Basic Immunology 1 Lecture 2022 PDF

Basic Immunology 1 Dr Timothy West Clinical Immunologist and Allergist, Campbelltown Hospital [email protected] 1 Learning objectives 1. Distinguish between innate immunity and adaptive immunity 2. Identify the basic components of the immune system, including a basic outline of the prin...

Basic Immunology 1 Dr Timothy West Clinical Immunologist and Allergist, Campbelltown Hospital [email protected] 1 Learning objectives 1. Distinguish between innate immunity and adaptive immunity 2. Identify the basic components of the immune system, including a basic outline of the principle cell types. 3. Identify the central and peripheral lymphoid organs and specify their organisation and functions 4. Outline the roles of the following cells; B lymphocytes, T lymphocytes, neutrophils, macrophages, dendritic cells, NK cells 2 Overview Introduction to Immunology. Importance of Immunology. Key definitions, function of the immune system, and what happens when the immune system does not function as expected. Overview of the immune response. Anatomy of the immune system. Innate vs adaptive immune system. Innate immune response in detail. Next lecture: antigen presentation and the adaptive immune response. 3 Overview Introduction to Immunology. Importance of Immunology. Key definitions, function of the immune system, and what happens when the immune system does not function as expected. Overview of the immune response. Anatomy of the immune system. Innate vs adaptive immune system. Innate immune response in detail. Next lecture: antigen presentation and the adaptive immune response. 4 5 6 Overview Introduction to Immunology. Importance of Immunology. Key definitions, function of the immune system, and what happens when the immune system does not function as expected. Overview of the immune response. Anatomy of the immune system. Innate vs adaptive immune system. Innate immune response in detail. Next lecture: antigen presentation and the adaptive immune response. 7 https://www.immunology.org/boy-in-the-bubble-1972 8 Abbas & Lichtmann, Cellular and Molecular Immunology, 9th Edition 9 https://www.aihw.gov.au/reports/chronic-respiratory-conditions/allergic-rhinitis-hay-fever/contents/allergic-rhinitis 10 F. Stephen Hodi et al, Improved Survival with Ipilimumab in Patients with Metastatic Melanoma, NEJM 2010 11 Overview Introduction to Immunology. Importance of Immunology. Key definitions, function of the immune system, and what happens when the immune system does not function as expected. Overview of the immune response. Anatomy of the immune system. Innate vs adaptive immune system. Innate immune response in detail. Next lecture: antigen presentation and the adaptive immune response. 12 The role of the immune system, and key definitions. Immunity: a state of resistance to disease, specifically infectious disease. Immune system: the body’s system for protecting us from foreign substances, principally infectious microbes, as well as cancer. Immune response: the coordinated response of the immune system in response to infectious microbes. Antigen: anything capable of eliciting an adaptive immune response. 13 The challenges the immune system faces https://n.neurology.org/content/neurology/95/12/552/F1.large.jpg https://images.emedicinehealth.com/images/slideshow/foot_photo_interdigital_athletes_foot_s6.jpg https://aho.org/fact-sheets/snakebite-envenoming-fact-sheet/ https://en.wikipedia.org/wiki/Inflammation 14 The challenges the immune system faces Range of pathogens: virus, bacteria, fungus, helminth. Infection anywhere in body; intra- vs extracellular infection. Titration of immune response to severity of infection. Cessation of immune response once infection cleared. Non-reaction to harmless or self antigens. Immunological memory. https://courses.lumenlearning.com/microbiology/chapter/types-of-microorganisms/ https://nypost.com/2019/12/10/watch-this-video-of-a-32-foot-tapeworm-at-your-own-risk/ https://www.nature.com/articles/nrmicro2644.pdf 15 Different sorts of infections… Janeway’s Immunobiology 9e. 16 Different sizes of infections… Janeway’s Immunobiology 9e. 17 When the immune system gets it wrong Too weak or ineffective: infection or cancer. Reacts to self: autoimmune disease. Reacts to harmless foreign antigens: allergy. Too strong or unregulated: autoinflammatory disease. 18 Challenges in learning immunology What is is trying to do is actually quite complicated. You can’t determine its function by looking at it; it happens at a microscopic level. We know a lot about it! 19 Overview Introduction to Immunology. Importance of Immunology. Key definitions, function of the immune system, and what happens when the immune system does not function as expected. Overview of the immune response. Anatomy of the immune system. Innate vs adaptive immune system. Innate immune response in detail. Next lecture: antigen presentation and the adaptive immune response. 