF-α Macrophage, local inflammation (alpha) Nk cells endothelial activation Figure 4. Cellular lineages from pluripotent stem cell to mature TNF-β T cells, killing blood cell1 (beta) B cells endothelial activation Develop in the thymus from precursors that arise from INTERLEUKIN hematopoietic stem cells Mature T cells are found in the: o Blood (60% to 70% of lymphocytes) Table 11. Cells of Humoral Natural/Innate Immunity o T-cell zones of peripheral lymphoid organs Cells Functions T-lymphocytes IL1 induces fever o production: bone marrow IL2 NK-lAK, a.k.a T-cell Growth Factor o maturation: thymus IL3 induces hematopoiesis, a.k.a. See Appendix 1. Principal classes of lymphocytes and their Multicolony-Stimulating Factor function WEEK 2 | 26 SEP 2024 | 1ST SEM A.Y. 2024-2025 CLUSTER 5 : LANDINGIN, MABILIN, MARQUINA, MENDOZA, MORALES, MOYA Page 4 of 13 DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY proliferate and migrate to peripheral site to eliminate infection TCR COMPLEX Figure 5. Overview of T-cell development1 Figure 7. T-cell Receptor (TCR) Complex2 Alpha and beta chains recognizes antigen (in the form of peptide-MHC complexes expressed on antigen-presenting cells, or APCs) o must be a complex since peptide alone is not sufficient to trigger TCR The linked CD3 complex and ζ chains initiate activating signals CD4 and CD28 are also involved in T-cell activation T-cells express other proteins that assist the TCR complex: o CD4 o CD8 o CD28 o Integrins 60% of mature T-cells are CD4+ and about 30% are CD8+ CD4+ T-cells o Function as cytokine-secreting helper cells that assist macrophages and B-lymphocytes to combat infection Figure 6. Positive and negative selection of T cells. The processes o a.k.a. T-helper cells of thymic selection result in mature T cells that are both self-HLA CD8+ T-cells restricted and tolerant of the body’s own peptide antigens.1 o Function as cytotoxic (killer) T-lymphocytes (CTLs) to destroy host cells harboring microbes Each T-cell recognizes a specific cell-bound antigen by means of an antigen-specific TCR o a.k.a cytotoxic cells Specificity limited for peptides displayed by cell surface MHC CD4 and CD8 serve as coreceptors in T-cell activation molecules During antigen recognition: o Antigen must be bound with an MHC molecule for o CD4+ molecules bind to class II MHC molecules recognition o CD8+ molecules bind to class I MHC molecules Long life span (vs. B-cells which are short-lived) Thymus-dependent (differentiation occurs in the thymus) T-lymphocytes are either CD4+ or CD8+ Table 12. Subpopulations of T-lymphocytes Figure 6. explanation: CD4+ CD8+ o T-cell progenitor develops in the bone marrow → migrate to thymus for maturation ⅔ of all T-lymphocytes ⅓ all of all T-lymphocytes o Matured T-cells: TH (T helper) Aid in B-cell TC Secrete ▪ that recognize MHC receives signals for survival; differentiation; (T cytotoxic) lymphotoxins ▪ that that interact with self-antigen are removed (cells stimulates and perforins must not trigger self-antigens which leads to other T-cell autoimmune diseases) population ▪ that encounter foreign antigens in the secondary process peripheral lymphoid organs are activated —> antigens to be presented to B WEEK 2 | 26 SEP 2024 | 1ST SEM A.Y. 2024-2025 CLUSTER 5 : LANDINGIN, MABILIN, MARQUINA, MENDOZA, MORALES, MOYA Page 5 of 13 DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY TReg Suppress TS Inhibit the Paternity Testing (T regulatory) immune (T suppressor) actions of other Forensic Medicine, Anthropology response to T-cells - turns o A1 and B8 → rarely detected in people in Central and self-antigens; off Eastern Asia also CD25 B-lymphocytes - o Bw57 → uncommon in whites and African Americans positive decreased in Disease Association TDTH secrete autoimmune o HLA-B27 → Ankylosing spondylitis (Delayed Type macrophage diseases o HLA-DR2 → Goodpasture’s Syndrome Hypersensitivity chemotaxin o HLA-DR3 → SLE, Type 1 DM T-cells) o HLA-DR4 → Rheumatoid Arthritis o Cw6 → Psoriasis vulgaris o HLA-B47 → Congenital Adrenal Hyperplasia MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) o They are autoimmune diseases B-CELLS Lymphocytes Short life span Thymus-independent (differentiation occurs in the BM) B-cells are indistinguishable from T-cells on blood, marrow and tissues except by special techniques Figure 8. Human Leukocyte Antigen Complex2 Function is to display peptide fragments of protein antigens for recognition by antigen-specific T-cells In humans, the MHC molecules are called human leukocyte antigens (HLA) Figure 9. B-cell and T-cell2 CLASS I MHC Display peptides that are derived from proteins CD3: T-cell: periphery/parafollicular areas (T for Three) o e.g. viral and tumor antigens, that are located in the CD20: B-cell: germinal center (B for Bente) cytoplasm and usually produced in the cell CD8+ T-cells recognize peptides only if presented as a Table 13. B-Cell Activation2 complex with Class I MHC molecules B Stem Cells Has TdT (terminal deoxynucleotidyl All nucleated cells express Class I HLA molecules transferase) Both T and B cells CLASS II MHC Pre-B Cells Appearance of heavy chains in the Present antigens that are internalized into vesicles cell’s cytoplasm o Typically derived from extracellular microbes and soluble Immature B Cells Light chains in the cell’s cytoplasm proteins IgM Class II-peptide complex is recognized by CD4+ T-cells Mature B Cells Light chains in the cell’s cytoplasm Class II MHC molecules are mainly expressed on cells that IgM and IgD present ingested antigens and respond to T-cell help Activated B Cells Exhibit identifying markers such as (macrophages, B-lymphocytes, and dendritic cells) (Plasma Cells, CD25 Encoded in a region called HLA-D, which has three Memory Cells) Abundant cytoplasmic immunoglobulin subregions: Antigen-stimulated B cells that are o HLA-D capable of responding with increased o HLA-DQ speed and intensity o HLA-DR USES OF MHC Table 14. Difference Between T-cells and B-cells2 Organ Transplantation T cells B cells o must be MHC compatible Develop in the THYMUS Develop in the BONE o Most important HLA → HLA-A and HLA-B MARROW o Autograft, Synergic graft, Allograft, Xenograft Identified by ROSETTE Identified by surface o Bone Marrow → most immunogenic organ FORMATION with SRBCs immunoglobulin o Cornea → least immunogenic organ End product: Cytokines End product: Antibodies WEEK 2 | 26 SEP 2024 | 1ST SEM A.Y. 2024-2025 CLUSTER 5 : LANDINGIN, MABILIN, MARQUINA, MENDOZA, MORALES, MOYA Page 6 of 13 DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY Surface Ag: CD2, CD3, C4 and Surface Ag: CD19, CD20, Table 16. Types of Antibodies2 CD8 CD21 and CD40 Heteroantibodies Antibodies produced in response to the (XENO) antigens of another species B lymphocytes use membrane-bound antibody molecules to Alloantibodies Antibodies produced in response to the recognize antigens of many different chemical types: proteins, antigens of same species polysaccharides, and lipids e.g. maternal antibodies Upon activation, B lymphocytes proliferate and then differentiate into plasma cells → secrete different classes of Autoantibodies Antibodies produced in response to the antibodies with distinct functions antigens of body’s own antigens associated with autoimmune disease CELLULAR ADAPTIVE (HUMORAL COMPONENT) Protects