[03.06] Mechanisms of Immunity V2.pdf

Module 03: Hematology and Immunology Mechanisms of Immunity Michelle J. de Vera, MD | September 20, 2023 | Onsite ▪ Next line of defense if microorganism successfully enters TABLE O...

Module 03: Hematology and Immunology Mechanisms of Immunity Michelle J. de Vera, MD | September 20, 2023 | Onsite ▪ Next line of defense if microorganism successfully enters TABLE OF CONTENTS the body (2027, 03.08) Learning Objectives 1 VII. Humoral Response to T 8 ﹣ Nonspecific: does not have a specific course of action for a I. Immunity 1 Cell Dependent Antigens ﹣ specific pathogen (2027, 03.08) A. Historical Perspective 1 A. Affinity Maturation 8 ﹣ “In” (inside) + “nate” (born) = “born with” (2027, 03.08) II. Components of the 1 B. Somatic Mutation 9 Immune System 1 C. Selection of High 9 ▪ Already present before birth (2027, 03.08) III. Innate Immunity 1 Affinity B Cells ▪ Genetically determined A. Anatomic Barriers 1 D. Signal Transduction 9 ﹣ Older evolution defense strategy (2027, 03.08) B. Physiological Barriers 2 VIII. T Cells and T Cell 9 Adaptive immune system C. Phagocytic/Endocytic 2 Activation ﹣ Slow response Barriers 2 A. T Cells 9 ﹣ Specific D. Inflammatory Barriers 3 B. T Cell Activation 9 ﹣ Present after birth (2027, 03.08) E. Cytokines 4 IX. Innate vs Adaptive 12 IV. Adaptive Immunity 4 Immunity A. Antigen Processing A. Links Between Innate 12 and Presentation 4 and Adaptive Immunity B. Antigen Presenting Summary 12 Pathways 5 Review Questions 12 V. B Cells and B Cell Rationale 13 Activation 5 References 13 A. B Cells 6 Appendix 14 B. B Cell Activation and Differentiation 8 VI. Isotype/Class Switching 8 A. Heavy Chain Isotype Figure 1. The Innate and Adaptive Immunity (de Vera, 2023) Switching III. INNATE IMMUNITY LEARNING OBJECTIVES Innate/Non-specific Host Defenses 1. Give a general overview of the innate and adaptive immune ﹣ Anatomic Barriers systems - its components and functions ﹣ Physiological Barriers 2. Discuss the generation of the immune response ﹣ Phagocytic Barriers a. Antigen processing and presentation ﹣ Inflammatory Barriers b. B and T cell activation ▪ Complement system: bridges the innate and the adaptive c. Main effector cells/mechanisms systems I. IMMUNITY A. ANATOMIC BARRIERS Immunis means “exempt” (source of word) Skin State of being exempt or protected from disease and noxious ﹣ Mechanical barriers retard entry of microbes substances ﹣ Outer epidermal layer has keratin (water-proofing) Distinguishes the self from non-self (foreign) ﹣ Dermis: connective tissue, blood vessels, hair follicles, A. HISTORICAL PERSPECTIVE sebaceous glands, sweat glands antimicrobial Thucydides (430 B.C.) ▪ Sebaceous glands produce sebum (lactic + fatty acids) ﹣ Great historian (Peloponnesian War) which maintains acidic environment (pH 3-5), retarding ﹣ Earliest reference to the idea of “immunity” during a plague in growth of microbes Athens ▪ Some people were infected with the mild form of disease and never got it again ▪ Only those who had recovered from the plague could nurse the sick as they would not contract the disease ﹣ Almost 2000 years passed before the concept of immunity was successfully converted into a medically effective practice Chinese and Turks (15th Century) ﹣ First crude attempt to induce immunity ▪ Crusts of smallpox pustules (from infected people) were Figure 2. Parts of the skin (de Vera, 2023) inhaled by healthy people or inserted into cuts in their skin Mucous membranes (variolation) ﹣ Lines conjunctivae, alimentary, respiratory, urogenital tracts ▪ The healthy people did not get sick, but they became ﹣ Saliva, tears, and mucous secretions wash away potential immune to smallpox, allowing them to take care of the sick invaders II. COMPONENTS OF THE IMMUNE SYSTEM ﹣ Mucous entraps foreign microorganisms Innate immune system ▪ Found in the gut, lungs, and upper respiratory tract (e.g. ﹣ Fast response nose) ﹣ Cilia propel microorganisms out of body ▪ Small hair-like projections (2027, 03.08) TG13 | Capuyan, Chua, Cunanan, Dy, Lopez, Ona, Seares, Severino, Song, Villanueva, Yang YL5 03.06 1 of 14 CG4 | Beltran, Billedo, Castro, Cruz, De Guzman, Jayme, Maliwat, Ong, Pimentel, Uy, Velasco  ▪ Possess a particular direction of movement that removes D. INFLAMMATORY BARRIERS any foreign material that may have entered the lungs while Phagocytes breathing (2027, 03.08) ﹣ Play an important role in inflammation ﹣ Normal flora (non-pathogenic) outcompete other microbes for Cardinal Signs of Inflammation attachment sites and nutrients tweakmicrobiome can ﹣ Cornelius Celsus (1st century AD) ▪ When a person takes antibiotics, normal flora is killed ▪ Rubor (redness) which increases their susceptibility to sickness and ▪ Tumor (swelling) infection ▪ Calor (heat) B. PHYSIOLOGICAL BARRIERS ▪ Dolor (pain) Temperature ﹣ Galen (2nd century AD) inflammatory not kills pathogens ▪ Functio laesa (loss of function) ﹣ Normal body temperature inhibits growth of pathogens ﹣ Fever response inhibits growth of some pathogens Steps in Inflammatory Response ▪ Inflammatory cytokines help increase body temperature Low pH ﹣ Acidity of stomach contents kills most ingested microorganisms Chemical mediators ﹣ Lysozyme (found in tears, mucous, and saliva) cleaves bacterial cell wall, leading to cell lysis and death ﹣ Interferon induces antiviral state in uninfected cells ▪ Used by a lot of phagocytic cells Nice! Neonates are more prone to GI infection because the pH of their gut is not as low as that of adults C. PHAGOCYTIC/ENDOCYTIC BARRIERS Endocytosis: uptake of cell material from the environment ﹣ Various cells endocytose and break down foreign ieiiem macromolecules into smaller fragments Phagocytosis: ingestion of large materials and whole organisms Figure 4. Steps of the inflammatory response (de Vera, 2023) by specialized cells (phagocytes) ﹣ Specialized cells phagocytose, kill, and digest whole 1. Damaged tissues release histamines, increasing blood flow in microorganisms the area. ﹣ Different types of phagocytes: ﹣ Capillaries become engorged (vasodilation) causing ▪ Innate immune system erythema rubor (redness) in the site of injury − Macrophages 2. Histamines cause capillaries to leak (vascular permeability), − Dendritic cells releasing phagocytes and clotting factors into the wound − Mast cells ﹣ This causes edema tumor (swelling) − NK cells ﹣ Diapedesis occurs when phagocytes exit the bloodstream − Basophils and enter the surrounding tissue ▪ Adaptive immune system ﹣ Release of inflammatory chemicals into the extracellular − T and B cells fluid Macrophage (refer to Fig. 3) ▪ Histamine and kinins cause vasodilation ﹣ Expresses receptors that recognize bacterial components ▪ Bradykinin, a type of kinin, causes pain ▪ E.g. receptors that recognize LPS, mannose, and glucan 3. Phagocytes engulf bacteria, dead cells, and cellular debris found in the cell wall of bacteria ﹣ Macrophages and cells of certain boundary tissues have ﹣ Once macrophages detect bacterial constituents through their receptors that enable them to recognize pathogens specific receptors, they release cytokines and chemokines which help 4. Platelets move out of the capillary to seal the wounded area the macrophage phagocytose the bacteria and call on other phagocytic cells Histamine vasodilation fffh.my release phagocytes diapedesis p Bradykinin pain Figure 3. Process of phagocytosis via the macrophage (de Vera, 2023) YL5 03.06 Innate and Adaptive Immunity 2 of 14  Steps in Inflammatory Response (2027, 03.08) 2. Tight binding: Lymphocytes release signaling so that ICAM-1 on the endothelium will connect to a receptor in lymphocytes LFA-1 forming a stronger bond 3. Diapedesis or transversion of the lymphocytes to the membrane is aided by the metalloproteinase enzyme released by the lymphocytes Squeezing into thetissue 4. Lymphocytes then migrate and follow the cytokines to the site of injury 1. Injured body 2. Release of 3. Receptors tissue inflammatory recognize Nice! chemicals pathogen Pus is a sign that the immune system is working ○ It consists of dead white blood cells, bacteria, tissue debris, and other substances ○ There is an immune deficiency disease wherein leukocytes do not slow down and thus, phagocytes cannot come to the site of injury. In this case, no pus is made because nothing is killed. Steps in Phagocyte Mobilization (2027, 03.08) 4. Release of cytokines 5. Redness and swelling 1. Leukocytosis Figure 5. Steps of the inflammatory response (de Vera, 2022) ﹣ Phagocytes enter bloodstream from the red bone marrow 2. Margination 1. Occurs when body tissues are injured by physical trauma, heat, ﹣ Phagocytes cling to capillary walls at the site of injury by or infection recognizing molecular signals on inflamed cells 2. Release of inflammatory chemicals (e.g. histamine) into the 3. Diapedesis extracellular fluid ﹣ Phagocytes squeeze out of the capillary 3. Macrophages and cells of certain boundary tissues have ﹣ A small portion of the cell slides through the pore at a time receptors that enable them to recognize pathogens ▪ The portion sliding through is momentarily constricted to 4. Cytokines, a type of inflammatory chemical, are released which the size of the pore cause local arterioles to dilate (vasodilation) and nearby ﹣ Neutrophils and macrophages can move through the tissues capillaries to leak slightly (vascular permeability) by ameboid motion 5. Excess of blood in the area causes redness and swelling 4. Chemotaxis ﹣ Causes pain due to the pressure on nearby nerve endings ﹣ Phagocytes migrate up the gradient of certain molecules that ﹣ Favorable strategy: rush of fluid sweeps foreign material into act as a honing device for the site of injury lymphatic vessels to be broken down in the lymph nodes ﹣ Phagocytes are now ready to eat intruders (phagocytosis) ﹣ Fluid delivers proteins important for clotting to aid in repair ﹣ Neutrophils and macrophages move toward the source of 6. Once inflammation has been initiated, phagocytes arrive to do chemical substance phagocytosis ▪ Some of the bacterial or viral toxins ﹣ First to rush in: neutrophils ▪ Degenerative products of the inflamed tissues ﹣ Next: macrophages ▪ Several reaction products from the complement pathway “Walling-Off” effect of inflammation ▪ Several reaction products caused by plasma clotting ﹣ Tissue spaces and lymphatics are blocked by fibrinogen clots E. CYTOKINES ﹣ Delays the spread of bacteria or toxic products signallingmolecules Steps in Lymphocyte Mobilization Non-antigen small molecules that cells use to influence each other ﹣ Colony stimulating factors, interleukins, chemokines, interferons, TNF Drive activation, development, proliferation or clonal expansion, differentiation into functional states Stimulates other organs in an endocrine-like function during inflammatory response Can work on the cell itself or other cells (like hormones) Can aid in the communication between cells of the immune system Can be found anywhere Figure 6. Steps in lymphocyte mobilization (de Vera, 2023) How do the lymphocytes get into the area if the blood flow is too fast? 1. Rolling adhesion: Reversible weak bond between lymphocytes and vascular endothelium mediated by E-selectins YL5 03.06 Innate and Adaptive Immunity 3 of 14  Typically, there is an adaptive immune response against an antigen within 5 to 6 days of initial exposure to an antigen Evolved over time (as opposed to the innate immune system) 4 key characteristics ﹣ Antigenic specificity ▪ To distinguish subtle differences among antigens ﹣ Diversity ▪ Allows recognition of billions of uniquely different structures on foreign antigens ﹣ Immunologic memory ▪ A 2nd encounter with the same antigen induces heightened state of immune activity − Memory B-cells and Memory T-cells created in response to previous infections can help protect us long after initial infection Figure 7. Cytokine network (de Vera, 2023) − Reason as to why vaccines are possible and why we only get some diseases once ▪ Can confer lifelong immunity after initial encounter ﹣ Self/non-self recognition ▪ Should be able to distinguish between self and non-self ▪ Responds only to foreign antigens ▪ Dysfunction in this mechanism can be a primary cause of autoimmune disease Main players in adaptive immune response are B-cells and T-cells A. ANTIGEN PROCESSING AND PRESENTATION For a foreign antigen to be recognized by a T cell, it must first be processed by the cell and then presented ﹣ Antigens are degraded into small antigenic particles Antigen Processing ﹣ Pathogens and their products are degraded to produce peptide antigens Figure 8. Selected cytokines and their effects (de Vera, 2023) After the foreign antigen has been processed, it will form a Figure above shows the more common cytokines ﹣ IL-1: involved in pro-inflammatory (causes fever) need memo no to complex with either MHC I or MHC II, depending on which type ﹣ IL-2: acts on itself ▪ Can make more T cells and activate it is expressed by the cell Antigen