20 Overview of the immune response If you get an infected cut on your toe… 1. The fact that bacteria have entered your tissues must be identified by cells resident within your finger. 2. Information about the bacteria, and a sense of danger, must be conveyed to the immune system at nearby lymph nodes. 3. An adaptive, targeted immune response must be generated. 4. A range of cells must enter the infected tissue, to kill the invasive microbes. 21 Janeway’s Immunobiology 9e. 22 Overview of the immune response 1. 2. 3. 4. When a pathogen breaks an epithelial barrier, it is recognised by cells of the innate immune system, causing with cytokine release, complement activation and phagocytosis of antigens. The innate immune system triggers an acute inflammatory response to contain the infection. Dendritic cells, a key type of antigen presenting cell, present antigen to T cells of the of the adaptive immune system to trigger an adaptive immune response. T cells then coordinate an adaptive immune-response targeted at the invading pathogen: 1. 2. For extracellular pathogens (e.g. most bacteria), CD4+ helper T cells trigger B cells to produce antibodies. This is the humoral immune system. For intracellular pathogens (e.g. viruses) , CD8+ cytotoxic T cells directly kill virally infected cells. This is the cellular adaptive immune system. We will cover (1) and (2) today, and (3) and (4) in the next lecture. 23 Overview Introduction to Immunology. Importance of Immunology. Key definitions, function of the immune system, and what happens when the immune system does not function as expected. Overview of the immune response. Anatomy of the immune system. Innate vs adaptive immune system. Innate immune response in detail. Next lecture: antigen presentation and the adaptive immune response. 24 https://openstax.org/books/anatomy-and-physiology/pages/21-1-anatomy-of-the-lymphatic-and-immune-systems © 1999-2021, Rice University. Creative Commons Attribution 4.0 International License. 25 Anatomy of the immune system Primary lymphoid organs – Bone marrow: haematopoiesis; all blood cells (including all immune cells) ultimately derive from bone marrow. B cells also mature here. – Thymus: T cell maturation. Peripheral lymphoid organs – Lymph nodes: antigen presentation; interface between innate and adaptive immunity. – Lymph vessels: bring lymphatic fluid (lymph) from tissues to lymph nodes. Connect lymph nodes with each other, and ultimately carry lymph to the subclavian veins. – Spleen and liver: antigen presentation; non-immune functions. – Specialised lymphoid tissue: antigen presentation. Mucosal associated lymphoid tissue (MALT) Bronchus associated lymphoid tissue (BALT) Gut associated lymphoid tissue (GALT) 26 Overview Introduction to Immunology. Importance of Immunology. Key definitions, function of the immune system, and what happens when the immune system does not function as expected. Overview of the immune response. Anatomy of the immune system. Innate vs adaptive immune system. Innate immune response in detail. Next lecture: antigen presentation and the adaptive immune response. 27 Innate vs adaptive immunity Innate immunity: the part of the immune response that does not require antigen specific clonal expansion to eliminate the pathogen. – Consists of cells, proteins and chemicals that are resident in tissues and can act immediately when microbes present. – Can fight off infection directly; essential in triggering the adaptive immune system. Adaptive immunity (aka specific, acquired immunity): the part of the immune response that is stimulated by microbes that invade tissue, and specifically targets that microbe. – Generates a specific immune response to the particular pathogen that has invaded. – Must be triggered by innate immune system. Takes several days to a week to become effective. 28 Comparison of innate and adaptive immune systems. Innate immune system Adaptive immune system Speed of response Fast: within minutes-hours. Slow: 2 – 7 days. Specificity Non-specific. Reacts to common shared patterns on surfaces of microbes. Specific. Reacts to antigens particular to an invading microbe. Diversity of epitopes recognised Thousands. > 10 million. Immunological memory No. Yes. Key anatomic components Skin, mucous membranes. Primary and secondary lymphoid organs. Key cells Phagocytes Antigen presenting cells Natural killer cells T lymphocytes B lymphocytes Key proteins Complement system Cytokines and chemokines Antibodies Cytokines and chemokines Found in Nearly all forms of life Jawed vertebrates. 29 Abbas & Lichtmann, Cellular and Molecular Immunology, 9th edition. 