against extracellular microbes and their toxins Mediated by B (bone marrow–derived) lymphocytes and their secreted products, antibodies (also called immunoglobulins, Ig) ANTIGEN Substances recognized as foreign by the body and have the capability to react with a complementary antibody Table 15. Homologous vs Heterologous HOMOLOGOUS HETEROLOGOUS Induces an antibody Reacts with an antibody it did production and reacts not induce (cross-reaction) specifically with it IMMUNOGEN - able to elicit Ab-mediated immune response HAPTENS - low molecular weight, non-antigenic substances Figure 10. Schematic design of an Immunoglobulin (IgG)2 but when combined with an antigen, it changes the antigenic specificity ADJUVANT - a compound that enhances an immune Table 17. Types of Antibodies2 response. Not immunogenic if given alone EPITOPE - an antigenic determinant of the antigen that binds 2 heavy chains mu to an antibody or T-cell receptor gamma alpha IMMUNOGEN delta epsilon able to elicit Ab-mediated immune response 2 light chains kappa o Foreignness lambda o Size (>10,000 daltons) Variable regions amino o Structural stability o Chemical composition - proteins and carbohydrates Constant regions carboxyl o Complexity - more complex Hinge region between CH1 and CH2 o Degradability - needs to be degrades o Dosage The variable region is the exposed portion where the epitope, 2 a part of the antigen, attaches HAPTENS The constant region is attached to cells o For example in APCs, the B-cell has an antibody on its Low molecular weight, non-antigenic substances but when external surface combined with an antigen, it changes the antigenic specificity Table 18. Fab vs Fc2 ADJUVANT Fab (Fragment antigen Fc (Fragment crystallizable) A compound that enhances an immune response binding) Not immunogenic if given alone Have the antigen binding No antigen binding ability site Spontaneously EPITOPE Each Fab consist of crystallizes at 4°C An antigenic determinant of the antigen that binds to an o One L chain antibody or T-cell receptor Important for o One H chain opsonization and complement fixation ANTIBODIES Fc is the constant fragment which is either buried within the Glycoprotein substances developed by plasma cells in cell or is exposed in the cell itself response to the presence of antigens Fc can trigger processes like the complement cascade WEEK 2 | 26 SEP 2024 | 1ST SEM A.Y. 2024-2025 CLUSTER 5 : LANDINGIN, MABILIN, MARQUINA, MENDOZA, MORALES, MOYA Page 7 of 13 DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY Table 19. Enzyme Digestion complement reaction, PAPAIN PEPSIN agglutination (reason why it is used during blood typing) cleaves 3 fragments cleaves 2 fragments (upper hinge region) (lower hinge region) IgE Protect against parasitic Monomer o 2 (two) Fab o 1 (one) Fab worms. Responsible for allergic reactions. (Actions o 1 (one) Fc o 1 (one) Fc elicited is somehow similar to Eosinophil) IgD Part of the B cell receptor. Monomer Activates basophil and mast cells IgE: Allergies and parasitism o Associated with eosinophils which have IgE on their J (JOINING) CHAIN surface IgM: Primary immune response IgG: Secondary immune response IgD: Function as receptor on B-cells cell surface IgA: Secretions ANTIBODY MUST KNOWS IgG opsonized microbes and targets them for phagocytosis. Additionally, there are four different kinds of IgG antibodies, and here are their characteristics: o IgG1: represents 65% of total IgG (majority of IgG) o IgG2: directed against polysaccharide antigens; role Figure 11. Immunoglobulin Chains against encapsulated bacteria o IgG3: effective activator of complement Yellow - Joining chain o IgG4: does not activate complement due to its compact Present at IgA and IgM since they are dimer and pentamer, structure respectively. o Opsonin makes microbes susceptible to the process of Absent at IgG, IgD and IgE Small polypeptide that regulates the multimerization of IgM phagocytosis and IgA o Remember: IgG1, IgG2, IgG3 are capable of triggering the A typical antibody has a similar structure to IgG complement system, while IgG4 does not IgA IgG and IgM activate the complement system by the classical o Can be monomeric or dimeric and therefore has 2 subunits pathway, and complement products promote phagocytosis and destruction of microbes IgM IgA secreted from mucosal epithelia neutralizes microbes in o A pentamer, therefore with 5 subunits the lumens of the respiratory and gastrointestinal tracts (and o Has better cross linking other mucosal tissues). o Used in blood typing due to better cross-linking IgE and eosinophil cooperate to kill parasites, mainly by ▪ If not compatible with antisera, agglutination occurs release of eosinophil granule contents that are toxic to the ▪ worms TH2 cytokine stimulate the production of IgE and activate Table 20. Antibodies (GAMED) eosinophils Name Properties Structure IgG Secreted by plasma cells in Monomer IMMUNOGLOBULIN CLASS SWITCHING the blood. Able to cross the Gene rearrangement generates antibodies of the same placenta into the fetus antigenic specificity but of different Ig classes Same assembled VH gene associate with different CH gene immunoglobulin with same specificity as IgM but with different biologic characteristics IgA Found in mucous, saliva, Dimer (Secretory) Dependent on cytokines released from T cells: IL-4, IL-5, tears and breast milk. or Monomer IFN-gamma, TGF-β Protects against pathogens (Blood) This is how we generate the primary and secondary immune response: IgM → IgG IgM May be attached to the Pentamer surface of a B cell or secreted into the blood. Responsible for the early stage of immunity. Most effective for WEEK 2 | 26 SEP 2024 | 1ST SEM A.Y. 2024-2025 CLUSTER 5 : LANDINGIN, MABILIN, MARQUINA, MENDOZA, MORALES, MOYA Page 8 of 13 DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY IMMUNITY Cont. Figure 12. Primary and secondary humoral immune responses Source: Cellular and Molecular Immunology, Abbas, 9th Edition. (This photo is not lifted from PPT) Causative agent → Susceptible host → Cellular response → Humoral response 1. Antigen Elimination 2. Primary Response - predominantly seen antibody is IgM Phases: a. Lag - no detectable antibodies b. Log - antibody increases c. Plateau - titer stabilized Figure 13. Complement Reaction Sequence d. Decline - antibodies are catabolized 3. Secondary Response - predominantly seen antibody is IgG a. Shorter lag phase due to quick response, with higher log Regarding the diagram, those in the second line are the value (greater amount of antibody) causing greater ‘triggers’ for the respective complement pathway response. o Classical: Immune complex (IgG or IgM) b. Exhibits the 4 phases o Alternative: Microbial surfaces o MBL: Mannose-binding lectin The phases of antibody production are similar to phases of bacterial growth Secondary immune response also has 4 phases but CLASSICAL PATHWAY remember: o Shorter lag phase Cell lysis is through MAC o Longer log phase C3b – most potent opsonin ▪ Means more antibodies are produced in the secondary C5a, C3a, C4a – anaphylatoxin response C5a - most potent chemotaxin o Takes longer to plateau and decline o Chemotaxin causes chemotaxis, the migration of leukocytes to site of infection C1 COMPLEMENT PATHWAY o C1q - attaches to Fc region of the antibody of the infected