Presentation dependent type on microorgani of ▪ Can activate B cells and make it mature ﹣ MHC-Peptide Complex travels to cell surface ﹣ IL-4: has a role in allergic reaction and helminthic responses ﹣ Peptide fragments are displayed to T-cells ﹣ IL-10: has a regulatory role (regulates immune system) After either MHC complex has been formed, a specific T cell will ﹣ Interferon-gamma (IFN-γ) recognize the complex ▪ Produced by NK and T cells ﹣ MHC I → CD8 (Cytotoxic T cells) ▪ Important for virus killing, opportunistic infection killing ▪ Interacts with TNF and TGF-beta ﹣ MHC II → CD4 (Helper T cells) Yffellular microorganis Why do we have 2 different antigen processing pathways? ACTIVE RECALL BOX ﹣ Each pathway stimulates the T cell population that is most 1. The following are physiological barriers except: effective in eliminating a particular type of antigen a. Low pH b. Temperature B. ANTIGEN PRESENTING PATHWAYS c. Mucous membranes o d. Lysozyme B-cells and T-cells recognize different types of antigens 2. Which molecule mediates the reversible weak bond between Table 1. Differences in B-cell and T-cell antigen recognition lymphocytes and vascular endothelium? B-cells T-cells a. P-selectins Recognize a variety of antigens Recognize only proteins 0 b. E-selectins c. ICAM-1 Proteins Polysaccharides Peptides d. VCAM-1 Nucleic Acids MHC-peptide 3. Which process involves the migration of phagocytes from the Complex Lipids bloodstream into the surrounding tissue, allowing them to reach the site of injury or infection? MHC Molecule Classes a. Vasodilation MHC Class I (MHC I) Molecule b. Erythema ﹣ Present intracellular/endogenous antigens c. Vascular permeability d. Diapedesis ▪ Live and replicate inside the host cell infinitely ﹣ E.g. Viruses Answers: 1C, 2B, 3D ▪ Under normal conditions IV. ADAPTIVE IMMUNITY − Peptides derived from the cytosol of any nucleated cell Also called the specific immune system are displayed by MHC I molecules as MHC peptide Displays a high degree of specificity and a remarkable property complex of memory ▪ When cell is infected by an intracellular pathogen (virus) YL5 03.06 Innate and Adaptive Immunity 4 of 14  − Peptides derived from the virus are presented by MHC-I for recognition by CD8 (Cytotoxic T-cells) and Natural Killer Cells (NK) MHC Class II (MHC II) Molecule ﹣ Present extracellular/exogenous antigens ▪ live and replicate outside the host cell ﹣ E.g. Extracellular bacteria, toxins, and parasites ▪ Antigen presenting cells internalize extracellular pathogens and break them down ▪ Peptides derived from the extracellular pathogen are presented by MHC-II for recognition by CD4 (Helper T-cell) Figure 10. Overview of MHC-II Antigen Presentation Pathway (Frank Lectures, 2017) MHC I Antigen Presentation Pathway (Frank Lectures, 2017) Steps for antigen processing and presentation Intracellular/endogenous antigen processing and presentation 1. Internalization of pathogen Target cell: cell infected with the virus a. Extracellular pathogens enters the cell via an endosome ﹣ The virus uses the cellular machinery of the cell to (an intracellular vesicle) synthesize viral proteins 2. Creation of an endolysosome ﹣ Occurs in the cytoplasm of the target cell a. From the fusion of the endosome and lysosome 3. Digestion of pathogen by the proteolytic lysosomal enzymes of the endolysosome a. Into peptide fragments now 4. Synthesis of MHC-II molecules in the RER your pathogen a. α and β chains of MHC II molecule associate with a third protein chain called invariant chain b. Invariant chain stops self-peptides from binding to MHC-II molecules 5. MHC II invariant chain complexes move to the Golgi, then to another vesicle 6. MHC-II peptide complex is released and moves to the cell Figure 9. Overview of MHC-I Antigen Presentation Pathway surface via the Golgi apparatus and secretory vesicles (Frank Lectures, 2017) a. Invariant chain is digested with a small fragment still bound Steps for antigen processing and presentation to the MHC-II molecule 1. Viral proteins are digested by proteasome (12-15 protein i. Small fragment is known as the Class II-associated subunits) in cytoplasm daffodils proteins Invariant chain Polypeptide (CLIP) tnpaihtstitlckhke.se 2. Peptides are transported to rough endoplasmic reticulum by Transporters associated with Antigen Processing (TAP) 7. Fusion of the vesicle containing MHC-II bound to CLIP and d vesicle containing the peptide fragments of the antigen Efrat (with 2 subunits: TAP-1 & TAP-2) 8. Displacement of the CLIP by the peptide fragments pathogen 3. Alpha and beta chains of the MHC-I molecule are synthesized m a. Which also bind to the peptide binding groove of MHC II and translocated into the ER molecule peptidetramentpathoftqkpsmpaage.se 4. The chains are assembled together in a group of chaperone proteins YE ff.tk b. Peptides are 11-15 amino acids long 9. Newly formed MHC-II peptide complex is transported to the 5. The peptide binds with the MHC-I molecule to form the MHC cell surface for presentation to T-cells Class I peptide complex On T cell recognition on the cell surface: 6. MHC-I peptide complex is released and moves to the cell ftp ﹣ T cells possess surface via the Golgi apparatus and secretory vesicles ▪ T cell receptors which recognize the peptides presented 7. From the cell surface, the peptide complex can be recognizediifdgon MnHn by MHC-II peptide complex by T cells ▪ Co-receptor CD4 which binds to the beta-II domain of the On T cell recognition: pinpfiae MHC-II molecule ﹣ T cells possess V. B CELLS AND B CELL ACTIVATION ▪ T cell receptors which recognize the peptides presented by MHC-I peptide complex A. B CELLS Table 2. Overview of B Cells ▪ Co-receptor CD8 which recognizes the alpha-3 domain of Origin and the MHC-I molecule Bone Marrow Maturation Site ﹣ T cells interact with BOTH the peptide and the MHC-I Divide and form millions of descendants molecule on the surface of the target cell 14 Each daughter cell has a different receptor from its MHC II Antigen Presentation Pathway (Frank Lectures, 2017) Mechanism parent and all its sibling Difference is caused by a slight shuffling in their DNA but Extracellular/exogenous antigen processing and presentation specifically for the receptor E.g. extracellular bacteria taken in via endocytosis orPettitte Primary phagocytosis Function Produce antibodies Cells involved: Antigen Presenting Cells (APCs) ﹣ Phagocytic cells that present peptides derived from Use cell surface-bound intramembrane immunoglobulin internalized pathogens molecules as B cell receptors (BCRs) ﹣ E.g. B cells, macrophages, dendritic cells ﹣ For antigen in a complex of immunoglobulin associated signaling molecules (2027, 03.08) Specificity of receptor is the same as the immunoglobulin that it maindifference between intra vs extra is able to secrete after activation YL5 03.06 Innate and Adaptive Immunity 5 of 14  ﹣ Make immunoglobulin receptor also immunoglobulin-like Immunoglobulin Structure (2027, 03.08) Antibody can recognize epitopes with incredible precision ﹣ Specific for that specific antibody/antigen; very precise Recognize the following antigens in soluble form (2027. 