Microbiology: Basic and Clinical Principles Chapter 12 - Adaptive Immunity PDF

Microbiology: Basic and Clinical Principles Second Edition Chapter 12 Adaptive Immunity Presented by Janet Dowding, Ph.D....

Microbiology: Basic and Clinical Principles Second Edition Chapter 12 Adaptive Immunity Presented by Janet Dowding, Ph.D. St. Petersburg College Copyright © 2023 Pearson Education, Inc. All Rights Reserved Clinical Case Copyright © 2023 Pearson Education, Inc. All Rights Reserved Introduction to Third-Line Defenses (1 of 2) After reading this section, you should be able to: Name the branches of adaptive immunity and compare adaptive to innate immunity. Compare and contrast T and B cells. Compare and contrast T helper versus T cytotoxic cells and discuss the various T helper cell subclasses. Define antigens, epitopes, and haptens and discuss the concept of immunogenicity. Copyright © 2023 Pearson Education, Inc. All Rights Reserved Introduction to Third-Line Defenses (2 of 2) After reading this section, you should be able to: Explain the role of T and B cell receptors in antigen recognition and state how receptor diversity comes about. Define self-tolerance and describe how and why the body screens immature T and B cells for this feature. Copyright © 2023 Pearson Education, Inc. All Rights Reserved The Adaptive Response is the Body’s Third and Final Line of Defense (1 of 9) Adaptive immune response IMMUNE SYSTEM INNATE ADAPTIVE IMMUNITY IMMUNITY Barrier Cellular and Adaptive defenses molecular defenses defenses Cellular response Chapter 11 Humoral response Chapter 12 Copyright © 2023 Pearson Education, Inc. All Rights Reserved The Adaptive Response is the Body’s Third and Final Line of Defense (2 of 9) Adaptive immune responses closely interact with innate immune responses Adaptive responses go into action when innate first- and second-line defenses fail to contain a threat Adaptive responses are a set of defenses that the body acquires as it responds to a specific antigen and learns to remember it Copyright © 2023 Pearson Education, Inc. All Rights Reserved The Adaptive Response is the Body’s Third and Final Line of Defense (3 of 9) Adaptive differ from innate responses: – Take longer to mount ▪ Primary exposure—Few days to more than a week between detection and response – Specific to a particular antigen Copyright © 2023 Pearson Education, Inc. All Rights Reserved The Adaptive Response is the Body’s Third and Final Line of Defense (4 of 9) Immunological memory – Secondary exposure to the same antigen is rapid and effective ▪ Frequently will not experience disease symptoms while our bodies eliminate the pathogen Copyright © 2023 Pearson Education, Inc. All Rights Reserved The Adaptive Response is the Body’s Third and Final Line of Defense (5 of 9) The adaptive immune system is subdivided into two branches which are highly dependent on each other: – Cellular response (T cell–mediated immunity) – Humoral response (antibody–mediated immunity) Goal of both branches is the same: Eliminate an identified antigen and remember it so that next time adaptive responses are faster Cellular and humoral responses both progress through four main stages Copyright © 2023 Pearson Education, Inc. All Rights Reserved Figure 12.2 General Steps ADAPTIVE IMMUNITY in an Adaptive Immune Cellular response Humoral response Response STAGE 1: ANTIGEN PRESENTATION Antigen-presenting cell (APC) Antigen Antigen T cell B cell STAGE 2: LYMPHOCYTE ACTIVATION T cells physically and chemically interact with B cells to fully stimulate a Cytokines humoral response. T cell activated B cell activated STAGE 3: LYMPHOCYTE PROLIFERATION AND DIFFERENTIATION Proliferation (clonal expansion) Differentiation Differentiation Memory T cell T effector cell Plasma cells are Memory B cell subsets effector B cells STAGE 4: ANTIGEN ELIMINATION AND MEMORY Lymphatic tissue Antigen Memory cells reside Memory cells reside in lymphatic tissue in lymphatic tissue and respond to later and respond to later antigen encounter Effector cells eliminate antigen antigen encounter Copyright © 2023 Pearson Education, Inc. All Rights Reserved The Adaptive Response is the Body’s Third and Final Line of Defense (6 of 9) Stage 1—Antigen Presentation – Dendritic cells and certain other white blood cells act as antigen-presenting cells (APCs) – APCs show antigen to T cells – B cells do not require APCs to show them antigens; instead they can directly interact with an antigen Copyright © 2023 Pearson Education, Inc. All Rights Reserved The Adaptive Response is the Body’s Third and Final Line of Defense (7 of 9) Stage 2—Lymphocyte Activation – Upon successful antigen presentation, lymphocytes are activated by a collection of released signaling molecules called cytokines – Activated T cells influence B cell activation Copyright © 2023 Pearson Education, Inc. All Rights Reserved The Adaptive Response is the Body’s Third and Final Line of Defense (8 of 9) Stage 3—Lymphocyte Proliferation and Differentiation – Activated B and T cells undergo multiple rounds of cell division to proliferate (clonal expansion) – Effector cells – engage in the response against the antigen – Memory cells – remain in lymphatic tissues to serve as a rapid recognition of the antigen if it’s encountered again later Copyright © 2023 Pearson Education, Inc. All Rights Reserved The Adaptive Response is the Body’s Third and Final Line of Defense (9 of 9) Stage 4—Antigen Elimination and Memory – Cellular and humoral responses collaborate to eliminate the antigen against which they were activated – Once the threat passes, effector cells die off – Memory cells endure for years in lymphatic tissues Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cells and B Cells Can Recognize Practically any Antigen (1 of 4) The most important adaptive immunity leukocytes (white blood cells) are lymphocytes – T cells – B cells Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cells and B Cells Can Recognize Practically any Antigen (2 of 4) T cells – Initially produced in the bone marrow – Thymocytes (immature T cells) migrate to the thymus – Undergo maturation B cells – Produced and mature in the bone marrow Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cells and B Cells Can Recognize Practically any Antigen (3 of 4) Mature B and T cells: – Present at relatively low levels in circulation – Mainly reside in lymphoid tissues T cells have roles in both the humoral and cellular branches of adaptive immunity B cells coordinate the humoral response by making antibodies Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cells and B Cells Can Recognize Practically any Antigen (4 of 4) Our immune system generates a vast array of B cells and T cells, which have the capacity to recognize virtually any antigen Copyright © 2023 Pearson Education, Inc. All Rights Reserved Immunogenicity (1 of 3) Antigen – Any substance that, if presented in the right context, may trigger an immune response – Mostly proteins or polysaccharides that come from a bacterium, virus, fungus, or protist – Cancer cells also frequently make proteins and/or polysaccharides antigens Copyright © 2023 Pearson Education, Inc. All Rights Reserved Immunogenicity (2 of 3) Any antigen that can successfully trigger an immune response is said to be immunogenic – Impacted by a combination of antigen size, molecular complexity, and chemical composition – Most immunogenic to least: ▪ Proteins > polysaccharides > lipids Copyright © 2023 Pearson Education, Inc. All Rights Reserved Immunogenicity (3 of 3) Haptens – Incomplete antigens – Unable to stimulate an immune response unless they are linked to a more complex protein or polysaccharide Copyright © 2023 Pearson Education, Inc. All Rights Reserved Antigen Features (1 of 6) Proteins (Example: hemagglutinin or neuraminidase proteins Increasing immunogenicity on influenza virions) Polysaccharides (Example: Haemophilus Complete influenzae capsule antigens polysaccharides) Lipids (Example: lipopolysaccharide (LPS) of Gram-negative bacterial cell wall) Small molecules Haptens (Example: various (incomplete drugs like penicillin) antigens) Copyright © 2023 Pearson Education, Inc. All Rights Reserved  Antigen Features (2 of 6) Epitopes—parts of an antigen that are recognized by B and T cells This is a model of an antigenic capsid protein from human papillomavirus. Its various epitopes are colorized. Epitopes Human papillomavirus of the antigen Copyright © 2023 Pearson Education, Inc. All Rights Reserved Antigen Diverse epitopes T cell receptor (TCR) Epitope of antigen Features (3 of 6) Antigen- binding site T cell receptors Covalent bond (disulfide bridge) (TCRs) and B cell T cell A given T cell recognizes Plasma membrane only one type of epitope. receptors (BCRs) Here the T cell can interact with the epitope are antigen represented as a triangle. Cytoplasm recognition B cell receptor (BCR) receptors Epitope of antigen Antigen- binding site B cell Plasma Covalent bond membrane A given B cell (disulfide bridge) recognizes only one type of epitope—here, Antibody represented as (secreted Cytoplasm a circle. BCR) Copyright © 2023 Pearson Education, Inc. All Rights Reserved Antigen Features (4 of 6) B cells and T cells have: – 1,000s of receptors on their surface – Each receptor on a cell recognizes the same epitope —monospecific Despite “one epitope type recognized per lymphocyte” rule… – Antigen recognition capacity is essentially unlimited because the body makes a vast number and variety of T and B cells Copyright © 2023 Pearson Education, Inc. All Rights Reserved Antigen Features (5 of 6) When a B or T cell binds to a specific epitope of an antigen the cell becomes activated Chemical signals cause B or T cell to undergo clonal expansion making clones – Some of the clones develop into effector cells, while others become memory cells Copyright © 2023 Pearson Education, Inc. All Rights Reserved Antigen Features (6 of 6) Activated B cells differentiate into effector cells called plasma cells – Plasma cells make antibodies, which are a secreted form of the BCR that binds to the antigen that stimulated the activation event T cell activation leads to differentiation into diverse effector cell lineages Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cells Fall into Two Main Classes: Helper or Cytotoxic Cells There are two main lineages of T cells: – T cytotoxic cells ( TC cells)—directly destroy infected or cancerous cells – T helper cells ( TH cells)—do not directly seek and destroy invaders; coordinate an adaptive immune response by stimulating other white blood cells We can tell these T cells apart by the presence of cluster of differentiation (CD) proteins Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Helper Cells (TH ) T sub H (1 of 4) T helper cells – Most abundant T cells – CD4+ T cells – “Help” coordinate the adaptive immune response by releasing cytokines – Activate other white blood cells (e.g., B cells, macrophages, T cytotoxic cells) – Main organizers of both the cellular and humoral branches of adaptive immunity Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Helper Cells (TH ) T sub H (2 of 4) Humoral branch of Cellular branch of adaptive immunity adaptive immunity T cytotoxic cell T helper cell B cell CD8 Cytokines CD4 Activated T cytotoxic cells Activated T helper cells B cells are stimulated by destroy infected cells, release cytokines that can T helper cells. Activated cancer cells, and stimulate or suppress B cells (plasma cells) transplanted tissues. other white blood cells. will secrete antibodies. Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Helper Cells (TH ) T sub H (3 of 4) Once activated, T helper cells may differentiate into a variety of subclasses that have specific functions Copyright © 2023 Pearson Education, Inc. All Rights Reserved Figure 12.7 Three Examples of T Helper Cell Subclasses CD4 Activated TH cells differentiate into diverse subclasses T helper cell subclasses T helper 1 cells T helper 2 cells T regulatory cells Cytokines Stimulate Stimulate T cytotoxic cells B cells CD8 Decrease Immune response once the threat has passed Cellular Humoral response response promoted promoted Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Helper Cells (TH ) T sub H (4 of 4) T helper 1 TH 1 cells – Activate T cytotoxic cells, macrophages, and natural killer cells to destroy intracellular pathogens T helper 2 TH 2  cells – Stimulate B cells to make antibodies T regulatory T  cells reg – Control functions of other white blood cells (e.g., dendritic cells, mast cells, B and T cells) Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cytotoxic Cells (TC ) T sub C T cytotoxic cells – Directly destroy cells that are virus infected, damaged, foreign/transplanted, or cancerous – CD8+ T cells Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cells and B Cells are Screened for Self- Tolerance (1 of 7) T and B cells recognize a wide variety of antigens due to gene shuffling mechanisms – Random process that gives rise to receptors that could bind to normal body cells – If allowed to mature, these lymphocytes would attack self-tissues To prevent that, the body has screening mechanisms that select for immune cells with self-tolerance Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cells and B Cells are Screened for Self- Tolerance (2 of 7) Yes Potentially Apoptosis T cells screened self-reactive? in thymus Yes No Recognizes MHCs? No Passes self-tolerance screening and migrates Apoptosis to lymphoid tissues B cells screened in bone marrow Could Yes make Apoptosis antibodies to self- No Passes self-tolerance antigens? screening and migrates to lymphoid tissues Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cells and B Cells are Screened for Self- Tolerance (3 of 7) For T cells, ensuring self-tolerance involves screening for the ability to recognize major histocompatibility complex (MHC) proteins MHCs are