BIOL1XX8_2024_L19_innate immunity.pdf

Innate immunity and inflammation Dr Rachael Ireland School of Medical Sciences Faculty of Medicine and Health At the end of this lecture, you will be able to 1. Define what is meant by immunity and describe where the immune system is found and its major functions 2. Describe...

Innate immunity and inflammation Dr Rachael Ireland School of Medical Sciences Faculty of Medicine and Health At the end of this lecture, you will be able to 1. Define what is meant by immunity and describe where the immune system is found and its major functions 2. Describe the general anatomy of the immune system including the major components of the innate immune system 3. Distinguish the difference between primary and secondary immune deficiencies 4. Describe the general characteristics (hallmarks) of the innate immune system 5. Explain the role of inflammation in immune function and why the resolution of inflammation is important 6. Describe events that occur as part of the inflammatory response including Vasodilation, Rolling, adhesion, extravasation, migration, chemotaxis and phagocytosis 7. Explain briefly how the innate immune system is able to discriminate self from non-self. © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland What is the immune system? – The immune system = the collection of cells, tissues and molecules that mediate reactions to pathogens and some non-infectious substances (e.g. harmless environmental molecules, tumours and self-molecules) – The coordinated, tightly controlled response of these cells and molecules is called the immune response © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland What is “immunity”? – Immunity is often defined as resistance to infectious diseases Bacterial, viral, fungal, parasitic infections – However, non-infectious substances, damaged cells and tumour cells can also elicit immune responses – Immunity is NOT just about killing microbes Immunity is part of a broader set of functions for keeping our bodies in good working order © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland Functions of the immune system – Prevent infection – Eradicate established infections – Control tissue regeneration (wound healing) – Detect and eliminate tumours – Tolerate self we explore these concepts next year in two units: “Immunobiology” and “Microbes, Infection and Immunity" © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland The power of the immune system – Vaccination © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland The power of the immune system – People with defective immune responses are at increased risk of serious infections Congenital (primary) immune deficiencies – e.g. patients who completely lack key cells and molecules of the immune system Acquired (secondary) immune deficiencies – e.g HIV infection leading to loss of key immune cells © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland David Vetter: “Bubble Boy” – 1971–1984 – Had a serious primary immunodeficiency called SCID (severe combined immunodeficiency) – Lived almost his entire 12 years of life in a specially constructed sterile environment (“bubble”) – Bone marrow transplant – Died from Burkitt’s lymphoma aged 12 © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland The power of the immune system – When the immune system overreacts Asthma Atopic or allergic reactions Autoimmune diseases (e.g. multiple sclerosis, SLE, Type 1 diabetes) – The impact of immunology goes beyond infectious diseases! © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland What you need to know – 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 Where is the immune system? – The immune system is integrated with other systems: Gastrointestinal, cardiovascular, respiratory, nervous, endocrine, skin – Immune cells are scattered throughout the body Many of them actively travel (migrate) around it Others sit in one place for a long period of time (tissue “resident” immune cells) © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland Where is the immune system? – Molecules of the immune system can act in an: Autocrine Paracrine, or Endocrine manner (when secreted) © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland The anatomy of the immune system – Physical & chemical barriers Epithelial cells of skin, gut, respiratory tract Secretions including sweat, wax and tears Mucus in the nose, trachea, gut Urine Proteolytic enzymes Low stomach pH Normal gut flora – The cells and molecules of the immune system access most organ systems in the body via: blood vessels lymphatic vessels © Copyright - The University of Sydney. May not be copied,Copyright: reproducedFigureor 2-11 Abbas, Abul. Cellular redistributed withoutand Molecular explicit Immunology, 7th Edition. W.B. written permission fromSaunders Company, Dr. Rachael 2011 Ireland The anatomy of the immune system – Immune cells originate from bone marrow stem cells Central Primary Bone marrow lymphoid organs Thymus Secondary Spleen lymphoid organs Lymph nodes Mucosal & cutaneous-associated lymphoid tissues Peripheral All other tissues and systems  