Adaptive Immunity in Human Disease PDF

Adaptive immunity in human disease Dr Rachael Ireland School of Medical Sciences Faculty of Medicine and Health © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  At the end of...

Adaptive immunity in human disease Dr Rachael Ireland School of Medical Sciences Faculty of Medicine and Health © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  At the end of this lecture you will be able to – Define the different types of adaptive immunity – Describes the main cell types involved in adaptive immune responses – Recognise that there must be a way for the adaptive immune system to “tolerate self” – Identify the two types of immunological tolerance: Central and Peripheral – Understand that a breakdown in immunological tolerance may lead to the developing of autoimmune disease – Recognise that human disease is a conspiracy between our genes and the environment in which we live – Link immunity to the cause and cure of some common human diseases – Argue using examples that targeting the immune system is leading to breakthroughs in the fight against human disease: Autoimmune diseases – which can be organ specific or systemic Cancer © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland Recall – Hallmarks of the innate immune system 1. Speed – Early – Rapid 2. Short-lived duration 3. Repetitive – Responds the same way each time a microbe is encountered 4. Interactive – With other cells of the innate immune system – With cells of the adaptive immune system 5. Non-reactive to the host © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  Lymph nodes Dendritic cells present antigen to lymphocytes Spleen © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland The adaptive immune system – Lymphocytes and their products E.g. antibodies – Lymphocytes express receptors that specifically recognise a wider variety of molecules (from microbes and non-infectious substances) These molecules are called antigens – Adaptive immunity requires expansion and differentiation of lymphocytes in response to microbes Effector cells Memory cells – Adaptive immune responses often use the cells and molecules of the innate immune system to eliminate microbes © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland There are two main types of lymphocytes B cells – “B” because they were first discovered in the bursa of Fabricius T cells – “T” because they mature in the thymus 6 © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland The thymus: It’s a university for T cells – A redundant organ? – Australian immunologist Jacques Miller is credited as the last person to have identified the function of a major organ. – The thymus is in fact a generative (or primary) lymphoid organ – This is where T cells learn how to be “good” T cells – (i.e. a cell that doesn’t “attack” self-cells) © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  Types of adaptive immunity – In humoral immunity, B cells secrete antibodies that eliminate extracellular microbes – In cell-mediated immunity, different types of T cells: help phagocytes to destroy ingested microbes and kill infected cells 8 © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  Antibodies IgM – Produced first – Pentamer structure IgG – Efficient anti-viral and Variable region antibacterial defence – Can only be made with T cell help IgE Constant region – Defence against worms and parasites – Activates basophils © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  Types of T cells – Helper T cells (Th cells) “help” other cells of the immune response different types of Th cells exist with specialised functions Some helper T cells suppress or regulate the immune response rather than activate the immune response – Cytotoxic T Lymphocytes (CTLs) CTLs kill their target cells in a highly specific way CTLs get “help” from helper T cells CTLs play a key role in: viral infections anti-tumour immunity 10 © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland Immunological tolerance – A system for determining which lymphocyte clones will be allowed to survive Central tolerance – Occurs in primary lymphoid tissues Peripheral tolerance – Mediated primarily by regulatory cells – A breakdown in tolerance can lead to autoimmune diseases Sir Frank Macfarlane Burnet OM, AK, KBE (1899 - 1985) Nobel prize winner in Physiology or Medicine 1960 with Peter Medawar: For their discovery of acquired immunological tolerance © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland The immune system: cause and cure – To prevent, treat and even cure these diseases you need to be able to manipulate the immune system – To manipulate the immune system you need to understand the immune system – To understand the immune system you need to know where and what it is: The key cells The key molecules How they interact © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland Immunology in human disease Autoimmune disease – Who gets autoimmune diseases? – What causes autoimmunity? – How does targeting the immune system help those with autoimmune disease? Cancer – Our Immune System is constantly on the look out for cancer – Can our immune system destroy cancer cells? – Can we harness the immune system to treat cancer? © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland Genetic Factors Many autoimmune diseases are linked to the genes responsible for: – T cell activation – Maintaining immunological tolerance finding and destroying self-reactive lymphocytes activity of regulatory cells – Many of these genes are inherited © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland Dyment, Ebers & Sadovnick Lancet Neurol 2004; 3: 104–10 © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland Environmental factors Autoimmune disease is often preceded by an infection Other environmental and host factors may contribute: – Many autoimmune diseases are more common in women – Local trauma leading to an inflammatory reaction may release previously hidden antigens that our immune system responds to (e.g. sunlight triggering SLE) © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland Autoimmune disease can be organ specific or systemic Copyright: Fig 15.11 Janeway’s Immunobiology, 8ed. (Garland Science 2012)  Autoimmune diseases involve all aspects of the adaptive immune response T cells B cells Antibody systemic lupus Pathogenic Make Pathogenic erythematosus Helper T cells auto-antibodies Type 1 Pathogenic Possibly Present but Diabetes Cytotoxic T cells pathogenic role unclear Multiple Pathogenic Pathogenic Possibly Sclerosis Helper T cells pathogenic  Multiple Sclerosis T cells Roll, Inflammation is T cells are caused by cells of the Adhere and Myelin is re-activated innate & adaptive Extravasate into immune system and destroyed inside the brain the brain their products Immunology in human disease Autoimmune disease – Who gets autoimmune diseases? – What causes autoimmunity? – How does targeting the immune system help those with autoimmune disease? Cancer – Our Immune System is constantly on the look out for cancer – Can our immune system destroy cancer cells? – Can we harness the immune system to treat cancer? © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  Anti-tumour immunity “It is by no means inconceivable that small accumulations of tumour cells may develop and, because of their possession of new antigenic potentialities provoke an effective immunological reaction with regression of the tumour and no clinical hint of its existence” Sir MacFarlane Burnet, 1957 Immune surveillance – The capacity to detect and destroy cancer cells © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  Evidence for Immune Surveillance – Patients with tumours that have been infiltrated by lymphocytes have a better prognosis – Enlarged tumour-draining lymph nodes = better prognosis – Transplanted tumours are rejected – Immunodeficient patients have a higher susceptibility to tumour growth Transplant patients on immunosuppressive therapy People with acquired immunodeficiencies Older populations, those with certain infectious diseases, exposure to environmental carcinogens (e.g. UV, radiation) © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland Killer T Cells: The Cancer Assassin © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland Promising new cancer therapies that target the immune system – Bone marrow transplantation certain types of leukemia – Re-engineered T cells Chimeric Antigen Receptor (CAR) T cells – Antibodies remove the immunological brakes apply the immunological accelerator D Pardoll Science 2014;344:149 © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland Take home messages – Immune genes and environmental insults conspire to cause autoimmunity – Autoimmune disease may by organ specific or systemic – Autoimmune diseases involve all aspects of adaptive immune responses – Most successful disease modifying therapies target the immune system – Our immune systems are constantly on the look out for cancer – The immune system can destroy cancer cells – Exciting new anti-cancer therapies target the immune system © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland