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BEYOND THE BRAIN:
 INFECTION AND INFLAMMA TION Hassan IsmahelPLAN FOR THE EVENING 1.Cover the key ILOs relating to inflammation and infection….immunology basically! 2.Scatter some interactive sections in between 🧠 3.Get you all exam ready! 🤓 Beyond the brain 2 ILOS S • Describe the white blood cells responsible for both innate and adaptive immune responses. • Describe the primary and secondary lymphoid organs and outline their functions. • Summarise antibody structure and function. • Explain how T lymphocytes develop. • Understand the basic responses to either an extracellular bacterial or a viral infection. • Summarise the role of T helper lymphocytes, in particular how they interact with B lymphocytes. • Describe inflammation both as a protective response and as a cause of pathology seen in certain conditions. • Detail the basic cellular processes that occur during the adaptive immune response • Describe, in a simplified form, how antibodies are produced • Relate the structure of antibody to its specificity and function • Understand the role of MHC in cell-mediated immunity and the activation of T lymphocytes Beyond the Brain 3 !INTERACTIVE QUESTION You’ve been out to Hive in uncomfortable 5-inch stiletto’s and get kicked out by the bouncers after one too many Pints of Fun – you decide to walk home barefooted, and end up stepping on some glass, leaving a bleeding cut on the bottom of your foot. Which arm of the immune system will be the first to respond? Innate Adaptive Beyond the Brain 4INTERACTIVE QUESTION You’ve been out to Hive in uncomfortable 5 inch stiletto’s and get kicked out by the bouncers after one too many Pints of Fun – you decide to walk home barefooted, and end up stepping on some glass, leaving a bleeding cut on the bottom of your foot. Which arm of the immune system will be the first to respond? Innate Adaptive Beyond the Brain 5SUMMARY OF IMMUNE RESPONSE Beyond the Brain 6SUMMARY OF IMMUNE RESPONSE Beyond the Brain 7 INNA TE IMMUNE SYSTEM Beyond t8e Brain INNA TE IMMUNE SYSTEM - OVERVIEW • Immunology = body’s natural defence to fight pathogens • Key featuresof the innate immune system: The innate immune system will respond the same way every timeand acts without memory • • Immediate: activated within seconds/minutes • Innate immune system has no memory ▯ mounts same immune response every time • Occurs at site of the wound (locally) • Deals with majority of pathogens • The innate immune system is composed of 2 things: 1) Soluble factors (substances released into extracellular fluid or mucosal surfaces) a. Antibacterial factors b. Complement system 2) Cellular factors a. phagocytes (neutrophils and macrophages) b. Mast cells, basophils, eosinophils, NK cBeyond the Brain 9SOLUBLE FACTORS 1 – 
 ANTIBACTERIAL FACTORS (NOT IMPORTANT) • Lactoferrin • Protein found at mucosal surfaces • Lactoferrin promotes rapid uptake of iron by the gut. In doing so, it reduces the amount of iron available to gut bacteria. • Chelates iron and therefore reduces soluble/free iron in the GI and respiratory tract • This Inhibits the growth of bacteria by reducing free iron available to them (since all bacteria need iron for growth) • Lysozyme • Enzyme present at mucosal surfaces e.g. nose, throat, respiratory tract, gut • Breaks down the gram +ve cell wall ▯ reduces chance of gram + bacteria causing symptomatic infectionSOLUBLE FACTORS 2 – 
 COMPLEMENT • The complement system is a collection of circulating and cell-membrane proteins that enhance (complement) the ability of antibodies and phagocytes to eliminate pathogens, whilst also promoting inflammation and killing pathogens directly. • Complement is particularly active in the blood, helping prevent the growth of blood- borne antigens • The complement system is an enzymatic cascade (similar to coagulation cascade) which involves sequential proteolytic cleavage that activates the next protein. Amplification occurs, with a small amount of activated compliment initially leading to a high number of effector moleculesMATCHING ACTIVITY – ZOOM
 MATCH THE COMPLEMENT ACTIVATION PATHWAYS WITH THEIR MECHANISM OF ACTIVATION CLASSICAL LECTIN ALTERNATIVE Beyond the Brain 12 SOLUBLE FACTORS 2 – 