03.08): ﹣ Proteins ▪ Conformational determinants ▪ Determinants exposed by denaturation or proteolysis ﹣ Nucleic acids ﹣ Polysaccharides ﹣ Some lipids ﹣ Small chemicals that act as haptens Also express surface receptors for: ﹣ Fc region of IgG molecules (CD32) ﹣ Activated complement components (C3d, CD21, C3b, or CD35) ▪ When B cells are activated, there is a receptor for first part of complement C1 ▪ Attachment allows complement system to work Figure 12. Immunoglobulin/Antibody Structure ▪ 3 antigen presenting cells: dendritic cells, macrophages, B Light Chain cells ﹣ Antigen receptor (2027, 03.08) Serve as APCs efficient at antigen processing, enhanced by a ﹣ Genes that code for the light chain can arrange themselves variety of cytokines billions of times (1015 times) to recognize any foreign antigen Primary function of B cells is to produce antibodies ﹣ For illnesses you are yet to be exposed to, you already have B Cells Antibody Specificity and Diversity sequence for it Heavy Chain ﹣ Two identical chains connected by disulfide linkages (2027, 03.08) ﹣ Becomes what kind of antibody needed effectorsite Human Immunoglobulin Classes Divided into five classes based on very similar heavy chain constant regions (depicted by a Greek letter) ﹣ IgG - Gamma (γ) heavy chains ﹣ IgM - Mu (μ) heavy chains ﹣ IgA - Alpha (α) heavy chains aiiai.in iiiiEienan ﹣ IgD - Delta (δ) heavy chains on SIGNAL ﹣ IgE - Epsilon (ε) heavy chains See Appendix for Table A1. Physical, Chemical, and Biologic Properties of Human Immunoglobulins and Graphic Representations Nice! Figure 11. Lymphocyte Gene Rearrangement Diagram Mother can transfer IgG to her baby via the placenta B cell maturation in BM: ordered sequence of gene IgA is of small size as it has to go through mucus membrane rearrangement = 1015 combination different antibodies IgM is heavy and has many chains Genome rearrangement is an essential feature of lymphocyte B. B CELL ACTIVATION AND DIFFERENTIATION differentiation ﹣ Gene rearrangement makes B cells very specific and diverse Overview of B Cell Activation and Differentiation B cells are effector cells that make antibodies. Nice! ﹣ Antibody formation takes over a few days to a week specific No other vertebrae cell type has been shown to undergo to the antigen present. genome rearrangement Antibody secretion ﹣ In general, antibodies either neutralize or kill pathogens Separate genes encode immunoglobulin V & C regions ﹣ Antibodies participate in host defense through: Genes are rearranged in the course of B cell differentiation ▪ Neutralization Each individual B cell express unique antibody antigenically − Antibodies recognize and bind to unbound toxins Mature B cell is antigenically committed committed − Antibodies bound to toxins neutralize them until a phagocyte recognizes and engulfs the toxin. ▪ Opsonization − Opsonin: used to tag foreign pathogens for elimination by phagocytes make umami ▪ Complement activation − Antibody has a receptor for the first part of the complement system (C1) YL5 03.06 Innate and Adaptive Immunity 6 of 14  − Once it connects, either it reactives the complement ▪ For instance, B cells have toll-like receptors that can cascade or leads to lysis and phagocytosis recognize the various microbial surface molecules o Complement cascade: forms a complex with MHC − Recognition and binding of the toll-like receptors to Ti and proceeds from there antigen generates the second signal for activation o Complements are also opsonins for phagocytes so After activation they recognize that and degrade the bacteria ﹣ B cells proliferate and differentiate into plasma cells that secrete IgM antibodies immediate ﹣ Memory cells are not produced pyponse ▪ Because production requires T cell help Figure 14. Summary of T Independent B Cell Activation Figure 13. Effector Antibody Mechanisms Responses to T-independent Antigens The mature naive B cells have receptors (BCRs) for recognizing specific antigens Antibody responses to T-independent antigens do not require ﹣ Mature B cells leave the bone marrow and recirculate cell-cell interactions between the blood, the secondary lymphoid tissues, and the Polymeric nature of these antigens allow for cross-linking of lymph antigen receptors on B cells resulting in activation When naive B cells encounter their specific antigens, they get ﹣ Activation of the B cell to produce the necessary antibody activated and differentiate into: ﹣ Does not need the help of T cells a. Antibody producing plasma cells ▪ But no memory cells are made → short-lived immune b. Memory B cells response Activation of B cell based on the type of antigen encountered; ﹣ Pathogens with multiple epitopes allows for easier can be either: cross-linking on the receptors on B cells ﹣ T cell independent No secondary responses, affinity maturation or class switching ﹣ T cell dependent occurs Signaling requires clustering or cross-linking of BCRs on antigen Activation of a subpopulation of B cells called CD5+ B cells (also recognition called B1 cells) ﹣ Clustering ▪ Activates multiple Igα/Igβ molecules and initiate signaling Humoral Response to T Cell Dependent (Frank Lectures, 2017) appse process Protein antigens cannot crosslink multiple BCRs Depends on the type of antigen encountered ﹣ Due to lack of repetitive and identical epitomes, requiring the ﹣ Antigens can be polysaccharides, glycolipids and nucleic help of T cells to be activated (B cells) acids Occurs in a 3 signal process: ﹣ Have multiple repeating epitopes that can directly crosslink B ﹣ Signal 1: Antigen recognition and binding by B cell cell receptors ▪ Mature naive B cells recognize and bind specific antigen ﹣ Can activate B cells to produce antibodies without T cell help by its B cell receptors. Antigen binding signal is then conveyed to the nucleus ▪ B cells process and display the antigens (MHC II-peptide Responses to T Cell Independent Antigens (Frank Lectures, complex) are Bells alsoAPCs 2017) ▪ B cells also display co-stimulatory receptor and cytokine T-independent or Thymus-independent (Ti) antigens receptors on their surface ﹣ Antigens that can activate B cells without the help of T cells − CD40: most important co-stimulatory receptor Antibody responses do not require cell to cell interactions ▪ The antigen is also recognized by mature naive CD4+ T cell No secondary responses such as affinity maturation or class (Helper T cells) switching occur − This process is independent from the B cell Ti antigens are multivalent − The processed antigen from the MHC II-peptide ﹣ Responsible for recognizing larger structure with identical or complex is presented to the T cell by dendritic cells. repeating epitopes (eg. polysaccharides on bacteria cell walls) ▪ T cells get activated and is now capable of recognizing B cell receptors are specific to corresponding antigens, these antigens facilitating cross-linking ﹣ Signal 2: Derived from the interaction between B and T cells Occurs in a 2 signal process ▪ The most important signal; in which B cells do not get ﹣ Signal 1: Clustering of B cell receptors triggers B cell activated without this step activation ▪ B cell and helper T cell come in close proximity ﹣ Signal 2: Derived from other molecules present on the ▪ Helper T cell recognizes the antigen and binds to MHC antigen II-peptide complex on the B cell’s surface; expressing ▪ Necessary for full activation CD40 ligand on their surface YL5 03.06 Innate and Adaptive Immunity 7 of 14  ▪ The CD40 receptor on B cell and CD40 ligand on T cell Nice! surface bind, triggering the production of IL by T cells ▪ The IL released by T cells acts on B cells, which Infections increase the amount of antibodies → more determines the antibody to be released by B cells memory cells ○ Memory cells do not necessarily lead to the production of − E.g. IL 4 stimulates IgM and IgE production more antibodies − E.g. IL 2 stimulates IgG and IgM production Why can’t people have lifelong immunity against certain ﹣ Signal 3: Cytokines released by T helper cell stimulate B cell diseases? ▪ Interaction of the B and T cells induce the expression of ○ Lack of exposure over time leads to waning of memory new cytokine receptors on the B cell cells ▪ The released cytokines (e.g. IL-4) binds to the cytokine ○ Lack of exposure to antigen → memory cell degradation receptor on the B cell → stimulates the proliferation and (based on the cell’s lifespan) Reason for vaccine boosting differentiation of B cells into antibody-secreting plasma ○ In the case of influenza → constantly evolving cells and memory B cells Can have lifelong immunity for one type but not the new type A. HEAVY CHAIN ISOTYPE SWITCHING Polysaccharide antigens elicit T-independent responses, stimulating IgM molecules Viruses and bacteria activate TH1 subset that secretes interferon gamma, the main inducer of IgG subclass Helminths activates TH2 subset, secreting IL-4 which induces switching to IgE Results of isotype switching: ﹣ Phagocyte response and complement activation by IgG ﹣ Better response to helminths from IgE ﹣ Mucosal immunity via IgA FIgure 15. Summary of T Dependent B Cell Activation Signals There are people who cannot switch from IgM to IgG which can Memory B Cells become problematic ﹣ IgM is short-lived which leads to poor immunity Figure 17. Heavy Chain Isotype Switching VII. HUMORAL RESPONSE TO T CELL DEPENDENT ANTIGENS Figure 16. Primary and Secondary Antibody Response Graph Activated B cells will now secrete antibodies Primary Antibody Response Antibodies are the main effectors of B cells ﹣ T dependent B cell activation makes memory cells The activated B cell undergoes a series of cell division and ﹣ In the first infection/exposure, antigen is present to activate differentiate into a population of both antibodies secreting the B cells, making plasma cells and memory cells plasma cells and memory cells ▪ Plasma cells: make IgG and IgM (always first to be produced) ▪ Memory cells: linger if HEY Secondary Antibody Response ﹣ Repeated infection/exposure ﹣ Memory cells from the first exposure to the same antigen remember and recognize foreign body, triggering the innate immune response (stronger and more rapid response) VI. ISOTYPE/CLASS SWITCHING Cytokines produced by activated TH2 cells ﹣ Stimulate proliferation and differentiation of B cells ﹣ Also help regulate the class of antibodies produced Different cytokines influence the switch of B cells to different Figure 18. Humoral Response to T cell Dependent Antigens classes of antibodies with different effector functions A. AFFINITY MATURATION ﹣ Switches from one isotype to another (e.g. IgM to IgG) Increased affinity as humoral response progresses initial titi Antibody response is tailored to suit the pathogen encountered ﹣ Somatic mutation occurs → Rearrangement in order to become more attracted to the antigen YL5 03.06 Innate and Adaptive Immunity I it IEii E 8 of 14  Due to somatic mutation of immunoglobulin genes followed by 3. Activation of enzymes at the bottom selective survival of B cells 4. At the end, transcription factors are made which are very ﹣ More efficiently binds to, neutralizes, and eliminates microbes important since they transform your DNA → RNA → proteins B. SOMATIC MUTATION (cytokines and other factors for immune response such as interleukins and antibodies) Seen in the Ig V genes of proliferating B cells in dark zone ﹣ Without transcription factors (end point of it all), you cannot Occurs mostly in the antigen binding complementarity make your interleukins, antibodies, etc. determining region (CDR) ﹣ Good target for therapy as they can inhibit creation of certain More mutations in IgG as compared to IgM proteins involved in mediating diseases Mutations correlate with increasing affinities of the antibodies for 5. Signaling occurs and these are good targets for therapy the antigen that induced the response ﹣ Transcription factors are targeted for cancer therapy Figure 21. Signal Transduction Figure 19. Somatic Mutation ACTIVE RECALL BOX C. Selection of High Affinity B Cells 4. Where does somatic mutation mostly occur? Germinal centers → to meet other T-cells or other cells of the 5. What are the 5 classes of Heavy Chains? immune system When the antigen and antibody connect (somatically changed) Answers: 4 Complementarity determining region (CDR), 5 IgG, they connect better