IMM1 Chapter 1, 2, 3 - Duinkerken-1 PDF

DT 1 Ch. 1-3|5|7-8 WG interactive quizzes Preparation assignment Preparation assignment DEADLINE...

DT 1 Ch. 1-3|5|7-8 WG interactive quizzes Preparation assignment Preparation assignment DEADLINE DEADLINE indicated on Canvas indicated on Canvas DT 2 Ch.4|6|9|11 PRAC 1  MENTIMETER Why do we have an immune system? Our immune system ensures we stay Recognize HEALTHY Remove www.dictionary.com Remember IMMUNE SYSTEM  A diffuse, complex network of interacting cells, cell products, and cell-forming tissues that protects the body  from pathogens and other foreign substances  destroys infected and malignant cells WOUND HEALING  and removes cellular debris http://podiatryhq.com.au/wound-healing/ 2 CBI 2023 INTRO  IMMUNITY Our immune system needs to discriminate between self and non-self AND harmless versus harmful SELF NON-SELF HEALTH HARMLESS HARMFUL NO YES IMMUNE RESPONSE YES NO SELF NON-SELF HARMFUL HARMLESS 3 CBI 2023 INTRO  IMMUNITY There is a delicate balance in immune activation (inflammation) and inhibition (tolerance) SELF NON-SELF HEALTH HARMLESS HARMFUL NO YES IMMUNE RESPONSE YES NO SELF NON-SELF HARMFUL HARMLESS BALANCE inflammation tolerance 4 CBI 2023 INTRO  IMMUNITY A dysbalance in immunity can cause (severe) disease auto-immune disease infection SELF NON-SELF DISEASE HARMLESS HARMFUL YES NO IMMUNE RESPONSE NO YES SELF NON-SELF HARMFUL HARMLESS DYS-BALANCE cancer allergy inflammation tolerance 5 CBI 2023 INTRO  IMMUNITY How to treat immune related disease? auto-immune VA C C I N E S disease infection SELF NON-SELF HEALTH HARMLESS HARMFUL NO YES IMMUNE RESPONSE YES NO SELF NON-SELF RESTORE HARMFUL HARMLESS BALANCE cancer allergy inflammation tolerance 6 CBI 2023 INTRO  IMMUNITY Before we can use our immune system for treatment, w e n e e d t o k n o w w h a t t h e r i g h t b a l a n c e i s , h o w i t ’s a c h i e v e d , and what exactly causes dysbalance. BALANCE DYS-BALANCE inflammation tolerance 7 CBI 2023 INTRO  IMMUNOLOGY Parham 5th edition INTRODUCTION & INNATE IMMUNITY IMM1 Chapter 1-3 Mon 30-10 Elements of the immune system and their role in defense Complement, Cells & Receptors ADAPTIVE IMMUNITY: T CELLS IMM 2 Chapter 5 & 7 Tue 31-10 T cell Antigen recognition and Development IMM 3 Chapter 5 & 8 Wed 01-11 Dendritic cells, T cell activation and immunity 8 CBI 2023 Overview  Chapter 1 Elements of the Immune System and Their Roles in Defense Goal: to know the components of the immune system I: What is the difference between innate and adaptive immunity? II: What is the function of these components in immunity? 9  IMMUNOLOGY Intro: immune system & defense PART II The complement system PART III Innate cellular responses 10 CBI 2023 Overview lecture  What components of the immune system do you remember? 11 CBI 2023 IMM1 PART I  Physical barriers form the first line of defense against pathogens Figure 1.5 Physical barriers separate the body from its external environment. 12 CBI 2023 IMM1 PART I  The innate immune system forms the second line of defense: Induction of inflammation SIGNALING MOLECULES Figure 1.7 Innate immune mechanisms establish a state of inflammation at sites of infection. * Lecture IMM1 PART II & III CYTOKINE signaling molecule for activation Figure 1.8 CHEMOKINE signaling molecule for migration CBI 2023 IMM1 PART I 13  The adaptive immune system forms the third line of defense Numerous highly selective and variable specificities *Lecture Figure 1.17 Comparison of the B-cell and T-cell receptor IMM2 & 4 Slow response Activation and proliferation of pathogen specific lymphocytes Figure 1.8  CLONAL EXPANSION  One becoming many Figure 1.9 Selection of lymphocytes by a pathogen. 14 CBI 2023 IMM1 PART I  The adaptive immune system: Development and activation occurs in lymphoid tissues PRIMARY DEVELOPMENT OF ADAPTIVE IMMUNE CELLS Bone marrow: B cells * Lecture IMM6 Thymus: T cells * Lecture IMM2 SECONDARY A C T I VAT I O N O F A D A P T I V E I M M U N E C E L L S Lymph nodes * Lecture IMM3 & 6 Spleen Gut Associated Lymphoid Tissues (GALT) Figure 1.21 Lymphoid tissues in the human body Figure 1.9 Selection of lymphocytes by a pathogen. * Digital computer practical lymphoid organs 15 CBI 2023 IMM1 PART I  T cells form the cellular defense, B cells producing antibodies the humoral defense * Lecture * Lectures IMM2|3 IMM5-7 https://bit.ly/3aQRAWB Figure 1.20 (Part 2) Antibody-mediated mechanisms that combat infection 16 CBI 2023 IMM1 PART I  Close interaction