Introduction to Immunology PDF

latrobe.edu.au PHA2PGB Introduction to immunology Content: Dr Cristina Keightley Reference: Chapter 1 – Introduction to the immune system in Abbas et al. 7th Ed. La Trobe University...

latrobe.edu.au PHA2PGB Introduction to immunology Content: Dr Cristina Keightley Reference: Chapter 1 – Introduction to the immune system in Abbas et al. 7th Ed. La Trobe University CRICOS Provider Code Number 00115M Module overview Module 1 Module 2 Module 3 Module 4 Module 5 Overview Pathogen Antigen Immuno- Cell Recognition presentation pharmacology development and the innate Innate Cells Immune immune system Clonal immunity involved synapse diversity Glucocorticoids Cells Inflammation Tolerance Barrier immunity  latrobe.edu.au What is immunology and why is it so important? — “The science of defense” — Study of the immune system – Protects us from infection using many lines of defence – Complex system of organs, cells and proteins that communicate with each other to mount an offensive against perceived microbial threats — Indispensable! – Faulty immune system results in disease: allergies, autoimmunity, cancers – Without a functional immune system, even normally harmless bacteria or pathogens causing everyday infections can become killers  latrobe.edu.au The immune system - what and how ? What does it do? — Recognises and combats various threats such as microorganisms or toxins — Destroys pathogens and dysregulated self (cancers) — Repairs wounds How does it do it? — Discriminates between Self (the body) and Non-self (everything else) — Operates two branches of immunity: – Innate, Natural – Adaptive, Learned  latrobe.edu.au The immune system and disease: a two-edged sword T he o o d ” “g T cha he lle n ges Ch 1 Basic Immunology Abbas et al, 7th Edition  latrobe.edu.au Defense against infection - vaccination — Dramatic decrease in cases of diseases with effective vaccination programs — Data collected from the US Ch 1 Basic Immunology Abbas et al, 7th Edition Pandemics are recurrent – crucial to deepen our latrobe.edu.au understanding of immunology https://www.visualcapitalist.com/history-of-pandemics-deadliest/#google_vignette  latrobe.edu.au Advances in Immunology have led to the related area of Immunopharmacology — Immunopharmacology is: – study of the regulation of the immune system by pharmacological agents – development of methods to selectively modify immune function to treat human disease — Includes inoculation, autoimmune disorders, allergic reactions, and cancer — Significant advances have resulted in new approaches to pharmacologically control the immune system — Drugs targeting or taking advantage of the immune system  latrobe.edu.au Immunopharmacotherapy — Immunomodulators – Immunosuppressants – e.g, cyclosporin, tacrolimus used in transplants – Immunostimulants – Specific: bacterial and viral vaccines; – Non-specific: colony stimulating factors (Neulasta), interferons, interleukins (Proleukin) – Immune checkpoint inhibitors – Antibodies blocking PD-1/PD-L1 and CTLA-4/B7-1/B7-2 — Vaccines — Antibodies  latrobe.edu.au Cell-based Immunotherapy — CAR-T cells — Tumour infiltrating lymphocytes — Engineered T Cell Receptor (TCR) Therapy — NK Cell Therapy  latrobe.edu.au Therapeutic Applications — Autoimmune diseases – Thyroiditis: autoantibodies to TSH, thyroglobulin – Myasthenia gravis: autoantibodies to AchR – Type I Diabetes: immune response to beta cells – Glomerulonephritis – Rheumatoid Arthritis — Organ / Tissue transplantation – Kidney, heart, bone marrow s – Pancreatic islets — Cancer  latrobe.edu.au Summary — The immune system is a complex network of organs, cells and proteins that communicate with each other to mount an offensive against perceived microbial threats — Recognises and combats various threats such as microorganisms or toxins — Destroys pathogens and dysregulated self (cancers) — Repairs wounds — Two major branches of immunity – Innate immunity provides rapid natural or generic defences against infection – Adaptive immunity occurs later and can create a diverse and specific range of responses — The immune system works hard to protect us from pathogens but can provoke a misguided response (transplant rejection, autoimmunity, etc) — Immunopharmacology is the study of the regulation of the immune system by pharmacological agents and development of methods to selectively modify immune function to treat human disease — Continued advances in development of vaccinations and treatments for diseases that target and/or harness the power of the immune system  Thank you latrobe.edu.au La Trobe University CRICOS Provider Code