30 Abbas & Lichtmann, Basic Immunology 6th edition, figure 1.3 31 32 Origins of immune cells All blood cells are ultimately derived from pluripotent haematopoetic stem cells in the bone marrow. The pluripotent stem cell divides into two key cell lines: the common lymphoid progenitor and common myeloid progenitor. The myeloid progenitor gives rise to most cells of the innate immunity as well as red cells and platelets. – Granulocytes: neutrophils, eosinophils, basophils. – Monocytes, macrophages and dendritic cells. The lymphoid progenitor gives rise to: – All cells of the adaptive immunity: B lymphocytes (B cells) and T lymphocytes (T cells). – NK cells, which are part of the innate immunity. 33 When blood is spun down in a lab… Plasma, containing all proteins in blood, is at the top. The white cells are in the “buffy coat”: which is white! – Hence leukocyte = white cell. The red cells are at the bottom. – Hence erythrocyte = red cell. 34 A word on terminology… Leukocytes (white cells) are often grouped by their appearance under the microscope. – Immediate division is granulocytes vs mononuclear cells. “Granulocytes” aka polymorphonuclear (PMN) leukocytes. – Contain granules in their cytoplasm. The granules contain enzymes which help with functions such as digesting and breaking down pathogens. They include neutrophils, basophils, eosinophils, and mast cells. – The nucleus of these cells contains multiple lobes (polymorphonuclear) as opposed to a single rounded lobe. – All of these cells are from the myeloid lineage. “Mononuclear cells” have by a single round nucleus within the cytoplasm and do not contain granules. A neutrophil, with a characteristic multilobed nucleus. – Lymphocytes (T, B and NK cells ) from the lymphoid lineage. – Monocytes, macrophages and dendritic cells from the myeloid lineage. So, the divisions under the microscope do not line-up perfectly with the cellular lineage. All granulocytes are myeloid cells (are of myeloid lineage). Some mononuclear cells are from the lymphoid lineage, whereas others are of myeloid lineage. A monocyte. 35 Overview Introduction to Immunology. Importance of Immunology. Key definitions, function of the immune system, and what happens when the immune system does not function as expected. Overview of the immune response. Anatomy of the immune system. Innate vs adaptive immune system. Innate immune response in detail. Next lecture: antigen presentation and the adaptive immune response. 36 Innate immune system Intact barriers and defensive mechanisms – – – – – Skin and mucosal epithelium. Cough reflex; movement of mucus by cilia. Ability to empty bladder. Acidic pH of stomach; lysozymes in saliva. Normal bacterial flora in gut and vagina. Cells Cytokines Complement system 37 Key definitions: phagocytes, micropinocytosis, antigen presenting cells, chemokines and cytokines. 38 Phagocytes Phagocytosis is the process by which a cell uses its plasma membrane to engulf a large particle or microbe. The microbe can then be killed. A cell that performs phagocytosis is a phagocyte. Key (“professional”) phagocytes are neutrophils, monocytes, macrophages, and dendritic cells. Macrophages tend to live in tissues (“resident tissue macrophages”) whereas monocytes and neutrophils circulate in blood. https://en.wikipedia.org/wiki/Phagocytosis 39 Macropinocytosis Macropinocytosis is a way that cells can “sample” the extracellular fluid around them. It is achieved by invagination of their cell membrane, which results in vesicle formation within the cell. Dendritic cells, a type of professional antigen presenting cells (APCs) use micropinocytosis to sample the fluid looking for foreign antigens, which they then present to the adaptive immune system. https://en.wikipedia.org/wiki/Pinocytosis 40 Antigen presenting cells (APCs) Antigen presentation is the process of displaying an antigen to T cells of the adaptive immune system, which can lead to the generation of an adaptive immune response. It is a key bridge between the innate and adaptive immune system. All nucleated cells are capable of antigen presentation. – Presenting endogenous antigens via MHC class I to cytotoxic T cells (CD8+ cells). – Allows detection of intracellular pathogens such as viruses. Professional antigen presenting cells additionally present exogenous antigens they have picked up through phagocytosis or micropinocytosis. – Presenting these via MHC class II to helper T cells (CD4+ cells). – Allows detection of extracellular pathogens such as bacteria. Key (“professional”) antigen presenting cells are dendritic cells, macrophages and B cells. – Thus note dendritic cells and macrophages function as both APCs and phagocytes, whereas neutrophils are phagocytes but not professional APCs. 41 Chemokines and cytokines Cytokines are peptides released as “chemical signals” by which cells communicate with each other. For example, in the immune system, they can convey a “danger signal” required to activate the adaptive immune system. Chemokines (chemo-attractive cytokines) are cytokines which attract cells to their site of release. Used to bring immune cells to the site of inflammation. There are many cytokines in both the innate and adaptive immune system. 