specialized “self-proteins” also known as human leukocyte antigens (HLAs) Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cells and B Cells are Screened for Self- Tolerance (4 of 7) As a T cell matures in the thymus it’s tested – Must recognize the “self” MHC – Cannot attack “self” cells Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cells and B Cells are Screened for Self- Tolerance (5 of 7) The mechanism for B cell self-tolerance screening differs from that of T cells – Occurs in the bone marrow – Process ensures future antibodies won’t cross-react with self-antigens and damage host tissues T and B cells that don’t exhibit self-tolerance are signaled to undergo apoptosis Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cells and B Cells are Screened for Self- Tolerance (6 of 7) Table 12.1 Comparing T Cells and B Cells Blank T cells B cells Adaptive immunity mediated: Cellular branch Humoral branch Include: T helper CD4  or THH  C D 4 super plus or T sub H Plasma cells (activated B cells that make stimulate B cells and other antibodies) Leukocytes T cytotoxic CD8  or Tc  C D 8 super plus or T sub C cells: seek and destroy cancer cells and cells infected with intracellular pathogens Site of maturation: Thymus Bone marrow Found in: Mainly in lymphatic tissues; Mainly in lymphatic tissues; low levels in low levels in circulation circulation Antigen recognition receptors: T cell receptors (T CRs) B cell receptors (B CRs), which are secreted as antibodies following B cell activation Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cells and B Cells are Screened for Self- Tolerance (7 of 7) Table 12.1 [continued] Blank T cells B cells Require antigen-presenting cell Yes No to become activated?* Memory cells made after Yes Yes activation? M H C 1 and 2. Major histocompatibility MHC I MH C 1 MHC I and II complex (MHC) proteins present on cell surface:* Considered antigen-presenting No Yes cells?* *Concept reviewed later. Copyright © 2023 Pearson Education, Inc. All Rights Reserved Cellular Branch of Adaptive Immunity After reading this section, you should be able to: Describe the cellular branch of adaptive immunity and name its key effector cells. Describe how the two types of MHCs present antigens, and summarize how MHCs impact transplant rejection. Explain the two-signal mechanism of T cell activation and discuss the factors that affect subclass differentiation. Summarize how superantigens activate T helper cells. Discuss how T helper and T cytotoxic cells eliminate antigens and summarize memory T cell roles. Copyright © 2023 Pearson Education, Inc. All Rights Reserved In the Cellular Response, T Cells Mobilize Against Diverse Antigens Both the cellular and humoral branches can be described as going through four general stages: 1) antigen presentation 2) lymphocyte activation 3) lymphocyte proliferation and differentiation 4) antigen elimination and memory Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 1: APCs Use MHC I or II to Present M H C 1 or 2 Antigens to T Cells (1 of 3) There are two main classes of MHCs important for antigen presentation: MHC I and MHC II – MHC I —found on the surface of all body cells except red blood cells ▪ Acts like the body’s uniform – MHC II —only on antigen-presenting cells (APCs) ▪ Macrophages, B cells, dendritic cells Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 1: APCs Use MHC I or II to Present M H C 1 or 2 Antigens to T Cells (2 of 3) Having two classes of MHCs makes sense if we consider that antigens can exist in two locations: – Either inside a host cell (intracellular antigen) ▪ Viral proteins inside an infected host cell ▪ Intracellular bacterium or protist ▪ Abnormal proteins made by cancer cells – Outside of a host cell (extracellular antigens) ▪ Extracellular bacteria, parasitic worms, and various fungi Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 1: APCs Use MHC I or II to Present M H C 1 or 2 Antigens to T Cells (3 of 3) Intracellular antigens are eliminated by killing the host cell – MHC I presents intracellular antigens to T cytotoxic cell Extracellular pathogens are directly attacked without the need to kill host cells – MHC II presents extracellular antigens to T helper cells Copyright © 2023 Pearson Education, Inc. All Rights Reserved  MHC I : Presenting Intracellular Antigens to M H C 1: T Cytotoxic Cells (1 of 4) All nucleated body cells An intracellular antigen (a viral protein in this case) is broken into have the capacity to Intracellular antigens fragments by the cell’s proteasome. present intracellular Proteasome The fragments antigens in the context of Antigen are transported ER fragments into the endoplasmic MHC I Transporter protein reticulum (ER) by a transporter protein. The protein MHC I–antigen fragments complex associate with MHC I in the ER. MHC I–antigen complexes make their way to the cell surface, where they are displayed for presentation to T cytotoxic cells. CD8 T cytotoxic cell Copyright © 2023 Pearson Education, Inc. All Rights Reserved  MHC I : Presenting Intracellular Antigens to M H C 1: T Cytotoxic Cells (2 of 4) When a virus infects a cell, viral proteins are made inside the host cell Viral proteins are chopped up by a proteasome Viral protein snippets are shipped into the cell’s endoplasmic reticulum There, MHC I molecules bind proteins to make MHC I - antigen complexes After binding, the MHC I – antigen complex migrates to the cell surface and displays antigen Copyright © 2023 Pearson Education, Inc. All Rights Reserved  MHC I : Presenting Intracellular Antigens to M H C 1: T Cytotoxic Cells (3 of 4) MHC I bind to a diverse collection of proteins in the ER— including self-proteins—and display them on the cell surface It is up to patrolling Tc cells to determine if the protein being displayed is a normal self-protein or not Only T cytotoxic cells that have been trained by APCs to recognize the given antigen can effectively patrol the body and eliminate cells displaying suspicious antigens Copyright © 2023 Pearson Education, Inc. All Rights Reserved  MHC I : Presenting Intracellular Antigens to M H C 1: T Cytotoxic Cells (4 of 4) To train T cytotoxic cells, APCs obtain viral antigen samples by being infected with the virus or by phagocytizing an infected host cell – If the APC is directly infected: ▪ It loads viral peptides with MHC I ▪ Displays them on the cell surface – If the infected host cell is phagocytized ▪ Viral antigens are engulfed ▪ Viral antigens complex with MHC I for presentation to T cytotoxic cells Copyright © 2023 Pearson Education, Inc. All Rights Reserved MHC II : Presenting Extracellular Antigens to M H C 2: T Helper Cells (1 of 3) Only APCs make MHC II they use it to present extracellular antigens to T helper cells – APCs phagocytize dead self-cells as well as potential invaders – APCs break down the ingested antigen – Snippets associate with MHC II proteins to form MHC II – antigen complexes – Migrate to the cell surface and display