Number 00115M © Copyright La Trobe University 2024 Cells & Tissues of the Immune System  latrobe.edu.au How does the immune response begin? The immune system is triggered by antigens antigen /ˈantɪdʒ(ə)n/ — A toxin or other foreign substance which induces an immune response in the body, especially the production of antibodies — Antigen – Ag – is an Antibody generator — Usually proteins, peptides (amino acid chains) and polysaccharides (chains of monosaccharides/simple sugars) — May originate from within the body ("self-antigen") or from the external environment ("non-self") — Vaccines are antigens that are administered to a recipient to induce the memory function of adaptive immune system to produce or artificially increase immunity to a particular disease  Immune response has 2 main branches: latrobe.edu.au innate and adaptive Innate Adaptive Dranoff (2004) Nature Reviews Cancer, 4, 11-22  latrobe.edu.au Innate and adaptive immunity timelines differ Innate Adaptive Rapid Slow Dranoff (2004) Nature Reviews Cancer, 4, 11-22  latrobe.edu.au Distinguishing features of innate and adaptive immunity Innate immune response – early Adaptive immune response – later — First line defence against an — Learned/adaptive response antigenic insult (eg infection) – Provides specificity and diversity of an individual’s immune response — Generic – Immunological memory Components include: — Humoral immunity: – Physical anatomical barriers – skin, mucus membrane – Antibody production for killing – Biochemical – complement, lysozyme, extracellular organisms interferons — Cell mediated immunity: – Cellular – macrophages, neutrophils – Cytotoxic / killer T cells > cell-mediated — Interacts with adaptive killing of virus and tumour cells immune response to prime it – Cytokine activation of phagocytes to kill ingested microbes  latrobe.edu.au The immune system responds with many types of cells — Antigen presenting cells (APCs) – Include dendritic cells, macrophages, B cells – Function: Capture antigens to display to lymphocytes — Lymphocytes Dendritic cell Macrophage – B lymphocytes (B cells) and T lymphocytes (T cells) – Function: recognise antigens — B lymphocytes mediate humoral immunity — T lymphocytes mediate cell-mediated immunity B lymphocyte T lymphocyte — Effector cells can be innate or adaptive – Include T lymphocytes (T cells), macrophages, granulocytes (neutrophils, basophils and eosinophils) – Function: Eliminate antigens  latrobe.edu.au Different blood lineages have different functions Table 23-1 Molecular Biology of the Cell (© Garland Science 2008) Figure 23-37e Molecular Biology of the Cell (© Garland Science 2008)  latrobe.edu.au Tissues of the immune system Ch 1 Basic Immunology Abbas et al, 7th Edition  latrobe.edu.au Summary — An immune response is triggered by an antigen — Innate immunity provides rapid natural or generic defences against infection: first response, happens within hours — Adaptive immunity creates a diverse and specific range of responses: later; ”learned” responses are remembered (immunological memory) — Immune cells fall into 3 major groups: antigen presenting cells, lymphocytes, and effector cells — They mostly function as first responders in the innate immune system or as highly specialised cells in the adaptive immune response — Innate and adaptive arms of the immune response operate on different timelines, and are distinguished in several ways — Generative and peripheral lymphoid organs are pivotal in generating, educating and maintaining cells of the immune system  Thank you latrobe.edu.au La Trobe University CRICOS Provider Code Number 00115M © Copyright La Trobe University 2024 Innate Immunity: Epithelial barriers  latrobe.edu.au latrobe.edu.au The innate immune system attempts to contain the initial infection in a multi-pronged defensive At portals of entry In the tissues In the blood Epithelial Humoral Cells barriers components Skin Neutrophils Complement Mucosal Monocytes Cytokines membranes Macrophages Natural killer cells Dendritic cells  latrobe.edu.au latrobe.edu.au Anatomical epithelial barriers have a physical component Barriers include: skin, mucosal surfaces in the mouth, nasopharyngeal, respiratory, gastrointestinal and urogenital tracts Epithelial cell layers provide a physical barrier to entry by pathogens Mechanical – tight junctions between cells Hair on skin; mucociliary escalator (mucus and cilia) on the mucosa  latrobe.edu.au latrobe.edu.au Anatomical barriers have a chemical component Epithelial cells secrete various chemicals that add to the barrier Fatty acids Antimicrobial peptides Enzymes (e.g. lysozyme) Carbohydrates