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Adaptive Immune System EDWARD HO, KEERTHANA RAJKUMAR, GURPREET VIRK, & JUN YU (JERRY) ZHOU PHM142 Fall 2016 Instructor: Dr. Jeffrey Henderson Overview • Introduction of Adaptive Immune System • T Cell Activation & Function • B Cell Activation & Function • Disease of the Adaptive Immune System • Application of the Adaptive Immune System • Summary Immune System: An overview • Protects against pathogen or other potentially damaging foreign bodies. • Identifies a variety of pathogenic threats, including viruses, bacteria, parasites & fungi. • Distinguishes the body's own healthy cells from cancer cells or cells from another individual. • Relies on Innate immune response - first line of defense Alberts et al. 2008 Innate vs. Adaptive Immunity • Unique and highly specific antigen receptor. • Tailored & potent response against the infecting pathogen. • Memeory of the antigens protect to protect from reinfection. Dranoff G. Nat Rev Cancer. 2004 Adaptive Immune System B and T lymphocytes are cells responsible for generating an adaptive immune responses. Two classes of adaptive imumune response : • Humoral Response Naïve B cells → Plasma B cells (antibody production) • Cell-mediate Response Naïve T cells -> Effector T cells (cytotoxin & cytokine production) Alberts et al. 2008 B Cell Activation Naïve B cells are activated by antigen presenting cells in the lymph nodes. Binding of specific antigen to a B-cell receptor results in signaling cascade and presentation on MHC-II on its surface. Murphy et al. 2008. B Cell Specific Mechanisms Affinity Maturation increases specificity of B cell receptor (over period of days). 1. Somatic hypermutation: Activation-induced cytidine deaminase (AID) increases variableregion diversity on the antibody. Ultimately, antibodies of higher affinity are produced. 2. Isotype switching: generates IgG, IgM, IgD, IgA or IgE, each with different effector functions. Murphy et al. 2008. B Cell Function Essential function similar to enhanced innate complement system but for a prolonged period of time • Neutralization • Opsonization • Compliment activation Murphy et al. 2008. T Cell Activation Naïve T cells interacts with antigen presenting cells in the lymph node or in circulation to become activated. When activated, effector T cells can interact with MHC I/MHC II complex and alter the response within other cells. Two main types of effector T cells: CD4+ and CD8+ T cells Formation of immunological synapse is critical to the secretion of cytokines (CD4+) and cytotoxins (CD8+). Murphy et al. 2008. T Cell Function Cytotoxic T Cells (CD8+) – Destroys target cell by infusing cytotoxin (perforin & granzymes) or by inducing apoptosis. Helper T Cells (CD4+) - Assists in cell-mediated immunity and humoral immunity, usually by costimulation. Different Subtypes of Helper T cells: Th1 – Stimulate immune responses against intraceullar pathogen using IL-2 & IFN-y. Th2 – Stimulate immune responses against extracellular pathogen using IL-4 & IL-5. Th17 – Stimulate immune responses at mucosal surfaces using IL-17. Treg – Suppresses immune responses to prevent overactivation. Michael LD. Nature. 2016 Severe Combined Immunodeficiency • 1 in 100,000 births. • Group of genetically inherited disorders that cause severe abnormalities of the adaptive immune system. • Reduced or malfunctioning T cells and B cells. • No humoral responses nor cell-mediated immune responses. Genetic Fact Sheets for Parents. 2014 X-linked SCID aka ‘bubble boy disease’ • Most common form of SCID. • Mutation on xq13.1 locus of the X-chromosome. • A common cytokine receptor protein (IL-2R 𝛾 chain) is CBS News. 2011 defective. Resulting in defects in cytokines signalling. • T cells and NK cells fail to develop, essentially no adaptive immune response. • Treatment: Bone Marrow transplantation and gene therapy. In 1970s, a boy had to live in a sterile environment (inside a plastic bubble). Application of the Adaptive Immune System Adoptive Cell Transfer (ACT) is an experimental treatment that utilizes autologous tumor infiltrating lymphocytes (TILs) to treat against nonchemoresponsive cancer. 1. Harvest: Tumor is broken down into smaller fragments and TILs harvested from patient. 2. Culture: CD4+ and CD8+ TILs are co-cultured with tumor fragments in proliferating environment (IL-2 & feeder cells). 3. Selection/Expansion: TILs with tumor antigen recognition AND effector function are expanded. 4. Reinfusion: Up to 1011 TILs are infused into the bone marrow irradiated/lymphodepleted patient. Steven et al. Science. 2018 Personalized Medicine TILs can be genetically modified to expresses antigen receptor that will target specific tumor antigen. Transgenic T cell Receptor Chimeric Antigen Receptor (Antibody variable domain with CD3 costimulatory domain) Michael et al. Nat Rev Cancer. 2013 Summary Adaptive lymphocytes are highly specific and have memory of specific antigens. Two broad classes: Antibody Response and Cell-mediated Response. • Carried out by B cells and T Cells, respectively. T cells become two type of effectors T cells -> Interacts with antigen presenting cells in the lymph node. • • Cytotoxic T cells (CD8+): secretes cytotoxin and induces apoptosis. Helper T cells (CD4+): secretes cytokines and stimulates immune response. B cells becomes plasma B cells -> Interact with antigenpresentings in the lymph node. • Plasma B cells produces antibodies: neutraliation, opsionzation and compliment activation. Severe Combined Immunodeficiency (SCID) • • Mutation in T cell or B cell genes = Reduced or malfunctioning T cells of B cells. Ie. XSCID: Mutation of xq13.1 on X- chromosome. IL-2R common 𝛾 chain is defective. Thus, T cells and NK cells fail to develop due to defects in cytokine signalling. Adoptive Cell Transfer - utilizes autologous tumor infiltrating lymphocyte to treat against non- chemoresponsive cancer. • Four general stages: Harvest, Culture, Selection/Expansion, and Reinfusion. References 3D structure of antibody protein. Protein Data Base Educational Portal. Retreived from https://pdb101.rcsb.org/motm/21. Alberts B, et al. Molecular Biology of the Cell 5th Edition. New York: Garland Science; 2008. "Bubble Boy" 40 years later: Look back at heartbreaking case. CBS News. 2011. Retrieved from http://www.cbsnews.com/pictures/bubble-boy-40-years-later-look-back-at-heartbreaking-case/12/ Buckley RH. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Ann Rev Immunol. 2004; 22:625-55. Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer. 2004; 4:11-22. Delves PJ. 2016. Merck & the Merck Manuals. Acquired Immunity. Available from http://www.merckmanuals.com/home/immune-disorders/biology-of-the-immune-system/acquired-immunity. [Accessed 26th Sept 2016]. Genetic Fact Sheets for Parents - FELSI. Star-G. 2014. Retrieved from http://www.newbornscreening.info/Parents/otherdisorders/SCID.html References Martin LJ. 2015. Autoimmune disorders. Available from https://medlineplus.gov/ency/article/000816.htm [Accessed 30th Sept 2016]. Michael LD. Cancer Immunotherapy: Killers on sterols. Nature. 2016; 531:583-584. Murphy K, Travers P, Walport M. Janeway’s Immunobiology 7th Edition. New York: Garland Science; 2008. Michael HK, Jennifer AW & Philip KD. Gene-engineered T cells for cancer therapy. Nat Rev Cancer. 2013; 13:525-541. Steven AR & Nicholas PR. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015; 348(6230):62-68. Zimmerman A. - Immune System: Diseases, Disorders & Function. Live Science. Weblog. Available from http://www.livescience.com/26579-immune-system.html [Accessed 26th Sept 2016].