antigen Copyright © 2023 Pearson Education, Inc. All Rights Reserved MHC II : Presenting Extracellular Antigens to M H C 2: T Helper Cells (2 of 3) Antigen-presenting cell (dendritic cell Extracellular shown here) takes up extracellular antigen antigens by phagocytosis. The endocytic vesicle fuses with a Endocytic lysosome to make a vesicle phagolysosome, where the antigen is MHC II Lysosome broken down. Vesicles carrying MHC II then fuse Phago- with the lysosome phagolysosome. ER Pieces of the antigen associate with MHC II. MHC II– antigen complex CD4 T helper cell The MHC II–antigen complex migrates to the cell surface to be displayed so that it can interact with T helper cells. Copyright © 2023 Pearson Education, Inc. All Rights Reserved MHC II : Presenting Extracellular Antigens to M H C 2: T Helper Cells (3 of 3) Table 12.2 Major Histocompatibility Complex Features Type MHC I MH C 1 MHC MHC II M HC 2 Location On all body cells except red blood Only on antigen presenting cells; serves as the body’s uniform cells (A PCs); main APCs are dendritic cells Interacts CD8 on T cytotoxic cells CD4 on T helper cells with: Antigens Intracellular Extracellular antigens presented: antigens Copyright © 2023 Pearson Education, Inc. All Rights Reserved A Note on MHCs and Tissue Transplants MHCs are the main proteins that must be matched between a tissue donor and recipient If they are not closely matched then the recipient’s immune system will recognize the transplanted tissue as foreign Allorecognition—process that lymphocytes use to differentiate self from foreign M HCs Transplant waiting lists exist because finding an adequate match is often difficult Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 2: T Cells are Activated by Antigen- Presenting Cells in Lymphatic Tissues (1 of 6) APC bearing MHC-antigen complexes on its cell surface migrates to lymphoid tissues Interacts with T helper and T cytotoxic cells T cell with a compatible receptor binds to one of the antigens presented by the APC T cytotoxic cells will interact with antigens presented in the cleft of MHC I molecules T helper cells will bind to antigens present in the cleft of MHC II molecules Copyright © 2023 Pearson Education, Inc. All Rights Reserved  Stage 2: T Cells are Activated by Antigen- Presenting Cells in Lymphatic Tissues (2 of 6) APCs bearing processed antigens T cytotoxic cell migrate to the lymph node MHC I–antigen complexes on APC interact with TC cells. Only TC cells that can specifically recognize the displayed epitopes will bind. APC Antigen (dendritic cell shown here) MHC I MHC II MHC II–antigen complexes interact with TH cells. Only TH cells that can specifically recognize the displayed epitopes will bind. T helper cell Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 2: T Cells are Activated by Antigen- Presenting Cells in Lymphatic Tissues (3 of 6) Due to TCR specificity, each T cell can only recognize one epitope of the antigen APCs present diverse epitopes from diverse antigens It is possible for >1 T cell to interact with the APC and become activated Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 2: T Cells are Activated by Antigen- Presenting Cells in Lymphatic Tissues (4 of 6) T cells require two signals for full activation: – Primary activation signal—TCR interacting with the MHC–antigen complex – Secondary activation signal involves co- stimulatory proteins on the surface of the APC binding to co-stimulatory proteins on the T cell’s surface Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 2: T Cells are Activated by Antigen- Presenting Cells in Lymphatic Tissues (5 of 6) Primary Antigen- activation presenting signal cell (APC) CD4 MHC II TCR Antigen TH CELL ACTIVATION Co-stimulatory proteins Secondary activation signal The primary activation signal for T cytotoxic cells is a little different from what is shown above for T helper cells. Here the primary activation signal involves CD8 interacting with an MHC I–antigen complex. CD8 MHC I TC CELL ACTIVATION Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 2: T Cells are Activated by Antigen- Presenting Cells in Lymphatic Tissues (6 of 6) When signal 2 is received, a signaling cascade is sparked There are diverse co-stimulatory proteins and therefore diverse signaling cascades The type of cascade triggered determines what class of interleukins and other factors the T cell will make This cascade then defines the specialized subclass of T cell Copyright © 2023 Pearson Education, Inc. All Rights Reserved Superantigens and T Helper Cell Activation (1 of 2) Superantigens—antigens that are especially potent T helper cell activators – Examples: bacterial toxins (e.g., streptococcal exotoxin, staphylococcal toxic shock toxin) – Not processed and presented to T helper cells – Directly crosslink MHC II and the T helper cell TCR to cause a broad, nonspecific activation – Large numbers of T helper cells are activated – Release of dangerous levels of cytokines – Can lead to shock and even death Copyright © 2023 Pearson Education, Inc. All Rights Reserved Superantigens and T Helper Cell Activation (2 of 2) Antigen- presenting T helper cell (APC) cell CD4 MHC II TCR Superantigen Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 3: Activated T Cells Undergo Proliferation and Differentiation (1 of 6) In secondary lymphoid tissues, TH and TC cells bind to an epitope presented by an APC T cells to undergo clonal expansion During these cell division events, chemical signals influence cell differentiation Copyright © 2023 Pearson Education, Inc. All Rights Reserved  Stage 3: Activated T Cells Undergo Proliferation and Differentiation (2 of 6) T cell activation Proliferation Differentiation Various TH Functions: Activate B cells, T cytotoxic cells, macro- subclasses T helper cell phages, and other white (CD4+) blood cells Memory TH Cytokines Functions: Long-lived cells that remain in lymphatic Proliferating T helper cells tissues; quickly mount release cytokines that affect immune response upon T cytotoxic cell proliferation. re-exposure Memory TC T cytotoxic cell Functions: Seek and destroy (CD8+) Various TC cells infected with intracellular subclasses pathogens and cancer cells; activate macrophages In secondary lymphoid tissues Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 3: Activated T Cells Undergo Proliferation and Differentiation (3 of 6) Clones will recognize the same epitope that activated the original parent cell As APCs and T helper cells interact in lymphatic tissues, APCs release various cytokines The types of cytokines released influence what T helper cell subclasses develop – TH1 cells  IL -12 and INF -  – TH 2 cells  IL - 2 and IL - 4 Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 3: Activated T Cells Undergo Proliferation and Differentiation (4 of 6) TH1 cell response – Leads to the cellular response – Cytokines activate T cytotoxic cells TH2 cell response – Leads to the humoral response – Cytokines