cells Classical Pathway o C1r - activates C1s Alternative Pathway o C1s - cleaves C4 and C2 (component of C3 convertase) MBL or Mannan (or Mannose)-binding lectin Pathway o Classical Pathway requires two Fc fragments to initiate the The complement system is both part of the acquire and innate response immune responses It is considered the ‘consequence’ of the preceding immune responses ALTERNATIVE PATHWAY All complement pathways have the same products, but different origins Cell lysis is through MAC 3 important products of the complement pathway ACTIVATION: lipopolysaccharides from the cell wall of the o Opsonin - C3b (most potent opsonin) bacteria, virally infected cells, fungi, tumor cells etc. o Anaphylatoxins - C3a, C4a and C5a Bypasses C1, C2 and C4 o Membrane Attack Complex - which causes cell lysis Factors unique in this pathway: o Factor B o Factor D o Factor P (Properdin) WEEK 2 | 26 SEP 2024 | 1ST SEM A.Y. 2024-2025 CLUSTER 5 : LANDINGIN, MABILIN, MARQUINA, MENDOZA, MORALES, MOYA Page 9 of 13 DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY Forms the complex C3bBb When the specific allergen binds to the IgE, C3 convertase cleaves C3 to C3a and C3b cross-linking of IgE induces degranulation Produces opsonin and anaphylatoxins of mast cells. IgE binding with mast cells produces an allergic response. MANNOSE-BINDING LECTIN (MBL) PATHWAY Degranulation produces allergy symptoms. IgG or IgM antibodies bind to cellular Cell lysis is through MAC antigen, leading to complement activation ACTIVATION: mannose-binding lectin which is an acute phase and cell lysis. IgG can also mediate ADCC reactant (lectins - are protein that bind to carbohydrates) II with cytotoxic T cells, natural killer cells, Start when MBL binds to mannose or other related sugars macrophages, and neutrophils. MBL is similar to C1q Type II hypersensitivity is associated with MBL is associated with three serine proteases: autoimmune diseases. o MASP-1 Antigen-antibody complexes are deposited o MASP-2: Cleaves C4 and C2 which follows the classical in tissues. pathway (most important) Complement activation provides o MASP-3 III inflammatory mediators and recruits neutrophils. REGULATORS OF COMPLEMENT ACTIVITY Enzymes released from neutrophils damage the tissue. Classical Pathway TH1 cells secrete cytokines, which activate o C1 Inhibitor - inactivates C1 by dissociating C1r and C1s IV macrophages and cytotoxic T cells from C1. It also inactivates MASP-2 MNEMONICS: ABCD o Decay Accelerating Factor - inhibit C3 convertase Type I Type II Type III Type IV formation Allergic, antiBody immune Delayed Alternative Pathway Anaphylaxis, Complex o Factor I - inactivates C3b and C4b and Atopy o Factor H - cofactor of Factor I to activate C3b and prevents Type I binding of Factor B to C3b o IgE mediated DEFICIENCY OF COMPLEMENT ACTIVITY o Fab receptor is for antigen, for cells Fc o Chemical mediators like histamine is released, causing MOST SERIOUS - deficiency of C3 vasodilation MOST COMMON - deficiency of C2 o Degranulation causes allergic symptoms: extravasation of fluid, vasodilation, urticaria (rashes) o C1 Inhibitor - Hereditary Angioedema Type II o C1, 2 and 4 - SLE-like syndrome o Can be IgM or IgG mediated o C3 - Severe Infections, Glomerulonephritis o Leads to complement activation via the classical pathway o C5-C8 - Neisseria Infection o Example: autoimmune disease o C9 - No known disease association Type III o DAF - Paroxysmal Nocturnal Hemoglobinuria o Immune complex mediated o Immune complex means an antigen-antibody complex HYPERSENSITIVITY o Also triggers complement activation via the classical pathway o Example: post streptococcal