IgA, IgM, IgE, IgD The ones that do not change get degraded over time (apoptosis) VIII. T CELLS AND T CELL ACTIVATION At the end, only B cells with high affinity receptors are destined A. T CELLS to survive (get B cells who can bind it better, stick better, and be more specific to the antigen) Overwhelming majority of antigens for T cells are proteins Antigen that sticks gets stronger and survives overtime Antigens must be fragmented and recognized in association with B cells that can be more specific and have higher affinity to MHC products expressed on the surface of nucleated cells (not antigen are kept longer in soluble form) Grouped functionally according to the class of MHC molecules that associate with the peptide fragments of proteins: ﹣ Helper T cells (CD4+) recognize only those peptides associated to MHC II molecules ﹣ Cytotoxic T cells (CD8+) recognize only those peptides associated to MHC I molecules T cell maturation: random rearrangement of gene segments to encode TCR (T Cell Receptor) Generates 1018 unique antigenic specificities ﹣ Diminished through selection process in thymus to eliminate T cell with self-reactivity receptors B. T CELL ACTIVATION (Frank Lectures, 2017) A complicated process 2 types of Mature T cells: ﹣ CD4+ T cell ﹣ CD8+ T cell fiftoxic ▪ Note: Both are naive T cells since they have not encountered any antigen yet. Activation of naive CD4+ T cells: ﹣ APC digests engulfs an extracellular antigen by phagocytosis → APC digests the engulfed antigen into fragments and Figure 20. Selection of High Affinity B Cells displays the peptide fragment on its surface → peptide is D. SIGNAL TRANSDUCTION presenting on the surface of APC as MHC II-peptide complex 1. Cross linking of membrane IG by antigen → there is activation (processes called: Antigen processing and presentation) → of the Src family kinases the APC travels from the site of infection to the lymph nodes 2. Phosphorylation of tyrosine YL5 03.06 Innate and Adaptive Immunity 9 of 14  where they present the antigen to the circulating naive T cells (CD4+). ﹣ The activation of the naive T cells requires 2 signals: ▪ Signal 1: TCR recognizes and binds the antigen and CD4 co-receptor binds the MHC II molecule → generates the first signal of T cell activation. ▪ Signal 2: Enhances the first signal, also known as co-stimulation. − Co-stimulation includes cytokines or a pair of plasma membrane molecules. More than 20 costimulators are known. o Most important known co-stimulator pair is B7 (CD80) and CD28. CD28 acts as a receptor present FIgure 23. Summary of CD8+ T Cell Activation and Differentiation on T cells and B7 is known as a ligand present on the APC. These molecules make the APC and T cell ACTIVE RECALL BOX adhere together for more time 6. CD8+ T cells are ____ T cells. CD4+ T cells are ____ T cells. a. Cytotoxic; Helper o Other stimulators include: CD2, CD28, and CD45 b. Helper; Cytotoxic − Note: Without costimulation, the T cells which recognize c. Naive; activated the antigen remain in a prolonged state of inactivity d. Lysozyme known as anergy. 7. True or False: Cytotoxic T cells are activated by the MHC ▪ The two signals activate the T cells → T cells synthesize II-peptide complex. and secrete cytokine IL-2. self stimulating ▪ IL-2 acts as an autocrine cytokine which means it binds to a. True b. False its specific receptor on the same T cell → T cell undergoes 8. B cells can differentiate into antibody-secreting plasma cells proliferation and differentiation rapidly → a population of on their own. T cells can become memory T cells when CD4+ effector T cells and CD4+ memory T cells is activated. generated. a. Only the first statement is correct. b. Only the second statement is correct. − The CD4+ effector T cells develop into diverse subsets c. Both statements are correct. of T helper cells d. Both statements are wrong. − CD4+ memory T cells have the ability to quickly Answers: 6A, 7B, 8B generate more effector and memory cells if encountered by the same antigen in the future. Helper T Cells (TH) (Frank Lectures, 2017) Activated CD4+ T cells become helper T cells Termed ‘helper’ since they help other cells of the immune system to eliminate pathogens 5 main subsets of helper T cells: ﹣ TH1 cells ﹣ TH2 cells ﹣ TH17 cells ﹣ TREG cells ﹣ TFH cells Figure 22. Summary of CD4+ T Cell Activation and Differentiation Activation of naive CD8+ T cells: ﹣ Similar to CD4+ T cell activation with a few differences ▪ Naive CD8+ T cells recognize antigen presented by MHC I molecule ▪ The costimulation also occurs by IL-2 and other cytokines produced by helper T cells. These helper cells are those that recognize and bind to the same antigen ﹣ Once activated, the CD8+ T cell proliferate and differentiate rapidly → generating CD8+ effector T cells and CD8+ memory T cells Figure 24. Helper T Cells ▪ Effector CD8+ T cells are cytotoxic and attack cells Classifications are based on: affected by the pathogen or antigen ﹣ Cytokines that induce their differentiation ▪ Memory CD8+ T cells quickly proliferate and differentiate ﹣ Master transcriptional regulator into more effector cells and memory cells if the same ▪ Regulates the expression of cytokines produced by the pathogen infects in the future. particular T cells subsets ﹣ Cytokines they produce and secrete Diverse types are needed by the immune system to respond to the diversity of pathogens effectively ﹣ Diverse types of pathogens and infections ﹣ Different target sites ﹣ Different target cells YL5 03.06 Innate and Adaptive Immunity 10 of 14  ﹣ Some resist killing by macrophages Regulatory T Cells (Treg) ﹣ Some are too large to be phagocytosed Once a pathogen is eradicated, regulatory T cells limit tissue Helper T cells work by secreting cytokines that communicate damage caused by immune response with other cells of immune system and activate them to eliminate ﹣ Function: suppress T cell responses and limit immune pathogens by appropriate immune response response T Helper Type 1 Cells (TH1) ﹣ Prevent autoimmunity Type 1 helper cells ﹣ Communicate with other cells of immune system and stop Helps macrophages fight intracellular infections their effector functions 1. Dendritic cells release IL-12 and migrate from site of infection to Produce IL-10 and TGF-β: help inhibit inflammation and the nearby lymph node to present the antigen to naive CD4+ T cell immune response 2. Antigen is recognized and IL-12 signal T cell to become TH1 cell ﹣ IL 10: Potent suppressor of macrophage functions 3. TH1 cell