promote B cell maturation Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 3: Activated T Cells Undergo Proliferation and Differentiation (5 of 6) T helper cell (CD4+) Cytokines released by the APC APC influence which T helper cell subclasses develop Cytokines Interleukin 12 and Interleukin 2 and interferon gamma interleukin 4 T H1 TH 2 Stimulate cellular Stimulate humoral response response NK cells T cytotoxic cells Antibody production Macrophages by plasma cells Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 3: Activated T Cells Undergo Proliferation and Differentiation (6 of 6) The type of T helper cell subclass(es) that develop(s) impacts the immune system’s overall defense strategy An example of this is seen in leprosy: – TH 2 response causes lepromatous form ▪ Disfiguring and deadly – TH1 response causes tuberculoid form ▪ Not disfiguring and not lethal Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 4: Effector T Cells Eliminate Antigens & Memory T Cells Remain in Lymphatic Tissues As the threat subsides, memory cells remain in lymphatic tissues ready to rapidly proliferate and differentiate upon a subsequent exposure Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cytotoxic Cell Roles in Antigen Elimination (1 of 3) When a cell is infected with a virus or if it is cancerous, interferons are released – Recruits activated T cytotoxic cells to the area – Enhances MHC I production inside host cells – Puts the immune system on high alert Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cytotoxic Cell Roles in Antigen Elimination (2 of 3) When the TCR of a patrolling T cytotoxic cell binds to an MHC I – antigen complex: – Releases perforins ▪ Forms pores in the target cell – Releases granzymes ▪ Enter through the pore ▪ Break down host cell proteins ▪ Induce apoptosis Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Cytotoxic Cell Roles in Antigen Elimination (3 of 3) Macrophage Interferons released by cancer cells and/or infected cells attract activated TC cells Antigen NK cell Cancer cell or Cytokines released by infected cell TC cells attract NK cells and macrophages Perforins form pores Pore Granzymes enter through pores and break down proteins The targeted cell undergoes apoptosis. Macrophages and NK cells clear the dead cells. Copyright © 2023 Pearson Education, Inc. All Rights Reserved T Helper Cell Roles in Antigen Elimination T helper cells do not directly attack invaders, cancer cells, or infected host cells Support the action of the cells that will actually do the work in the immune response – B cells, T cytotoxic cells, and innate immunity leukocytes such as macrophages and natural killer cells – THH1 cells favor the action of T cytotoxic cells – TH 2 cells promote the humoral response Copyright © 2023 Pearson Education, Inc. All Rights Reserved Humoral Response of Adaptive Immunity After reading this section, you should be able to: Explain how T-dependent and T-independent antigens activate B cells. Describe the basic structural and functional features of antibodies. Explain what isotype switching is and state why it’s advantageous. Discuss the structural and functional features of each of the five antibody classes. Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 1: B Cells are Antigen-Presenting Cells B cells have two different paths to activation: – T-independent antigens bind to B cells and instigate a direct activation cascade – T-dependent antigens require T helper cells (especially TH2 cells) for full activation Copyright © 2023 Pearson Education, Inc. All Rights Reserved  Stage 2: B Cells are Activated by T-dependent and T-independent Antigens (1 of 4) Most antigens are T dependent, and require T helper cells to fully activate B cells Primary activation signal Extracellular MHC II–antigen CD4 T cell receptor antigen complex CD40 CD40L T helper cell B cell Cytokines An extracellular antigen binds to a The antigen enters the cell by The MHC II–antigen complex Cytokines are B cell receptor (BCR). endocytosis, is processed, and on the B cell surface is released upon Secondary epitopes are displayed on the cell bound by a T helper cell that proper TH cell surface by MHC II. can recognize the presented activation binding. epitope. signal Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 2: B Cells are Activated by T-dependent and T-Independent Antigens (2 of 4) Activation pathway is a two-signal mechanism: – First signal is the binding of the antigen to the B cell receptor (BCR) ▪ B cell with a bound receptor internalizes the antigen, processes it, and displays it ▪ T helper cells then interact with the MHCII-antigen complex on the B cell surface – Co-stimulatory proteins interact ▪ T helper cell releases activating cytokines Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 2: B Cells are Activated by T-dependent and T-independent Antigens (3 of 4) Repetitive antigens may act as T-independent antigens – Example: bacterial capsule polysaccharides In T-independent activation, multiple BCRs on the given B cell directly bind to the antigen – Causes proliferation and differentiation to make plasma cells – Limited capacity for memory – Do not tend to confer the same long-term protection as T-dependent antigens Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 2: B Cells are Activated by T-dependent and T-independent Antigens (4 of 4) Polysaccharide (T-independent Epitope antigen) B cell receptor Multiple binding events activate B cell Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 3: Activated B Cells Proliferate and Differentiate Into Plasma Cells & Memory Cells (1 of 2) Once fully activated, B cells undergo proliferation and eventually differentiate into effector cells and memory cells – All the resulting B cell clones recognize the exact same epitope of the antigen – Clones become effector cells called plasma cells and a small number become memory B cells that will reside in lymphatic tissues Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 3: Activated B Cells Proliferate and Differentiate Into Plasma Cells & Memory Cells (2 of 2) B cell activation Proliferation Differentiation Plasma cells Different epitopes Release antibodies Antigen Only this epitope of the antigen Memory cells can activate Long-lived cells that this B cell remain in lymphatic tissues Quickly mount immune response upon If the B cell interacts with an re-exposure epitope on a T-independent antigen, then a T helper cell is needed to advance to poliferation. If the B cell interacts with epitopes on a T-dependent antigen, then the B cell can proliferate without further interactions. Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 4: Antibodies Help Eliminate Antigens (1 of 3) Plasma cells secrete proteins called antibodies, also known as immunoglobulins (Ig) Antibodies bind to the antigen that triggered the B cell’s activation Antibodies can activate complement cascades, neutralize antigens, and promote phagocytosis of targeted antigens Copyright © 2023 Pearson Education, Inc. All Rights Reserved  Stage 4: Antibodies Help Eliminate Antigens (2 of 3) Antibodies Activate complement Increase phagocytosis can… Complement Phagocytosis is enhanced Pathogen as antibodies precipitate, protein Neutralize antigens agglutinate, or opsonize antigens. Antibodies block toxins or antigens Complement from binding to host cells cascade leads to Cytolysis Opsonization Inflammation Precipitation Agglutination Opsonization Water Copyright © 2023 Pearson Education, Inc. All Rights Reserved Stage 4: Antibodies Help Eliminate Antigens (3 of 3) Activated complement proteins lead to cytolysis, inflammation, and opsonization Antibodies directly neutralize antigens to prevent them from interacting with target host cells Antibodies increase phagocytosis by: – Precipitation – Agglutination – Opsonization Copyright © 2023 Pearson Education, Inc. All Rights Reserved Antibody Structure and Isotopes (1 of 4) An antibody’s single-unit, monomeric structure consists of: – 2 heavy chains – 2 light chains – Held together by covalent bonds––specifically, disulfide bonds Copyright © 2023 Pearson Education, Inc. All Rights Reserved Antibody Structure and Isotopes (2 of 4) The tips of the molecule are the antigen-binding sites Antigen – sometimes referred to Epitope Antibody recognizes as the antibody’s one specific epitope Antigen-binding variable region site Antibody’s constant Light chain region is the stem portion of the “Y”- shaped Covalent bonds (disulfide bridges) molecule Heavy chain Antibody Copyright © 2023 Pearson Education, Inc. All Rights Reserved Antibody Structure and Isotopes (3 of 4) A given plasma cell makes antibodies that all recognize the same epitope A given B cell can’t change what epitope it recognizes, it can undergo isotype switching – Alters what class of antibody is made – 5 antibody isotypes: IgG, IgA, IgM, IgE, IgD Different isotypes have different specializations and also predominate in different areas of the body Copyright © 2023 Pearson Education, Inc. All Rights Reserved Antibody Structure and Isotopes (4 of 4) Table 12.3 Five Antibody Isotypes Isotype IgG The figure illustrates I g G as a Y-shaped monomer. IgA The figure illustrates I g A as a Y-shaped monomer, and two monomers attached end to end as a dimer. IgM The figure illustrates I g M as a Y-shaped monomer, and five monomers arranged radially as a pentamer. IgE The figure illustrates I g E as a Y-shaped monomer. IgD The figure illustrates I g D as a Y-shaped monomer. Structure Monomer Monomer or Monomer or Monomer Monomer dimer pentameter Proportion of Most abundant Second most Third most Rare Rare antibody pool abundant abundant Neutralization Strong Strong Some Negligible Negligible Complement Strong Some Strong Negligible Negligible activation Opsonization Strong Some Negligible Negligible Negligible Agglutination/ Some Negligible Strong Negligible Negligible precipitation Half-life 21 days 6 days 10 days 2 days 2 days Notes Crosses Main antibody in Made early in Fights parasites; Bound to B cells; placenta; breast milk; infection; mediates allergic poorly made later in resistant to large structure responses understood infection destruction by limits where stomach acid it migrates Copyright © 2023 Pearson Education, Inc. All Rights Reserved Immunoglobulin G (IgG) IgG – Constitutes 85% of antibody in human blood – Found in all bodily fluids – Longest half-life of about 21 days in circulation – Detecting IgG to a particular antigen indicates the patient has been exposed to that antigen – Monomer – Crosses the placenta, activates complement, neutralizes antigens and is a powerful opsonin Copyright © 2023 Pearson Education, Inc. All Rights Reserved Immunoglobulin A (IgA) IgA – Accounts for up to 15% of total antibodies – Half-life of about 6 days – Prevalent in mucous (e.g., mucous membranes of the gut, respiratory tract, and urogenital tract) – Found in secretions (e.g., tears, saliva, sweat, and breast milk) – Exists as a monomer or as a dimer – Neutralizing and opsonization capabilities Copyright © 2023 Pearson Education, Inc. All Rights Reserved Immunoglobulin M (IgM) IgM – Mainly in blood – Accounts for up to 10% of total antibodies – Half-life of about 10 days – Made early in infection upon a primary antigen exposure – Exists as either a monomer or pentamer – Functions in agglutination, precipitation, and complement activation (not a strong opsonin) Copyright © 2023 Pearson Education, Inc. All Rights Reserved Immunoglobulin E (IgE) IgE – Present in very low concentrations – Found mostly in lungs, skin, and mucous membranes – Monomer with a half-life of only 2 days – Functions to fight parasites and mediate allergic responses – Causes mast cells and basophils to release allergy mediators (e.g., histamine, leukotriene) Copyright © 2023 Pearson Education, Inc. All Rights Reserved Immunoglobulin D (IgD) (1 of 2) IgD – Sparsely represented antibody – Mainly found on the surface of B cells – 2-day half-life – Monomer – Precise function remains unknown Copyright © 2023 Pearson Education, Inc. All Rights Reserved  Immunoglobulin D (IgD) (2 of 2) Some silly memory devices to help keep track of the various cells involved Fog of (Microbial) War Here are some silly, but hopefully memorable, ways to remember the cast of key characters in adaptive Immunity. Field Scout: General: T Helper Cell Antigen-Presenting Cell These commanders mainly hang out in secondary lymphatic Dendritic cells are the main tissues waiting for APCs to bring back processed antigens APCs. These scouts search held in the grasp of MHC II. Once activated, they the body and collect antigens release cytokines that help by phagocytosis. Using MHC I mobilize B cells and T cytotoxic and MHC II, they display cells for the coming battle. antigens on their cell surface and Sharpshooter: migrate to central B Cell command When activated, B (secondary lymphatic cells become plasma tissues)to show the cells that pump out collected antigens antibodies. A given B to T cells. cell can only make Foot Soldier: T Cytotoxic Cell These warriors signal infected cells and antibodies that cancer cells to commit suicide (apoptosis). recognize one type Antigens in the clutches of MHC I activate these of epitope. cells; that means almost any body cell as well as APCs can activate these lethal agents. Copyright © 2023 Pearson Education, Inc. All Rights Reserved A Deeper Exploration of Humoral Memory After reading this section, you should be able to: Describe immunological memory and compare it to a primary response. Define antibody titer and state how it differs in a primary versus secondary antigen exposure. Name and describe the four categories of adaptive immunity and state which confer long-term protection and why. Copyright © 2023 Pearson Education, Inc. All Rights Reserved Memory Cells Allow for Fast, Amplified Response Upon Re-exposure to an Antigen (1 of 4) Effector cells die off once