glomerulonephritis Type IV o T-Cell mediated cytotoxicity o Not just antibodies are involved o Example: transplant rejection Table 22. Types of Hypersensitivity and its associated disorders and mediators Type Alternative Names Associated Mediators Figure 14. Hypersensitivity Reaction Disorders Atopy I Allergy (Immediate) Anaphylaxis IgE An exaggerated response to a harmless antigen that results in Asthma injury to tissue damage or even death. Autoimmune In hypersensitivity, the trigger is not pathogenic yet the hemolytic anemia immune response is exaggerated and presents clinically in Thrombocytopeni patients II Cytotoxic a IgM or IgG o Type IV has the most severe immune response antibody-dependent Erythroblastosis Complement fetalis Table 21. Types of Hypersensitivity Reactions Goodpasture’s syndrome Type Mechanism Membranous Allergen-specific IgE antibodies bind to nephropathy I mast cells via their Fc receptor. Graves’ disease WEEK 2 | 26 SEP 2024 | 1ST SEM A.Y. 2024-2025 CLUSTER 5 : LANDINGIN, MABILIN, MARQUINA, MENDOZA, MORALES, MOYA Page 10 of 13 DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY Serum sickness ▪ Recall: Neutrophil is a phagocyte that engulfs bacteria. Arthus reaction When neutrophil’s Cytochrome B is defected and Rheumatoid H2O2 is decreased, it cannot digest the bacteria. arthritis Post-streptococc MPO Deficiency III Immune complex al IgG o MPO is a primary granule of neutrophils disease glomerulonephriti Complement o Phagocytosis takes place normally but bacterial killing is s innefficient Lupus nephritis o Fungal killing is more seriously impaired Systemic lupus erythematosus G6PD (SLE) o Aerobic system of neutrophils is impaired results in Extrinsic allergic decrease in H2O2 which is susceptible to catalase alveolitis organism (hypersensitivity pneumonitis) CR3 (IC3b) Receptor Deficiency Delayed-type Contact o Decrease or absent specific complement component hypersensitivity, dermatitis receptor resulting to adherence related functions on IV cell-mediated Mantoux test T Cells neutrophils, monocytes, and lymphocytes immune memory Chronic o Defective margination, diapedesis, chemotaxis, and response, transplant phagocytosis antibody-dependent rejection o T lymphocytes adhere poorly to target cells Multiple sclerosis Specific Granule Deficiency o Neutrophils fail to develop specific granules during myelopoiesis IMMUNODEFICIENCIES Chediak Higashi Syndrome Table 23. List Immunodeficiencies o Abnormal fusion of primary granule resulting to impaired degranulation Phagocytic Cell Deficiencies 1. Chronic Granulomatous o The patient may have albinism and photosensitivity Disease (CGD) 2. MPO Deficiency Lazy Leukocyte Syndrome 3. G6PD Deficiency o Job syndrome, also known as HyperIgE and poo 4. CR3 (IC3b) Receptor chemotaxis Deficiency o Tuftsin deficiency, where Tuftsin is a chemotaxin 5. Specific Granule Deficiency 6. Chediak Higashi Syndrome o Actin dysfunction resulting to decreased cell motility 7. Lazy Leukocyte Syndrome B-Lymphocyte Deficiencies 1. X-linked Bruton’s Agammaglobulinemia 2. Common Variable B-LYMPHOCYTE DEFICIENCIES Hypoglobulinemia B-Lymphocyte deficiencies account for more than ½ of all 3. Selective IgA Deficiency immunodeficiencies 4. Neonatal Hypogammaglobulinemia X-linked Bruton’s Agammaglobulinemia T-Lymphocytes Deficiencies 1. DiGeorge Syndrome o Sex-linked 2. Nezelof Syndrome o Usually recognized early in life when antibodies failed to Combined T and 1. Severe Combined develop B-Lymphocytes Deficiencies Immunodeficiency Disease o Pre-B may be found in the basement membrane but do not (SCID) 2. Wiscott Aldrich Syndrome mature (WAS) o Immunoglobulins are