starts releasing interferon gamma (IFN-𝛄) ﹣ TGF-β: Induces generation of more regulatory T Cells ﹣ IFN-γ activates macrophages and enhances its microbicidal Follicular Helper T Cells (TFH) activity to kill ingested bacteria Secrete IL-21 ﹣ IFN-γ stimulates production of antibodies that promote ﹣ Guide B cells to make appropriate antibodies to clear a phagocytosis of microbes particular infection ▪ Antibodies act as complement proteins: enhances Like T helper type 2 cells, follicular help B cells eradicate phagocytosis by opsonization infections 4. TH1 also releases IL2 ﹣ IL-2 promotes growth and differentiation of other T cells Cytotoxic T Cells (TC) T Helper Type 2 Cells (TH2) CD8+ T cells become Cytotoxic T cells ﹣ Also known as killer T cells of Cytotoxic T lymphocytes (CTLs) Type 2 helper cells ﹣ Main function Stimulate immunity against parasites ▪ Kill cells that have been infected by viruses and 1. Infection by parasite intracellular bacteria 2. Cells of innate immune system release IL-4 ▪ Kill tumor cells and transplanted foreign cells ﹣ Naive T cell recognizes the antigen presented by the dendritic ▪ Eliminate reservoir of infection cell When there is an intracellular infection (e.g.viral infection) 3. In the presence of IL-4, T cell differentiates into TH2 ﹣ Dendritic cells from site of infection migrate to a nearby lymph 4. TH2 cell secretes IL-4, IL-5, IL-13 node and present viral antigens in the form of MHC I antigen ﹣ IL-4: stimulates B cells to produce IgE antibodies complex ﹣ IL-5: activates mast cells and eosinophils ALLCELLS ▪ CD8+ recognize the bound antigen ﹣ IL-13: stimulates production of mucus in intestines 5. Cytokines on the elimination of larger parasites: ▪ Nearby activated TH1 cells secrete IL-2 MIEI ▪ Recognition of the antigen by CD8+ T cell and the signals a. IgE coat parasite surface from T helper cells b. Mast cells and eosinophils bind to the Fc region of the bound − Result in the activation of CD8+ T cell antibodies to the parasite since they have receptors for it o Proliferates and differentiates into cytotoxic T cells c. Enzymes released by degranulation of the cells result to the and memory T cells destruction of the parasite Nice! Larger parasites cannot be phagocytosed Mucus from the intestines act to promote the expulsion of the parasites from the gut T Helper Type 17 Cells (TH17) Produces IL-17 and IL-22 ﹣ Aid in fighting against fungal and extracellular bacterial infections When there is an infection by fungi or extracellular bacteria, IL-6 and TGF-β are produced by cells of innate immunity ﹣ Naive T cells recognize the extracellular bacteria presented by Figure 25. Effector Cytotoxic T Cell Activation dendritic cell Effector Cytotoxic T Cells (Effector Tc) ﹣ IL-6 and TGF-β induce T cell to differentiate into TH17 Secretes more IL-2 and become self-stimulating IL-17 secreted by cells recruit leukocytes, specifically neutrophils ﹣ They leave the lymph node and migrate to the site of infection to the infection site ▪ To attack virally infected cells ﹣ Induce inflammation Under normal conditions ﹣ Neutrophils help fight against the extracellular bacteria and ﹣ All nucleated cells express MHC I on their surface fungi ﹣ Display the host’s proteins or self-antigens Patients with defective genes that encode for IL-17 If there is an infection ﹣ More susceptible to fungi and bacterial infections ﹣ These cells display foreign antigen IL-17 and IL-22 ﹣ Viral antigens are displayed on the infected cell surface as ﹣ Stimulate epithelial cells to produce antimicrobial peptides MHC I antigen complex that resist microbial invasion ﹣ Effector Tc recognize and bind these MHC I antigen complex on the infected cells YL5 03.06 Innate and Adaptive Immunity 11 of 14  ﹣ Cells killed by Tc are known as target cells T cells produce cytokines that activate important effector To perform its killing function pathways of innate immunity, for example, macrophages and NK ﹣ Tc needs to make direct contact with the target cell cells ﹣ Direct contact is mediated by T cell receptor and core Cells of the innate immune system (for example, macrophages) receptor CD8 produce cytokines such as IL-12 that direct T cells to become ▪ T cell receptor binds antigen displayed by MHC I molecule TH1 T cells that produce interferon-γ, and are important effector ▪ CD8 binds the MHC I molecule pathways for intracellular microbial organisms ﹣ Once contact has been established, Tc undergo degranulation Antibodies (opsonins) enhance the phagocytic pathway of the ▪ Granules migrate to the site of contact where contents are innate immune system released Complement type 2 receptor functions as a coreceptor for ﹣ Tc contains specific cytotoxic granules humoral immune responses, and links the complement pathway ▪ These proteins are synthesized and loaded into granules as via C3d with antibody production soon as naive CD8+ Tc encounters its specific antigen SUMMARY & KEY POINTS ▪ Perforin The innate and adaptive immune system are two separate − Forms pores in the membrane of target cell components of our immune system that work together to − Damages target cell end augment our bodies’ immune responses. o Forms a passage for other granule contents into the Anatomic barriers such as the skin and mucous membrane and target cell physiological barriers such as a high temperature, low pH, and ▪ Granzymes − Enter target cell through these pores Mghheskill chemical mediators are the major players in the innate immune system. o Cause apoptosis (programmed cell death) The main players in the adaptive immune response are B-cells o Target cell is degraded from within and T-cells which each play an important role in generating o Through activating enzymes such as nucleases and humoral immunity and cell-mediated immunity, respectively. by damaging the mitochondria B cell activation results in either the production of antibodies (via ▪ Granulysin differentiation into plasma cells) or strengthening our bodies’ − Antimicrobial activity and contributes to apoptosis of secondary immune responses (via differentiation into memory target cell B-cells). Degraded cells are rapidly ingested and digested by phagocytes T cell activation results in either the killing of cells (via Cytotoxic T cells also secrete cytokines differentiation into cytotoxic T-cells), the production of cytokines ﹣ TNF-α that activate cytotoxic T-cells and also B cells (via differentiation ﹣ IFN-γ into T-helper cells), or the suppression of T-cell responses (via ▪ Function to activate macrophages and recruit them to the differentiation into regulatory T-cells). site of infection REVIEW QUESTIONS IX. INNATE VS ADAPTIVE IMMUNITY #1: A workup on an ill child revealed low levels of com- Phagocytic cells crucial to nonspecific immune response plement C3 in her blood. Which one of the following involved in activating specific immune response presentations did this child most likely manifest? Soluble factors produced by specific immune response can A. Chronic Eczema augment activity of phagocytic cells B. Bernard Soulier syndrome Carefully regulated interplay between innate and adaptive C. Immune hemolytic anemia immune systems work to eliminate foreign pathogens O D. Recurrent infections with extracellular bacteria #2: What type of T-cell will interact with antigens presented via the MHC-I Presentation Pathway? O A. Cytotoxic T-cell and NK cells B. Helper T-cell C. CD8 and TCR D. Cytotoxic T-cell and Helper T-cell #3: Consider the following statements: (1) The Class II-associated Invariant chain Polypeptide (CLIP) digests the extracellular pathogen into smaller peptide fragments. (2) T-cells bind to the beta-II domain of the MHC-II molecule via the t-cell receptors. A. Statement (1) is true, while statement (2) is false B. Statement (2) is true, while statement (1) is false C. Both statements are true D. Both statements are false O#4: The T-cell interacts solely with the peptide fragment of Figure 26. Characteristics of Innate and Adaptive Immunity the MHC molecules presented in the surface of the cell A. LINKS BETWEEN INNATE AND ADAPTIVE IMMUNITY A. True O Macrophages, dendritic cells, and B cells express pattern B. False recognition receptors and serve as antigen-presenting cells for #5: Which interleukin is primarily associated with allergic the adaptive immune response reactions, helminthic responses, and plays a key role in the Cytokines produced by activated T-cells stimulate the expression regulation of immune responses? of important co-signaling molecules (B7-1/B7-2) on the surface A. IL-1 of antigen-presenting cells B. IL-2 YL5 03.06 Innate and Adaptive Immunity 12 of 14 0 C. IL-4 D. IL-10 down by proteasomes still have to go through the endoplasmic reticulum for processing. #6: Pus is a sign that the immune system is not working. 8. [D] — Affinity maturation in B cells increases as humoral response progresses. Somatic maturation occurs in the Ig V genes of A. True proliferating B cells. B. False 9. [A] — Co-stimulation is needed to enhance the first signal during #7: Which of the following statements is true? T cell activation. Without it, T cells which recognize the antigen A. In lymphocyte mobilization, an irreversible weak bond is formed remain in a prolonged state of inactivity known as anergy. between lymphocytes and the vascular endothelium as mediated 10. [D] — All of the options are results of heavy chain isotype by E-selectins. switching. B. Memory B-cells and Memory T-cells are created in response to REFERENCES previous infections and vaccinations. REQUIRED RESOURCES C. The CD40 receptor is an important co-stimulatory receptor found De Vera, M.J. (2023, September). Innate & adaptive & effector in T cells. molecules Parts 1-3 D. In the MHC-I antigen presentation pathway, viral peptides are no Frank Lectures. (2017, May 1). MHC I Antigen Presentation longer transported to the rough endoplasmic reticulum because pathway (FL-Immuno/25). these are already immediately degraded by proteasomes. https://www.youtube.com/watch?v=QsMaTgCf_aY #8: Consider the following statements: Frank Lectures. (2017, May 1). MHC II Antigen Presentation (1) Affinity maturation in B cells remains constant as Pathway (FL-Immuno/26). humoral response progresses. https://www.youtube.com/watch?v=VRuHxEUggS0 (2) Somatic maturation occurs in the Ig C genes of proliferating B cells. Frank Lectures. (2017, May 21). T cell Activation and A. Statement (1) is true, while statement (2) is false differentiation (FL-Immuno/31). Youtube. B. Statement (2) is true, while statement (1) is false https://youtu.be/JPh9P1aEfMI C. Both statements are true Frank Lectures. (2017, May 25). Helper T Cells: TH1 cells, TH2 O D. Both statements are false cells, TH17 cells, TFH cells and Treg cells (FL-Immuno/32). Youtube. https://youtu.be/Qs1H5P0SaLU #9: When does anergy occur in T cells? o A. When there is a lack of co-stimulation during T cell activation. SUPPLEMENTARY RESOURCES B. When B cells are unable to present an antigen to T cells. ASMPH Batch 2027. (2022). T03.08: Innate and Adaptive C. When the cytokine storm is so strong that it overwhelms the Immunity. machinery of T cells. ASMPH Batch 2027. (2022). T03.09: Effector Mechanisms. D. Anergy does not occur in T cells. Evaluate us! #10: Which of the following is a result of heavy chain isotype switching? ✔ Feedback Form: bit.ly/2028EvalsYearRoundForm A. Phagocyte response and complement activation by IgG ✔ Errata Tracker: tinyurl.com/HemaErrataTracker28 B. Better response to helminths from IgE FREEDOM SPACE C. Mucosal immunity via IgA D. All of the above E. None of the above Answer Key 1D, 2A, 3D, 4B, 5C, 6B 7B, 8D, 9A, 10D RATIONALE TO ANSWERS OF REVIEW QUESTIONS 1. [D] — Complement C3 is important in the complement pathway which leads to the formation of MAC and recruitment of phagocytes. Chronic eczema, immune hemolytic anemia, and Bernard Soulier syndrome would not involve the complement pathway. 2. [A] — MHC-I molecules present intracellular/endogenous antigens. When a cell is infected by an intracellular pathogen, peptides derived from the virus are presented by MHC-I for recognition by CD8 (Cytotoxic T-cells) and Natural Killer Cells (NK). 3. [D] — (1) Proteolytic lysosomal enzymes in the endolysosome are what digest the pathogen into peptide fragments. (2) T-cells bind to the beta-II domain via the CD4 co-receptor of the MHC-II molecule 4. [B] —T-cells interact with both the peptide fragment (via the T-cell receptor) and the MHC molecule (via the CD8/4 co-receptors) 5. [C] — IL-4 has role in allergic reaction and helminthic responses 6. [False] Pus is a sign that the immune system is working. Pus contains dead white blood cells, bacteria, tissue debris, etc. 7. [B] — A reversible weak bond is formed between lymphocytes and the vascular endothelium as mediated by E-selectins. The CD40 receptor is found in B cells, not T cells. In the MHC-I antigen presentation pathway, viral peptides which were broken YL5 03.06 Innate and Adaptive Immunity