Acid pH Found in : sweat, breastmilk, mucus, saliva, tears, semen, digestive juices https://courses.lumenlearning.com/microbiology/c hapter/anatomy-and- normal-microbiota-of-the- skin-and-eyes/  latrobe.edu.au latrobe.edu.au Anatomical barriers have a biological component Epithelial layers are also host to lots of commensal microorganisms (harmless bacteria) Commensal microorganisms: interact with epithelial layers secrete chemicals that contribute to chemical barriers Source: mhttps://www.alamy.com/stock- photo/skin-bacteria-sem.htmlicroorganisms  latrobe.edu.au latrobe.edu.au Active parts of the epithelia barriers ← biological ← chemical ← cellular Abbas et al. – see Fig 2-8 in 7th edition Mucosal immune system: gut latrobe.edu.au latrobe.edu.au 1. Commensal bacteria 1 2. Mucus secretion 2 3. Antimicrobial peptides 4 6 4. Specialised epithelial cells promote transport of antigens from lumen into 3 underlying tissues 5. Cells in lamina propria (DCs, T cells, macs) > 5 5 innate/adaptive defense 6. IgA produced in mucosa is transported to lumen to bind and neutralize microbes Abbas et al. – see Fig 1.16 in 7th edition  latrobe.edu.au Cutaneous immune system: skin outside world — Epidermis: body – Keratinocytes – Langerhans cells (tissue-resident dendritic cells acting as sentinels) – Intraepithelial lymphocytes — Dermis: – T cells – dendritic cells – macrophages Abbas et al. – see Fig 1.17 in 7th edition  latrobe.edu.au latrobe.edu.au Summary: barriers and innate immunity Innate immunity constitutes the natural or generic defences against infection and involves epithelial cells, active effector cells and humoral components Anatomical barriers provide a physical barrier as a first defence Augmented by epithelial-derived chemical antimicrobial secretions and natural microflora IgA and mucus secretion are an important part of mucosal immunity Epithelial layers contain effector cells that can destroy microorganisms Antigen presenting cells drain into lymph nodes to alert the adaptive immune system  Thank you latrobe.edu.au La Trobe University CRICOS Provider Code Number 00115M © Copyright La Trobe University 2024 Innate Immunity: Cells of the innate immune system  latrobe.edu.au latrobe.edu.au The innate immune system attempts to contain the initial infection in a multi-pronged defensive Epithelial Humoral Cells barriers components Skin Neutrophils Complement Mucosal Monocytes Cytokines membranes Macrophages Natural killer cells Dendritic cells  latrobe.edu.au latrobe.edu.au Leukocytes (white blood cells) in peripheral blood Blood film stained with Romanowsky type dyes (e.g. eosin and methylene blue) to differentiate white cell features  latrobe.edu.au latrobe.edu.au Phagocytes: Neutrophils (PMNs) most common leukocyte in the blood distinctive lobed nucleus > polymorpho- nuclear (PMN) leukocyte neutrophils rapidly raised in response to infection: esp. bacterial and fungal signalled by colony stimulating factor (a protein in the cytokine class) dominant cells in acute inflammation limited life span  latrobe.edu.au latrobe.edu.au Neutrophil functions Ø First responders to injury or infection neutrophils phagocytose bacteria at the site neutrophil NET bacteria red blood cell Generate reactive oxygen species (ROS) e.g., hypochlorous acid (HOCl), and cytokines contain granules that store microbicidal products: Elastase, myeloperoxidase, cathelicidins, defensins, and matrix metalloproteinases Extrude neutrophil extracellular traps (NETs) composed of decondensed chromatin and antimicrobial proteins Ø Kill bacteria, fungi, and parasites Image Source: Wikimedia Commons Ø Prime the adaptive immune system  latrobe.edu.au latrobe.edu.au Phagocytes: Monocytes/Macrophages Less abundant than neutrophils Monocytes are present in blood During inflammation, some monocytes enter tissues where they mature into macrophages Long lived  latrobe.edu.au What macrophages and neutrophils look like in real life Harriet Manley, unpublished Lattice lightsheet microscopy of live macrophage and neutrophils captured inside zebrafish larvae  latrobe.edu.au latrobe.edu.au Maturation of Monocytes to Macrophages Note: Blood monocytes and tissue macrophages are separate stages of the same cell lineage Abbas et al. 7th edition  latrobe.edu.au latrobe.edu.au Macrophage functions Activated macrophages Produce cytokines and regulate inflammation Phagocytose and destroy microbes in blood and tissues Present antigens to T cells Clear dead tissue and cell debris Stimulate tissue repair Abbas et al. 7th edition  latrobe.edu.au latrobe.edu.au Mast cells found in skin and mucosa epithelium FcεRI IgE bound to