markedly decreased 3. Bare Lymphocyte o Treatment: Gamma globulin preparations Syndromes Common Variable Hypoglobulinemia o Acquired PHAGOCYTIC CELL DEFICIENCIES o One or two immunoglobulin classes are deficient o If IgG is deficient, the patient will suffer more bacterial Chronic Granulomatous Disease (CGD) infections o Ineffective killing of bacteria and yeast by neutrophils (bacteria is not digested)Defect in Cytochrome B resulting Selective IgA Deficiency to decrease in H2O2. o Most common congenital immunodeficiency o Diagnosed through Nitroblue Tetrazolium (NBT) Reductase Test since CGD neutrophils fail to reduce NBT Neonatal Hypogammaglobulinemia dye o Normal (physiologic) o Suffers from recurrent infection with catalase positive o Immaturity of neonatal immune system organisms o Acceptable at less than 6 months of life WEEK 2 | 26 SEP 2024 | 1ST SEM A.Y. 2024-2025 CLUSTER 5 : LANDINGIN, MABILIN, MARQUINA, MENDOZA, MORALES, MOYA Page 11 of 13 DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY T-LYMPHOCYTE DEFICIENCIES 11. Example of agglutination tests a. Titration DiGeorge Syndrome b. Cryptococcal Antigen Latex Agglutination Test o Abnormal development of thymus during embryogenesis (CALAS) ▪ Recall: T-cell matures in thymus c. Hemagglutination o T-Lymphocytes are decreased d. Direct Bacterial Agglutination Test e. Flocculation Test o Increased CD4:CD8 ratio o Impaired cell-mediated immunity 12. What is measured in EIA (Enzyme Immunoassay)? ▪ Weak adaptive response a. Product / Enzyme substrate product Nezelof Syndrome 13. What is measured in RIA (Radioactive Immunoassay)? o Patients are athymic (no thymus) a. Radioisotopes o Viral and fungal infections can be fatal to patients with Nezelof Syndrome 14. Immunoblotting test that uses protein? a. Western blotting 15. What kind of test is this? COMBINED B/T-LYMPHOCYTE DEFICIENCIES Most serious of the immunodeficiencies Severe Combined Immunodeficiency (SCID) o Markedly decreased B and T lymphocytes Wiskott Aldrich Syndrome (WAS) o Characteristic triad of WAS: Thrombocytopenia, Immunodeficiency, and Eczema (TIE) ▪ Thrombocytopenia: low platelet Bare Lymphocyte Syndrome o Defects in Class I and/or Class II MHC Antigens a. Immunofluorescence POST LECTURE AND LABORATORY QUIZ 1. Primary lymphoid organs REFERENCES a. Bone Marrow and Thymus 1. Blanco, R. (2024). Immunology [Lecture PPT] 2. Cotran, R. S., & Robbins, S. L. (2021). Robbins & Cotran Pathologic Basis of Disease 2. Injection with Tetanus toxoid confers what type of Immunity? (10th edition). Elsevier. a. Artificial Active Immunity 3. Which type of immunity is acquired through exposure to pathogens? a. Adaptive / Acquired Immunity 4. Humoral response to acquired immunity involves what type of lymphocytes? a. B Lymphocytes / B Cells 5. MHC binds ______ and presents it to ____ cells a. Polypeptides ; T cells 6. Immunoglobulin that crosses the placenta a. IgG 7. Immunoglobulin responsible for the early stage of immunity a. IgM 8. Immunity present at birth and does not need prior exposure to pathogens a. Passive Natural Immunity 9. IgE mediated hypersensitivity confers what type of hypersensitivity reaction? a. Type I Hypersensitivity 10. Component considered as a potent opsonin a. C3b WEEK 2 | 26 SEP 2024 | 1ST SEM A.Y. 2024-2025 CLUSTER 5 : LANDINGIN, MABILIN, MARQUINA, MENDOZA, MORALES, MOYA Page 12 of 13 DMED108: MICROBIOLOGY AND PARASITOLOGY (LECTURE) IMMUNOLOGY APPENDIX Appendix 1. Principal classes of lymphocytes and their function2 Appendix 2: Hypersensitivity Reaction WEEK 2 | 26 SEP 2024 | 1ST SEM A.Y. 2024-2025 CLUSTER 5 : LANDINGIN, MABILIN, MARQUINA, MENDOZA, MORALES, MOYA Page 13 of 13