the threat subsides, but memory cells are long-lived Memory cells reside in lymphoid tissues and provide immunological memory Our memory cells allow for a rapid reactivation of the cellular and humoral adaptive response if the same antigen is encountered again later Copyright © 2023 Pearson Education, Inc. All Rights Reserved Memory Cells Allow for Fast, Amplified Response Upon Re-exposure to an Antigen (2 of 4) Secondary immune response requires the coordinated activity of memory B and T cells Primary exposure to a given antigen generates IgM antibodies first, then IgG In a secondary response to the same antigen: – Activated memory cells Quickly generate a high antibody titer of high affinity IgG antibodies and only a small amount of IgM antibodies Copyright © 2023 Pearson Education, Inc. All Rights Reserved  Memory Cells Allow for Fast, Amplified Response Upon Re-exposure to an Antigen (3 of 4) Primary Antigen Exposure Secondary Antigen Exposure lgG ANTIBODY TITER lgM lgG lgM 0 7 14 21 28 0 7 14 21 28 DAYS DAYS Copyright © 2023 Pearson Education, Inc. All Rights Reserved Memory Cells Allow for Fast, Amplified Response Upon Re-exposure to an Antigen (4 of 4) Serological testing assess a patient’s antibody titers to help determine if a person has been exposed to a disease or was vaccinated (e.g., HIV, dengue, Zika, Chikungunya, and SARS-CoV-2) Convalescent plasma can be used in infectious diseases for which there are no approved therapies Monoclonal antibodies are antibodies that are highly specific for a single epitope Copyright © 2023 Pearson Education, Inc. All Rights Reserved Humoral Immunity is Acquired Naturally or Artificially, and is Either Passive or Active (1 of 2) There are four classifications for adaptive immunity: – Naturally acquired active immunity – Artificially acquired active immunity – Naturally acquired passive immunity – Artificially acquired passive immunity Copyright © 2023 Pearson Education, Inc. All Rights Reserved Humoral Immunity is Acquired Naturally or Artificially, and is Either Passive or Active (2 of 2) Is the process natural? Yes No Naturally acquired Artificially acquired immunity immunity Is the individual benefiting from the antibodies the one who made them? Yes No Yes No Naturally Naturally Artificially Artificially acquired acquired acquired acquired active passive active passive immunity immunity immunity immunity Immunity Antibodies Vaccination Antivenom from pass triggers neutralizes a previous across the immune toxins infection placenta response Copyright © 2023 Pearson Education, Inc. All Rights Reserved Natural Active Immunity Naturally acquired active immunity – Contracting an infection that triggers the patient’s immune system – Memory cells and antibodies are formed – Confers long-term protection – Can be developed from either symptomatic or asymptomatic infections Copyright © 2023 Pearson Education, Inc. All Rights Reserved Artificial Active Immunity Artificially acquired active immunity – Vaccines to trigger an immune response – Results in formation of memory cells and antibodies – Confers long-term protection Copyright © 2023 Pearson Education, Inc. All Rights Reserved Natural Passive Immunity Naturally acquired passive immunity – Patient receives antibodies to an antigen through nonmedical means – Example: maternal antibodies – No memory cells or antibodies – Does Not confer long-term protection – Temporary protection Copyright © 2023 Pearson Education, Inc. All Rights Reserved Artificial Passive Immunity Artificially acquired passive immunity – Patient receives protective antibodies from a medical treatment – Source of the antibodies is often a horse, rabbit, or goat – Antiserum—preparation of antibodies developed to neutralize specific toxins or venoms – Temporary protection – Patient may have an immune response Copyright © 2023 Pearson Education, Inc. All Rights Reserved Visual Summary: Innate Immunity and Adaptive Immunity (1 of 2) Three Lines of Immune Defense Chapter 11 Chapter 12 Pathogen-specific responses INNATE INNATE Cellular response Antigen exposure (viruses, bacteria, BARRIER CELLULAR ADAPTIVE T cell mediated fungi, protists, cancer DEFENSES AND DEFENSES cells, transplanted Humoral response tissue, etc.) MOLECULAR B cell/antibody mediated DEFENSES Invader overcomes Invader is detected first- and second-line defenses by third-line defenses First-Line Defenses Second-Line Defenses MECHANICAL CHEMICAL Molecular defenses Inflammation Cytokines: Stimulate inflammation andVASCULAR LEUKOCYTE RESOLUTION tissue repair; recruit leukocytes; generate CHANGES RECRUITMENT fever; promote leukocyte and lymphatic Chemical alarmCytokines recruit Inflammation tissue development; antiviral; immune signals increase leukocytes. signals system regulation blood flow andNeutrophilis and decrease; Tears rinse Lysozyme vessel macrophages tissue repair microbes away kills bacteria permeablility.phagocytize initiated. Iron-binding proteins: Limit availability of free iron to reduce bacterial growth invaders. Damaged Free iron tissue Host iron- binding Chemical Macrophage protein signals Mucus traps Stomach acid invaders limits pathogens Monocyte Bacterium Neutrophil PHYSICAL (throughout body) Complement proteins: PATHWAYS TO ACTIVATION Fever Hormone level changes, Complement shivering, and increased C3 cascade metabolism raise body Microbes AMP destroys leads to temperature––also, blood blocked by skin pathogens Opsonization Cytolysis Inflammation vessels constrict such that heat loss through the skin is reduced. Lymphoid TissuesLeukocytes of Innate Immunity PRIMARY LYMPHOID SECONDARY LYMPHOID Granulocytes Agranulocytes TISSUES TISSUES Monocytes (mature Adenoids Neutrophilis: Basophils: into macrophages): Thymus Phagocytic; Fight parasites; Phagocytes; serve as MALT Tonsils fight pathogens roles in allergy antigen-presenting cells Peyer’s patches Bone (especially Dendritic cells: Appendix marrow Spleen bacteria) Phagocytes; serve as Eosinophils: Mast cells: antigen-presenting cells Fight parasites; Fight parasites Lymph nodes Natural killer cells: Innate roles in allergy and bacteria; roles in allergy; immunity lymphocytes; fight reside in tissues pathogens and cancer cells Copyright © 2023 Pearson Education, Inc. All Rights Reserved Visual Summary: Innate Immunity and Adaptive Immunity (2 of 2) Third-Line Defenses (Adaptive Immunity) Antibodies Antigen Antibody STAGE 1: Antigen-presenting recognizes ANTIGEN cells (APCs) one specific PRESENTATION epitope Antigen- binding MHC I MHC II site B cells (activated) Light Epitopes STAGE 2: T cytotoxic cells T helper cells chain LYMPHOCYTE (activated) (activated) ACTIVATION Covalent bond CD8 CD4 Heavy (disulfide bridge) chain Antibodies can: Neutralize antigens STAGE 3: Antibodies block toxins or antigens from LYMPHOCYTE binding to host cells. PROLIFERATION ANDEffector Memory Effector Memory Plasma Memory Activate complement DIFFERENTIATION Tc cells Tc cells TH cells TH cells cells B