many granules/vesicles FcεRI secrete: vasodilators (histamine) lipid mediators (prostaglandins, leukotrienes) proteolytic enzymes > destroy bacteria and/or toxins https://embracingnutrition.co.uk/mast-cell-activation-syndrome/ cytokines (tumour necrosis factor (TNF)) defend against helminths and other pathogens involved in allergic symptoms protection against snake and insect venoms https://www.sciencephoto.com/media/938209/view  latrobe.edu.au latrobe.edu.au Innate lymphoid cells (ILCs) similar to T cells but do not make T cell antigen receptors > “innate counterpart” of T cells are always present in tissues (unlike T cells which migrate into tissues) provide early defence against infection in tissues secrete various cytokines participate in immune responses to virus, bacteria, https://blog.benchsci.com/overview-of-innate-lymphoid- parasites and transformed cells cells-ilcs-subtypes-characterization-and-function participate in tissue homeostasis not yet fully understood Jacquelot, N., Seillet, C., Vivier, E. et al. Innate lymphoid cells and cancer. Nat Immunol 23, 371–379 (2022)  latrobe.edu.au latrobe.edu.au Natural killer (NK) cells NK another type of lymphocyte related to ILCs do not express T cell receptors or immunoglobulins ~10% of blood lymphocytes recognize and kill infected or stressed cells secrete the cytokine interferon-γ (IFN-γ) that activates macrophages to kill phagocytosed microbes macrophages secrete IL12 > enhances NK activity Ø cooperative interaction between macrophages and NK cells from Abbas et al 2024; see Fig 2-13 in 7th ed.  latrobe.edu.au latrobe.edu.au Dendritic cells Found all along the epithelial barrier long processes Sentinels: sense microbes and produce many different cytokines Two functions: initiate inflammation stimulate adaptive immune responses Have long processes Major function is to capture protein antigens and display them to T cells: Behnsen et al,, Source: PLoS Pathogens - http://pathogens.plosjournals.org/perlserv/?request=get- professional antigen presenting cell (APC) document&doi=10.1371/journal.ppat.0030013, CC BY2.5, https://commons.wikimedia.org/w/index.php?curid=2327334 Important bridge between innate and adaptive response  latrobe.edu.au latrobe.edu.au Summary: cells of the innate immune system Cells of the innate immune system include cells present in the blood and skin and mucosal epithelium Specific cell types include neutrophils, monocytes, macrophages, mast cells, innate lymphoid cells, natural killer cells and dendritic cells All produce cytokines Neutrophils, monocytes and macrophages are phagocytes Dendritic cells and macrophages are antigen presenting cells The different cell types of the innate immune system cooperatively interact to kill and destroy invading microorganisms, e.g., natural killer cells and macrophages Cells of the innate system can prime the adaptive immune response  latrobe.edu.au Thank you latrobe.edu.au La Trobe University CRICOS Provider Code Number 00115M © Copyright La Trobe University 2024 Innate Immunity: Humoral components  latrobe.edu.au latrobe.edu.au The innate immune system attempts to contain the initial infection in a multi-pronged defensive Epithelial Humoral Cells barriers components Skin Neutrophils Complement Mucosal Monocytes Cytokines membranes Macrophages Natural killer cells Dendritic cells  latrobe.edu.au latrobe.edu.au What is the complement system? A dynamic system responsive to infection involving ~20 circulating proteins and also proteins attached to the surface of cells Identified by its ability to amplify and “complement” the action of antibodies Complement proteins made mainly by the liver Most are inactive until triggered by infection Some components of complement are also Rooijakkers et al. (2009) Nature Immunology 10: 721 PRRs activated directly by pathogen- Three dimensional structure of the complement protein C3b (opsonin in cyan) shown as a ribbon diagram (α associated immunostimulants helices are shown as coiled ribbons. β strands as arrows and non-repetitive coils or loops as thin lines)  latrobe.edu.au latrobe.edu.au Complement system function Complement process involves Initiation of the complement activation Early steps producing protein C3b and opsonisation (coating of microorganisms) Late steps where complement induced phagocytosis or lysis of the microorganism occurs which can be accompanied by inflammatory reactions Watch this video to see an animation accompanied by song on how the classical and alternative complement pathways work: The Complement System Song | How The Complement System Works  latrobe.edu.au Steps of complement activation — Initiated by 3 distinct pathways, all lead to the production of C3b (activation) — Early steps: – C3b production; C3a > inflammation – C3b opsonises microbe > signal for phagocytosis – C3b initiates late steps > formation of membrane attack complex (MAC) — Late steps: – MAC (C6-9) lyses thin-walled microbes – C5a > inflammation  latrobe.edu.au Complement is activated by 3 different pathways triggered by spontaneous triggered when IgM or triggered by binding of circulating hydrolysis of C3 protein in certain subclasses of lectins, i.e., plasma mannose-binding plasma at a low level IgG bind to antigens lectin (MBL) or ficolins, to microbial innate humoral immunity adaptive humoral immunity polysaccharides innate humoral immunity  latrobe.edu.au Functions of Complement — A: C3b is an opsonin: it coats microbes and is recognised by complement receptor 1 (CR1) on phagocytes > phagocytosis — B: C3a and C5a bind receptors on neutrophils and stimulate inflammatory reactions — C: The membrane attack complex creates pores in cell membranes and induces osmotic lysis of microbes  latrobe.edu.au latrobe.edu.au Summary Complement is a dynamic system involving complement proteins and cells of the innate immune system (e.g. macrophages) that is activated by the presence of microorganisms There are 3 complement pathways Classical involving antibody opsonisation (adaptive) Alternative involving C3b opsonization (innate) Lectin binding involving lectin protein opsonisation (innate) C3b opsonisation leads to phagocytosis or lysis of the microbe Complement functions to stimulate Opsonisation and phagocytosis Lysis of microorganisms Inflammatory reactions Cytokines of the innate immune system  latrobe.edu.au latrobe.edu.au Cytokines: soluble proteins secreted by immune cells Cyto-kines, from Greek: TNF kytos, 'cavity, cell’ + kinēsis, 'movement’ Responsible for communications between leukocytes and between leukocytes and other cells Many innate immune cells (esp. macrophages, dendritic cells and mast cells) secrete cytokines http://www.rcsb.org/structure/1TNF Three dimensional structure of the Stimulus: recognition of bacterial cell wall cytokine, Tumour necrosis factor (TNF) shown as a ribbon diagram (α helices are shown as coiled ribbons. β strands components such as LPS and peptidoglycans or as arrows and non-repetitive coils or loops as thin lines) recognition of microbial nucleic acids Ø Outcome: immune and inflammatory reactions  latrobe.edu.au Examples of cytokines produced by innate immune cells Common cytokines are TNF (tumour necrosis factor) interleukins (IL) interferons (IFN) Growth factors (colony stimulating factors (CSF))  latrobe.edu.au latrobe.edu.au Cytokines mediate communication between cells bind to high-affinity receptors on target cells most cytokines act on nearby cells – paracrine action some act on the cells that produce them – autocrine action if enough dendritic cells and macrophages are activated large Which action is the above amounts of cytokines are produced > an example of? active distant from their site of secretion – endocrine actions  latrobe.edu.au Functions of cytokines in innate immunity Various functions in host defence — TNF and IL-1: – recruit blood neutrophils and monocytes to sites of infection – systemic effects, including inducing fever by acting on the hypothalamus – and IL-6: stimulate liver cells to produce proteins of the acute phase response, such as CRP and fibrinogen > microbial killing and walling off infectious sites — TNF also promotes thrombus formation on the endothelium and reduces blood pressure by a combination of reduced myocardial contractility and vascular dilation and leakiness > high levels of TNF > Septic shock — IL-12 from macrophages and DCs activates NK cells — IFN-γ from NK cells activates macrophages — Type I IFNs from DCs inhibit viral replication and prevent spread of infection  latrobe.edu.au latrobe.edu.au Summary: cytokines of innate immunity Small proteins secreted by immune (and other cells) Can have paracrine, autocrine or endocrine responses Cytokines of the innate immune system have various functions in host defence: TNF, IL1 and chemokines recruit blood borne neutrophils and monocytes to sites of infection induce fever and secretion of other proteins of the acute phase response Severe bacterial infections can lead to overproduction of cytokines and septic shock Ø Cytokines are important in inflammation and antiviral defence  latrobe.edu.au Cytokines get things moving!  latrobe.edu.au Thank you latrobe.edu.au La Trobe University CRICOS Provider Code Number 00115M © Copyright La Trobe University 2024