42 Innate immune system activation 43 Innate immune system When a microbe breaches an epithelial barrier, it will encounter tissue macrophages, the resident phagocytic cells in tissue. These cells recognise that microbes using pattern recognition receptors (PRRs) which recognise pathogen associated molecular patterns (PAMPs) on the surface of the microbes. PAMPs consist of various structures which occur on foreign microbes but not on human cells, such as bacterial lipopolysaccharides (LPSs), double-stranded RNA and many others. – Damage/danger associated molecular patterns (DAMPs) are expressed by human cells when they are damaged by infection or trauma, and are also recognised by PRRs. PRRs are protein receptors that specifically recognise PAMPs. Many kinds: TOL-like receptors, RIG-like receptors, etc. PRRs are both on the cell surface, and within the cytoplasm. Macrophages then: – Release cytokines to signal danger and enhance immune response. – Release chemokines to attract other immune cells (early: dendritic cells; neutrophils; monocytes; later: lymphocytes). Dendritic cells are recruited from blood, also identify microbe antigens via phagocytosis and micropinocytosis, then travel to lymph nodes to activate the adaptive immune system via antigen presentation. The complement system is also activated. – Various mechanisms not covered in this lecture! 44 Cytokines The effect of cytokine release by macrophages, DCs and the complement system is to: – Attract further immune cells, particularly neutrophils, to the site of infection (via chemokines). – Provoke inflammation. 45 Inflammation Dilatation of blood vessels causes increased blood flow to the area, causing both heat and redness (erythema). Increased permeability of the blood vessel walls results in the leakage of fluid into the tissues, resulting in swelling. Swelling of the tissue, and the release of multiple different chemicals into the area, stimulates pain fibres, resulting in pain. Thus the cardinal signs of inflammation are heat, redness, pain, and swelling. https://en.wikipedia.org/wiki/Inflammation 46 Cellular recruitment Key cells attracted (via chemokines) to the site of inflammation are: – Neutrophils which function to phagocytose bacteria and fungi. Neutrophils enter rapidly (within hours). – Lymphocytes are later recruited to the site of inflammation after dendritic cells bearing the foreign antigen have migrated to the local lymph node and stimulated them. This process takes 2 – 7 days. Acute versus chronic inflammation can therefore be partly distinguished by the predominant cell type in the tissue visible (neutrophils vs lymphocytes). 47 Cells of the innate immune system Granulocytes: white blood cells containing granules in their cytoplasm. Capable of phagocytosis. – Neutrophils, eosinophils, basophils. Monocytes and macrophages. Large cells involved in phagocytosis and antigen presentation. Dendritic cells (DCs). The most important antigen presenting cell. Natural killer (NK) cells. 48 Three key roles of innate immune system; three key cells A simplistic view: Raising the alarm: macrophage Alert adaptive immune system (antigen presentation): dendritic cell Kill invading pathogen/phagocytosis: neutrophil (“foot soldier”) Janeway’s Immunobiology, 9th edition. 49 Macrophages and monocytes Macrophages are resident in almost all tissues (“tissue macrophages”), but some circulate in blood (“monocytes”). First cellular line of innate immunity: phagocytose microbes, release cytokines/chemokines to draw in other cell types. Also have role in antigen presentation, although DCs more important in this role. Janeway’s Immunobiology, 9th edition. 50 Dendritic cell Dendritic cells are most important surveillance cells in the immune system. They migrate from the blood to the tissues on activation. When they encounter foreign antigen, they ingest it, then migrate to lymph nodes and present the foreign antigen on their surface to the lymphocytes for activation of adaptive immunity. – In this way, dendritic cells are the key bridge between the innate and adaptive immune systems. – More on this in lecture 2. Dendritic cells can ingest: – Micobes via phagocytosis. – Free proteins in blood, and some microbes, via macropinocytosis. This allows them to pick up pathogens without recognisable receptors, or fragments of damaged, virus-infected host cells. Janeway’s Immunobiology, 9th edition. 51 Neutrophil Granulocytes (aka polymorphonuclear cells) comprise neutrophils, eosinophils and basophils. Neutrophils are the most numerous leukocytes in blood. They are the main phagocytes of the immune system: they efficiently phagocytose and destroy a range of microbes, particularly bacteria and fungi. They are rapid, crucial early responders; their absence can lead to rapid, overwhelming bacterial infection such as febrile nueutropaenia in patients on cytotoxic chemotherapy. Janeway’s Immunobiology, 9th edition. 