Common Common Self-renewing Lymphoid Myeloid haematopoietic Progenitor Progenitor stem cell Innate immune Adaptive system immune system Neutrophil Basophil Eosinophil Monocyte Lymphocytes © Copyright - The University of Sydney. May not be copied,Copyright: reproduced or from Images redistributed without Chapter 2: Abbas, explicit Abul. written Cellular permission and Molecular from Dr. Immunology, Rachael 7th Edition. Ireland W.B. Saunders Company, 2011 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 Components of innate immunity 1. Epithelial barriers 2. Cells in circulation & tissues 3. Molecules Phagocytes – Cytokines e.g. tumour necrosis factor (TNF) – Blood proteins Exocytes © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland The innate immune system recognises patterns – Epithelial, endothelial and resident immune cells express receptors on their surface that allow them to sense danger – Different microbes express different “patterns” – Our own cells do not express these patterns This is one way in which the innate immune system can tell the difference between self and non-self © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  What is the World’s Deadliest Animal? as measured by number of people killed © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  https://www.gatesnotes.com/ © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  Image by NIAID Copyright: Tom Connell illustration Flare – redness due to dilation of blood vessels Wheal – swelling due to release of serum into the tissue © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  Mast cells – Mast cells reside in peripheral tissues exposed to the environment Skin, lung, gut – Mast cells have receptors on their surface that allow them to sense danger – Mast cells increase vascular Prof Scott Byrne, University of Sydney permeability and promote inflammation © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  What are cytokines? – Proteins produced and secreted by many different cell types – Cytokines modulate inflammatory and immune reactions – Key mediators of communication between cells – Can target cells in an autocrine/paracrine/endocrine manner © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  Fig 2.17. Abbas. Basic Immunology: Functions & Disorders of the Immune System, 20 Tissue-resident cells are 1st responders When danger is detected: – release of histamine & inflammatory cytokines – dilated blood vessels allow for more blood flow to the area (redness) and fluid to come in (swelling) carrying innate immune cells and plasma proteins – induces the expression of adhesion molecules on endothelial cells lining the blood vessels attracts innate immune cells (neutrophils mainly) © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  How quickly are neutrophils recruited to peripheral sites? McDonald et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330 (2010) from Ng et al. Visualizing the Neutrophil Response to © Copyright - The University of Sydney. May not beTissue Sterile copied,Injury in Mouse Dermis Reveals a reproduced or redistributed without explicit written Three-Phase Cascade of Events. J Invest Dermatol permission from Dr. Rachael Ireland 131 Chemokines make cell migration possible – Chemo-tactic cytokines – Different cells express different chemokine receptors – this allows the cell to respond to different chemokines Chemokine receptor Chemokine concentration Direction of cell migration © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland  Chemotaxis © Copyright - The University of Sydney. May not be copied, Copyright: Janeways Immunobiology reproduced 7th Edition; or redistributed without Garland explicit written Science permission from Dr. Rachael Ireland  © Copyright - The University of Sydney. May not be copied, Leukocytewithout reproduced or redistributed Rolling explicit written Copyright: Janeways Immunobiology permission 7thIreland from Dr. Rachael Edition; Garland Science  Inflammation: Good or Bad? – A little bit of inflammation (e.g. that caused by cytokines) in response to an infection may be considered “good” – it gets the immune system going – Too much inflammation may be “bad” – septic shock – chronic inflammation can lead to severe diseases arthritis (shown) cancer Inflammatory Bowel Disease (IBD) diabetes – May even lead to death © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland 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 David Vetter: Had to rely almost entirely on innate immunity © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland Take home messages – Our immune system is “everywhere” – Innate immune responses involve specialised cells that recognise and respond to danger – These innate immune cells are responsible for causing inflammation – A little bit of inflammation is “good for you”. Too much might kill you – When innate immune responses fail to contain a pathogen, the pathogen may spread and initiate an adaptive immune response © Copyright - The University of Sydney. May not be copied, reproduced or redistributed without explicit written permission from Dr. Rachael Ireland