cells Complement activation leads to cytolysis, opsonization, and inflammation. STAGE 4: Destroy Memory Release Memory Plasma cellsMemory Increase phagocytosis ANTIGEN infected cells, factors that release Phagocytosis is enhanced as antibodies ELIMINATION cancer cells, help T antibodies agglutinate, precipitate, or opsonize AND MEMORY and cytotoxic cell antigens. transplanted and B cell Five antibody isotypes: tissue activation lgG Crosses placenta; made Lymphocytes of Adaptive Immunity later in infection Activated Site of Antigen Require APCMajor histo- lgA cell types maturationrecognitionto become compatibility activated? complex (MHC) In secretions T cytotoxic cells: T cytotoxic Interact with lgM cell antigens presented (CD8+ or TC) Thymus T cell in the context of Made early in T cells receptors Yes MHC I infection (TCRs) (cellular response) T helper cells: T helper Interact with lgE Fights parasites; cell antigens presented (CD4+ or TH) in the context of mediates allergic MHC II responses lgD Bound to B Plasma cells B cell receptors Directly interact (activated B cells that Bone cells; poorly (BCRs), which with antigens B cells make antibodies) marrow understood are secreted as antibodies No (humoral response) following B cell activation Copyright © 2023 Pearson Education, Inc. All Rights Reserved Think Clinically: Be S.M.A.R.T. About Cases (1 of 7) Summary of the case: – Hassan, a middle schooler, complained of feeling tired and leg pains – His dad gave him Tylenol and sent him to bed earlier assuming he was just suffering from overexertion at soccer practice – A few weeks later Hassan had a fever and complained that he felt short of breath – His mom took him to the local urgent care center – Hassan was treated for a suspected bacterial infection – The doctor advised if symptoms worsen, or if new symptoms developed, then she should immediately follow up with Hassan’s pediatrician Copyright © 2023 Pearson Education, Inc. All Rights Reserved Think Clinically: Be S.M.A.R.T. About Cases (2 of 7) Summary of the case: – Hassan’s fever resolved within a few days of starting antibiotics – Over the next few weeks, Hassan’s leg pain worsened and he could barely muster the energy to go to school – One morning Hassan called his mom to come and get him from school because he had spiked another fever and the pain in his legs was causing him to limp – Kelly’s mom got him into the pediatrician’s office for that day. – The pediatrician treated Hassan as though he had another bacterial infection, but because of the bone pain and splenomegaly, the doctor ordered additional tests (complete blood count, a peripheral blood smear, several tests to profile the coagulation features of Hassan’s blood, and various serum chemistry tests) Copyright © 2023 Pearson Education, Inc. All Rights Reserved Think Clinically: Be S.M.A.R.T. About Cases (3 of 7) Summary of the case: – Test results suggested that Hassan was suffering from acute lymphoblastic leukemia (ALL) – Hassan was referred to a pediatric oncologist – The oncologist explained that patients with ALL usually have: ▪ An increased number of abnormal lymphocytes in their circulating blood ▪ These lymphocytes divide uncontrollably in the bone marrow ▪ Cause pain as they crowd out healthy cells and normal tissue in the bones ▪ Patients tend to develop a low red blood cell count causing anemia and fatigue Copyright © 2023 Pearson Education, Inc. All Rights Reserved Think Clinically: Be S.M.A.R.T. About Cases (4 of 7) Summary of the case: – More tests led Hassan to being diagnosed with a type of ALL that causes immature B cells (pre-B cells) to divide uncontrollably – Hassan’s cancer did not respond well to chemotherapy – His oncologist recommended radiation to eliminate his immune system cells and followed up with a bone marrow stem cell transplant – Hassan’s older sister was a compatible donor (Only about a 25 percent chance that a sibling will be a compatible tissue donor!) – A year out from the transplant, Hassan had not developed graft-versus- host disease (GVHD) ▪ Scenario where the white blood cells that develop from the donated bone marrow attack the tissues of the new body they inhabit because they are seen as “foreign” Copyright © 2023 Pearson Education, Inc. All Rights Reserved Think Clinically: Be S.M.A.R.T. About Cases (5 of 7) Summary of the case: – After years of therapy and monitoring, Hassan was eventually declared cured – Based on his antibody titers, he had to get vaccinated with a number of routine childhood vaccines that he had already completed well before his cancer onset – After his revaccination, his titer levels were sufficiently high to be considered protective – This was another good indicator that Hassan had re- established a normal immune system Copyright © 2023 Pearson Education, Inc. All Rights Reserved Think Clinically: Be S.M.A.R.T. About Cases (6 of 7) 1. Predict some of the basic abnormalities that would have been detected upon microscopic evaluation of Hassan’s blood before treatment. Explain how these observed features relate to Hassan’s symptoms. 2. Despite an increase in B lymphocytes in his blood before his treatment, why would Hassan’s antibody titers to illnesses that he had been previously vaccinated against be so low as to necessitate revaccination? 3. What category of adaptive immunity would Hassan develop upon revaccination? Explain your reasoning. Copyright © 2023 Pearson Education, Inc. All Rights Reserved Think Clinically: Be S.M.A.R.T. About Cases (7 of 7) 4. Assuming Hassan did have a bacterial infection when he went to the urgent care center, what would his likely antibody isotypes and general titer profiles possibly have looked like compared with those of a healthy patient? 5. Based on your chapter readings, explain what the phrase “compatible tissue donor” means and discuss why this reduces the risk for GVHD. 6. Explain what type of immunological response would develop if an incompatible bone marrow tissue was used for a transplant; you should also describe how such a response would progress. 7. Hassan’s dad asks you why siblings aren’t guaranteed to be good tissue matches. As a member of Hassan’s healthcare team, what would you say? Copyright © 2023 Pearson Education, Inc. All Rights Reserved Copyright This work is protected by United States copyright laws and is provided solely for the use of instructors in teaching their courses and assessing student learning. Dissemination or sale of any part of this work (including on the World Wide Web) will destroy the integrity of the work and is not permitted. The work and materials from it should never be made available to students except by instructors using the accompanying text in their classes. All recipients of this work are expected to abide by these restrictions and to honor the intended pedagogical purposes and the needs of other instructors who rely on these materials. Copyright © 2023 Pearson Education, Inc. All Rights Reserved