 COMPLEMENT ACTIV A TION • There are 3 methods of complement activation, which then converge onto a common pathwayresulting in anti-infective effects 1) Classical pathway: antibodies bind to target antigens on the pathogen surface, and their Fc region acts as a site for complement binding and activation 2) MB-lectin pathway: liver produces a molecule called “mannose binding lectin” which binds to mannose on the pathogen surface, triggering complement activation 3) Alternative pathway: the surface of the pathogen creates an environment which directly activates complementSOLUBLE FACTORS 2 – 
 COMPLEMENT OUTCOMES • The 3 main outcomes of complement activation are: 1. Recruitmentof inflammatory cells 2. Opsonization of pathogens • Complement coats bacteria and makes it more palatable to phagocytes ▯ makes phagocyte want to engulf it 3. Killing of pathogens through the membrane attack complex (MAC) • The MAC consists of a combination of C5b, C6, C7, C8 and C9 • The MAC punches multiple holes through the membranes of pathogens, causing lysis by destabilising the cell membraneBeyond the Brain 15BUT HASSAN, QUICK TANGENT – WHAT ARE CYTOKINES AND CHEMOKINES? 😕 • Cytokines: proteins made by a cell that affect the behaviour of other cells, particularly immune cells • If made by lymphocytes they are often called “interleukins” • Chemokines: a subset of cytokines. Small chemoattractant proteins that promote the migration and activation of cells, particularly immune cells • E.g. IL-8 which induces neutrophil chemotaxis towards the site of injury Beyond the Brain 16 CELLULAR FACTORS 1
 MACROPHAGES • Macrophages found in tissue are derived from monocytes in blood • MACROPHAGES ARE NOT FOUND IN BLOOD!! • Functions: 1. Phagocytosis: specialises in destruction of pathogens. Also remove harmless debris e.g. tattoo pigment 2. Cytokine production: M1 macrophages – inflammatory: TNF alpha etc; M2 macrophages – regulator: IL10 etc 3. Antigen presentation: macrophages can process engulfed antigens and travel to the nearest draining lymph node to present it to T cells via MHC II PATTERN RECOGNITION RECEPTORS AND TLRs •On their surface, macrophages have multiple pattern recognition receptors which recognise conserved patterns found on microorganisms •Toll-like receptors (TLRs) are a subtype of PRR expressed on innate cells e.g. macrophages, dendritic cells and NK cells, which recognise pathogen-associated molecular patterns (PAMPs) PAMPS are highly conserved structures found on • microorganisms •E.g. LPS on the surface of “gram -“ bacteria •Once a PAMP is recognised by a TLR, it activates an inflammatory response involving phagocytosis, antigen presentation via MHC Beyond the brain 18 CELLULAR FACTORS 2
 NEUTROPHILS • The “foot soldier” of the immune system • This analogy refers to the fact that like soldiers, neutrophils arrive at the infection and die at the site • Neutrophils constitute 50-70% of WBCs – majority of cells • Provide a rapid response to infection Functions: 1. Chemotaxis: migrate towards bacterial products (e.g. LPS) via TLRs on their surface, chemokines (e.g. IL8), and “danger signals” (e.g. complement components) 2. Phagocytosis: will ingest and destroy pathogens using proteases, ROS (e.g. hydrogen peroxide), lysozyme etc 1. Neutrophil response also destroys cells through enzymes, H2O2 etc 3. Degranulate: release toxic granules extracellularly. These granules contain cytotoxic factors which kill pathogens 4. Die locally: producing pus, resulting in purulent fluid WBC EXTRA V ASA TION • Neutrophils are among the inflammatory response in an • Adhesion molecules, such upregulated on the surface of basement membrane epithelial cells • IL-8 is an important chemokine in attracting neutrophils to the site of injury along a chemotactic gradient • Diapedesis - movement of neutrophils out of blood vessel and into the interstitial fluid Beyond the Brain 20 CELLULAR FACTORS 3