52 Eosinophils and basophils Main evolutionary role is thought to be in defence of parasites, which are too large to be ingested by neutrophils or macrophages. Key cells involved in allergic reactions; targeted by new drugs to treat diseases such as asthma. Less numerous than neutrophils and significantly less important; their absence does not seem to predispose to infection. Janeway’s Immunobiology, 9th edition. 53 Mast cells Granulocytes which reside in tissue rather than blood (although they originate in bone marrow). Main role is in allergic inflammation. Janeway’s Immunobiology, 9th edition. 54 Natural killer cells Lymphocyte origin (like T and B cells), but function as part of the innate immune system). Unlike T and B cells, they do not display antigen recognition receptors. They play a key role in surveillance for abnormal cells in the body, for example tumour cells or cells infected by virus. 55 Complement system As well as encountering macrophages and DCs, microbes will trigger the complement system. Complement system is a set of proteins which enhance (or complement) the ability of antibodies and phagocytic cells to fight infection. Synthesised in liver and circulate in blood as inactive precursors. When triggered, they interact in a cascade, the end result of which is: – Release of potent inflammatory cytokines. – Opsonisation: complement proteins coat the surface of bacteria, which aid in their phagocytosis by phagocytes. – Formation of a “membrane attack complex” (MAC) which can puncture holes in bacterial cell walls, causing them to lyse. Microbes can trigger the complement system in three ways: – Classical pathway: triggered by antigen/antibody complexes. – Alternative pathway: via binding of complement proteins to microbial surface. – Mannose-binding lectin pathway: by plasma lectin binding to microbes. https://en.wikipedia.org/wiki/Complement_system 56 Coordination of the innate and adaptive immune system Different parts of the innate immune system must be activated in response to varying threats. This is one function of the adaptive immune system. The innate immune system raises the alarm about infection and notifies the adaptive immune system. The adaptive immune system then tunes up / activates the best parts of the innate immune system to fight 57 off the infection. Summary The immune system is a complex, dynamic system broadly broken down into the innate and adaptive systems. The innate system comprises a range of barriers such as the skin, specialised cells which perform phagocytosis and antigen presentation and the complement system. The innate immune system and adaptive immune systems have separate roles but work closely together. 58 Next time Antigen presentation. The adaptive immune system, including humoral and cell-mediated immunity. – Generation of lymphocyte receptor diversity. – Antibodies. – Tolerance. – Immunological memory. 59 Question Mrs GH is a 64 year old female undergoing chemotherapy for the treatment of breast cancer. She completed a cycle of chemotherapy 1 week before presenting to the ED with a high fever. Blood tests reveal a severe deficiency of neutrophils in the blood (neutropenia), with a level of 0.2 (normal range 4.0-7.0) Which of the following responses are likely to be true? A. B. C. D. E. The patient has developed an infection because the chemotherapy has impaired her adaptive immune system. The patient has most likely developed a severe viral infection. Specific antibodies against the infecting organism should appear in the blood in large amounts within hours. Antibiotics should be given urgently because the patient has most likely developed an acute bacterial infection. Fungal infection is more likely to occur in the setting of neutropenia. 60 Question Mrs GH is a 64 year old female undergoing chemotherapy for the treatment of breast cancer. She completed a cycle of chemotherapy 1 week before presenting to the ED with a high fever. Blood tests reveal a severe deficiency of neutrophils in the blood (neutropenia), with a level of 0.2 (normal range 4.0-7.0) Which of the following responses are likely to be true? A. B. C. D. E. The patient has developed an infection because the chemotherapy has impaired her adaptive immune system. The patient has most likely developed a severe viral infection. Specific antibodies against the infecting organism should appear in the blood in large amounts within hours. Antibiotics should be given urgently because the patient has most likely developed an acute bacterial infection. Fungal infection is more likely to occur in the setting of neutropenia. 61 [email protected] 62