 EOSINOPHILS • Classically respond to parasites • Play a role in allergic reactions and asthma • Constitute 1-6% of all WBCs Functions: 1.Chemotaxis: migrate in response to chemokines e.g. eotaxin (an eosinophil-specific chemokine) 2.Degranulation: release toxic substances onto the surface of parasites E.g. major basic protein, eosinophil cationic protein, eosinophil peroxidase 3.Cytokine production: they produce cytokines which drive inflammation (particularly Ab-mediated inflammation): IL1, IL2, IL4, IL8, TNF CELLULAR FACTORS 4
 BASOPHILS • Basophils in blood are the precursors of mast cells in tissue • Mast cells are the “border guard” of the immune system, guarding mucosal sites • Play a major role in allergy Functions: 1. Cytokine production: store many pre-formed cytokines that are ready for release to attract and drive an immune response 2. Degranulation: rapid release of pre-formed granules containing cytokines and mediators, in particular histamine 1. Responsible for the wheal and flare reactionCELLULAR FACTORS 5
 NK CELLS •NK cells are found in peripheral blood and are GRANULAR lymphocytes – they are very rapid and take part in the immune response •These also help kill virus- infected cells and cancer cells by perforin and granzymes CELLULAR FACTORS BONUS:
 DENDRITIC CELLS • The dendritic cell is the link between the innate and adaptive immune response • They are derived from the same precursor as macrophages • at pathogen destruction, however dendritic cells are very good at sampling the environment and presenting antigens • Functions: 1. Phagocytosis: unlike macrophages, dendritic cells are not specialised in destruction of pathogens. Instead, they ingest and process the antigen and function as antigen presenting cells 2. Migration: dendritic cells sit within tissues and have processes that allow them to constantly sample the environment. Once activated, they migrate to the nearest draining lymph node 3. Antigen presentation: dendritic cells present antigens to CD4 T-cells to initiate an adaptive immune response QUESTION! A PATIENT PRESENTS TO HIS GP COMPLAINING OF SHORTNESS OF BREATH, COUGH AND WHEEZE WHENEVER HE GOES FOR A MORNING RUN IN VERY COLD WEATHER. HIS GP EXPLAINS THAT HE IS LIKELY EXPERIENCING ATYPICAL ASTHMA. WHICH CELL TYPE IS HIGHLY INVOLVED IN THIS RESPONSE? A – Macrophages B – NK cells C – Mast cells D - Neutrophils E – Complement 25 QUESTION! A PATIENT PRESENTS TO HIS GP COMPLAINING OF SHORTNESS OF BREATH, COUGH AND WHEEZE WHENEVER HE GOES FOR A MORNING RUN IN VERY COLD WEATHER. HIS GP EXPLAINS THAT HE IS LIKELY EXPERIENCING ATYPICAL ASTHMA. WHICH CELL TYPE IS HIGHLY INVOLVED IN THIS RESPONSE? A – Macrophages B – NK cells C – Mast cells D - Neutrophils E – Complement 26QUESTION! Which two inflammatory cells are considered ‘antigen presenting cells’? A.B cells and Mast cells B.Macrophages and Eosinophils C.Neutrophils and Eosinophils D.Macrophages and B cells E.Eosinophils and Mast cells Beyond the brain 27QUESTION! Which two inflammatory cells are considered ‘antigen presenting cells’? A.B cells and Mast cells B.Macrophages and Eosinophils C.Neutrophils and Eosinophils D.Macrophages and B cells E.Eosinophils and Mast cells There are 3 main antigen presenting cells: • Macrophage, Dendritic cell, and B cells Beyond the brain 28BREAK TIME / QUESTIONS Beyond the Brain 29ADAPTIVE IMMUNE SYSTEM Beyond 30e BrainADAPTIVE IMMUNE SYSTEM - 🔑 POINTS •Driven by T and B lymphocytes •Triggered by APCs •Occurs in lymph nodes •Shows memory •Allows for a more rapid and effectiveimmune response if the same infection is encountered again, since plasma cells (memory cells) can produce the specific antibody to directly combat the infection. Beyond the Brain 31MCQ TIME! Which cell binds to, and thus may become activated by, MHC class 2 receptors expressed by antigen presenting cells? A – B cells B - CD4 T cells C - CD8 T cells D – Dendritic cells E – Macrophages Beyond the Brain 32MCQ TIME! Which cell binds to, and thus may become activated by, MHC class 2 receptors expressed by antigen presenting cells? A –B cells – antigen presenting cell which expresses MHC II on surface during immune response B - CD4 T cells – the co-receptor CD4 is expressed on helper T cells and binds to class II MHC proteins C - CD8 T cells – the co-receptor CD8 is expressed on cytotoxic T cells and binds to class I MHC proteins D – Dendritic cells – antigen presenting cell which expresses MHC II on surface during immune response E – Macrophages – antigen presenting cell which expresses MHC II on surface during immune response Beyond the Brain 33 MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) • MHC antigens = self-antigens found on the plasma membrane of cells • Allows for antigen presentation to T cells • The MHC class II pathway involves engulfment of extracellular molecules by APCs: If it is a normal molecule, the APC will do nothing with it • •If a molecule is pathogenic, it will be broken down and processed onto an MHC II molecule to form an MHC:antigen complex which is expressed on the surface of the APC where it awaits interaction with the TCR on CD4 T cells •HLA class II proteins bind peptides/antigens derived from extracellularand cell surface proteins including peptides derived Hassan top from bacteria tip: • The MHC class I pathway involves presentation of intracellular Remember, pathogens by all nucleated cells “one for all” •HLA class I molecules bind peptides/antigens derived from intracellular proteins including peptides derived from viruses •The MHC I molecule is expressed on the surface of the cell where it awaits interaction with CD8 T cells which induce apoptosis via perforin and granzymes 34WAIT…WHA T’S THE DIFFERENCE BETWEEN TLRs AND MHC?? Many individuals share the same TLRs, however MHC antigens are individual-specific unless individuals are identical twins (reason organs may be rejected during a transplant) Beyond the Brain 35 L YMPHOID ORGANS •organsy lymphoid •Secondary lymphoid organs • Where lymphocytes are activated •and maturephocytes are formed • Lymph nodes • Bone marrow – B cells • Spleen • Thymus – T cells •tissue (MALT) – tonsils, appendix etc. BONE MARROW AND THYMUS Bone marrow (red bone marrow specifically) #Function and drainage of lymph • • B lymphocytes are produced and mature in the bone marrow • T lymphocytes are produced in the bone marrow, but mature in the Thymus • Thymus • Site where T lymphocytes mature • Do not return to thymus after maturing • Whilst in the thymus T lymphocytes are NAÏVE and haven’t become activated • T cell precursors leave the thymus as either CD4 “helper” or CD8 + “killer” T cells • Thymus checks lymphocytes before release into circulation and removes auto-reactive T cells to prevent autoimmunity • Allows T lymphocytes which respond to foreign antigens, but not self-antigens (autoimmunity) leave the thymus. Destroys autoreactive lymphocytes to prevent autoimmunity. 38 L YMPH NODES • Lymph nodes serve as filters for lymph (protein-rich fluid absorbed into lymphatics from the interstitium) Lymph drains into a lymph node via several afferent lymphaticson the convex surface. It gets filtered and • exits via one efferent lymphatic vesselat the hilum. • The parenchyma of a lymph node consists of a cortex of dense lymphoid tissue found peripherally, and a more loosely arranged medulla closer to the hilum more centrally • The cortex is divided into an outer cortex and a deep cortex/paracortex • Outer cortex: Consists of lymphoid nodules which are the clusters of activated and proliferating B lymphocytes (and site of memory B cell production) • The lighter centre of lymphoid nodule is called the germinal centre. This is where B lymphocytes proliferate and differentiate inplasma cells • Paracortex(deep cortex/T-cell area/thymus-dependant region of lymph node): between the cortex and medulla • Site of activation & proliferation of T cells, & production of memory T cells • The medulla contains strandsof dense lymphoid tissue – the medullary cords – which are surrounded by lymph in the medullary sinuses. Medullary cords contain plasma cells which secrete antibodies during a humoral response Beyond the Brain 39 L YMPH NODES #SIMPLIFIED TLDR? Here’s a quick summary! • B cells: found in outer cortex. Presence of a germinal centrealways indicates a humoral response is occurring • Plasma cells: found in medullary cords • T cells: found in paracortex (deep cortex) • Macrophages: found in subcapsular and medullary sinuses Beyond the Brain 40 SPLEEN Similar to lymph nodes but receives blood instead of lymph Structure Function • White pulp – immune function. 1. Removing old or effete blood cells nd Consists of mostly lymphocytes and other blood components by macrophages phagocytosis • Initiates an immune response by B 2. Storing iron recycled from red blood and T cells in the spleen in response to foreign antigens in the cells within macrophages of RES blood 3. Initiating immune responses by B cells • Red pulp – filtering function. and T cells in response to antigens in • Worn out and defective RBCs are circulating blood broken down by macrophages in red pulp; with the haeme, globin and iron recycled to make new RBCs Beyond the Brain 41Beyond the Brain 42INTERACTIVE QUESTION
 IS THIS A T CELL OR A B CELL? T cell B cell Beyond the Brain 43INTERACTIVE QUESTION
 IS THIS A T CELL OR A B CELL? BOTH! T cell B cell Beyond the Brain 44CELLS OF THE ADAPTIVE IMMUNE SYSTEM 
 - LYMPHOCYTES • Unable to recognise antigens directly, so need to have epitopes displayed to them directly via MHC receptors • Most lymphocytes are not circulating, but rather sitting in lymph nodes B Lymphocytes - mediators of humoral immunity. • • Capable of producing antibodies which bind to extracellular pathogens e.g., bacteria • T Helper cells (CD4+) • T lymphocytes only recognise peptide fragments of protein antigens that are bound to specialised peptide display molecules called Major Histocompatibility Complex (MHC) molecules on the surface of antigen-presenting cells (APCs). • When T helper cells are activated, they produce cytokines which promotes activation of macrophages, inflammation and proliferation and differentiation of T and B Lymphocytes. • T Killer Cells (CD8+) - these are cytotoxic T lymphocytes which kill cells harbouring intracellular microbes. These mediate cell-mediated immunity against intracellular pathogens e.g., viruses Beyond the Brain 45Beyond the Brain 46 ADAPTIVE IMMUNITY 1 – 
 HUMORAL IMMUNITY Humoral immunity = antibodies = B cellssss This is mediated primarily by B cells. B cells mature into plasma cells which •synthesise and secrete specific antibodies (immunoglobulins) which target antigens on pathogens •Functions to neutralise and eliminate extracellularpathogens •e.g. bacteria and fungi outside cells in extracellular fluid(blood, lymph, interstitial fluid etc) • Binding of a B cell receptor to an antigen stimulates B cell activation, clonal expansion , and differentiation into plasma cells which synthesise and secrete antibodies with the same specificity as the B cell receptor that bound to the antigen. This assures that the antibody produced by the plasma cell will bind to the antigens found on the pathogen.Under the influence of helper T cells and other stimuli (e.g. IL4) the B cells become activated and proliferate, B CELLS CONT’D resulting in clonal expansion. B cells differentiate 4 different ways: 1. Differentiate into plasma cells: mature cells which secrete antibodies which have the same specificity as that of the B-cell receptor which recognised the antigen 2. Some undergo isotype switching (class switching): the B cell switches the isotype of antibody it is producing into a more specific, and hence effective, antibody. 3. Repeated exposureto an antigen results in the production of antibodies with increased affinity for the antigen. This is called affinity maturationand results in antibodies which can better bind to and neutralise the pathogen 4. Some differentiate into memory B cells: These long-lived cells allow for a more rapid and effective immune response if the same pathogen is encountered again, since the memory B cells produce specific antibodies which directly combat the infection Beyond the Brain 48 ANTIBODIES • The main output of B cells….well, plasma cells technically • Antibodies have 4 chains • 2 light chains at the top • 2 heavy chains at the bottom • Top end = variable region (Fab region) which acts as the antigen binding site Bottom end = constant region (Fc region) which binds to cell- • surface receptors called Fc receptors, allowing antibody to bind to other components of the immune system. Binds to phagocytes and activates complement (via classical pathway) • 3 characteristic features • 1) sticky • 2) specific • Has same specificity as B cell receptor ▯ only binds initiallyn antigen which bound to the B cell surface • 3) bind cells Beyond the Brain 49QUESTION TIME! Beyond the Brain 50 ANTIBODY CLASSES • 1) IgM • 10 binding sites - chances of antigen binding Initially released by immune system to increase chances of binding • with antigen • Does not cross placenta due to large size 2) IgA • a. “Antiseptic paint” -Present in secretions and lines epithelial and mucosal surfaces • 3) IgD • Found on B cells as B cell receptors – involved in B cell activation • 4) IgG • Most common antibody in blood – only antibody which can cross the placenta to give foetus passive immunity. • Main antibody involved in memory immune response • 5) IgE • Binds to mast cells and basophils and triggers hypersensitivity reactions through the release of histamine and other inflammatory mediators Remember: M A D G E Beyond the Brain 51 ADAPTIVE IMMUNITY 2 – 
 CELL-MEDIA TED IMMUNITY Cell-mediated immunity = T cells •Primarily mediated by 2 key cells: CD4 T cells and CD8 T cells •Helper T cells do not directly attack pathogens. Instead, they facilitate the immune response by directing B cells and CD8 T cells, and through cytokine secretion •Cytotoxic T cells directly attack invading pathogens •Particularly effective against: •Intracellular pathogens e.g. viruses, bacteria or fungi within cells •Some cancer cells ADAPTIVE IMMUNITY 2 – 
 CELL-MEDIA TED IMMUNITY CONT’D •Once activated, helper T cells divide and specialise into various T cell subtypes: T 1 cells: involved in cell-mediated immunity. Interact primarily with macrophages, cytotoxic T • H cells to maximise killing ability of macrophages and proliferation of CD8 T cells. •Memory tip: MHC 1 and Th1 are involved in cellular immunity •Primarily secrete IFN •Defence against intracellular microbes •Involved in inflammation •Overactivation ▯ type IV hypersensitivity •T 2 cells: involved in humoral immunity. Interact primarily with B cells, eosinophils and mast H cells. Induce B cell isotype switching. •Memory tip: MHC 2 and Th2 are involved in humoral immunity •Secretion of interleukins, predominantly IL4 •Host defence against helminths (parasitic worms) Involved in allergic reactions • •Overactivation ▯ type I hypersensitivity Not important (yet), but I know ur gonna peek anyways Beyond the Brain 54Beyond the Brain 55PUTTING IT ALL TOGETHER Beyond the Brain 56WHEN THINGS GO WRONG - 
 HYPERSENSITIVITY • There are 3 different ways the immune system can go wrong: 1. Hypersensitivity – inappropriate response to external antigen 2. Autoimmunity – inappropriate response to self-antigen 3. Immunodeficiency – insufficient immune response •Hypersensitivity refers to diseases in which immune responses to foreign antigens causes inflammation and damage to self •Hypersensitivity reactions may occur in 2 situations 1. Response to foreign antigens may be dysregulated or uncontrolled, resulting in tissue injury 2. The immune response may be directed against self (autologous) antigens as a result of failure of self-tolerance. This is called autoimmunity Beyond the Brain 57These ones important for you guys-especially asthma & anaphylaxis MCQ FUN 1) During the inflammatory response, leukocytes extravasate from the circulation to the site of tissue damage.   What is the name given to the part of the process indicated by 3 in the above diagram A) Diapedesis B) Tight binding C) Intergration D) Chemotaxis E) Rolling adhesion MCQ FUN 1) During the inflammatory response, leukocytes extravasate from the circulation to the site of tissue damage.   What is the name given to the part of the process indicated by 3 in the above diagram A) Diapedesis B) Tight binding C) Intergration D) Chemotaxis E) Rolling adhesion MCQ FUN What antibody class are best at activating complement A) IgA B) IgD C) IgE D) IgG E) IgM MCQ FUN What antibody class are best at activating complement A) IgA B) IgD C) IgE D) IgG E) IgM Look at all those potential binding sites 😍MCQ FUN What is happening on Saturday 5 November at the Royal college of Physicians and Surgeons of Glasgow? A) Halloween B) New year C) Christmas D) Fuy Gawkes night E) 10 anniversary Glasgow neuro conference 😍😍😍 Beyond the Brain 63MCQ FUN Beyond the Brain 64Beyond the Brain 66SEE U L8R 🐊 Hassan Ismahel 2364876I@student.gla.ac.uk