between innate and adaptive immunity for optimal pathogen clearance COLLABORATION 1. Activation of adaptive immunity by innate dendritic cells * Lecture IMM3 2. Specific activation of innate immune cells by adaptive immunity: T cells and antibodies * Lecture IMM3 & 6 NEUTROPHIL MACROPHAGE Antibodies Figure 1.10 T cells 17 Figure 1.25 CBI 2023 IMM1 PART I  Immune cells arise from two common progenitors during hematopoiesis Figure 1.13 Blood cells and some tissue cells derive from a common pluripotent hematopoietic stem cell GRANULOCYTES TISSUE (APC) LYMPHOCYTES INNATE ADAPTIVE INNATE 18 CBI 2023 IMM1 PART I  What is correct concerning your innate immune system? A. It is composed of immune cells only B. The response takes some days to occur C. It forms the second line of defense D. It includes T cells, B cells and antibodies 19 CBI 2023 IMM1 PART I  Which statement is true? Lymphocytes A. have the same common precursor as myeloid cells B. include T cells, B cells and NK cells C. can arise from monocytes D. are always adaptive immune cells 20 CBI 2023 IMM1 PART I  Intro: immune system and defense o The immune system includes: leukocytes or immune cells, complement, antibodies & lymphatics o The immune system is subdivided in two main categories Innate immunity: from birth, fast response (minutes, hours)  First line of defense: barriers  Second line of defense: complement & innate immune cells  granulocytes (neutrophils), monocytes and macrophages, NK cells, dendritic cells Adaptive immunity: adaptable, slow response (days, weeks)  Third line of defense: T- and B cells, antibodies o Hematopoiesis is the development of immune cells Two common precursors for lymphocytes (adaptive, except NK cells) and myeloid cells (innate) o The lymphatic system is important for adaptive immunity Primary lymphoid organs for development (bone marrow & thymus) Secondary lymphoid organs for activation (lymph nodes, spleen, GALT) 21 CBI 2023 IMM1 PART I  IMMUNOLOGY Chapter 2 / 3 Innate immune response Goal: Understanding the working mechanism of the innate immune system I: What is the complement system and how does it work? II: Which cells and receptors are important and what is their function? 22 BMW 2023-2023 Chapter 2/3  IMMUNOLOGY PART I Intro: immune system & defense The complement system PART III Innate cellular responses 23 CBI 2023 Overview lecture  The complement system plays an important role during inflammation upon bacterial infection Figure 1.7 Innate immune mechanisms establish a state of inflammation at sites of infection. 24 CBI 2023 IMM1 PART II  Figure 2.3 Complement activation Yo u r c o m p l e m e n t s y s t e m c o m p l e m e n t s o n g o i n g i n f l a m m a t i o n and consists of plasma proteins with enzymatic activity COMPLEMENT  Most important factor is C3  Activated upon cleavage for tag & recruit  Cleaved into C3a and C3b (enzymatic reaction)  C3a: a n a p h y l a t o x i n immune cell recruitment inactive  C3b: c o m p l e m e n t f i x a t i o n TAG RECRUIT pathogen binding for phagocytosis and lysis  Phagocytosis and destruction of pathogen Figure 1.6 Immune defense involves pathogen recognition followed by pathogen destruction. 25 CBI 2023 IMM1 PART II  INFLAMMATION Anaphylatoxins (C3a) enhance inflammation within minutes through activation of endothelium and immune cell recruitment Figure 2.16 C3a and C5a are anaphylatoxins that augment the inflammatory response to infection. 26 CBI 2023 IMM1 PART II  Complement fixation (C3b) leads to enhanced phagocytosis by binding of complement receptors (CR) on phagocytes COMPLEMENT FIXATION  Recruited immune cells express complement receptors (CR)  Efficiently bind opsonized C3b  CR-C3b binding induces pathogen uptake by phagocytes  Endo- or phagocytosis  Degradation via fusion with acidic lysosomes Figure 2.10 Phagocytes have complement receptors that facilitate the uptake and degradation of pathogens coated with C3b. 27 CBI 2023 IMM1 PART II  Three pathways lead to complement activation, though are activated sequentially by different factors 1 2 3 S P O N TA N E O U S INDUCED activation activation hydrolysis protein binding to pathogen C3 convertase Figure 2.5 Three pathways of complement activation. TAG RECRUIT 28 CBI 2023 IMM1 PART II  Activation of C3 convertase is essential for cleavage of C3 Figure 2.7 The C3 convertase consists into C3a and C3b of two subunits 1. A LT E R N AT I V E PAT H W AY  First, a soluble C3 convertase is activated via C3 hydrolysis followed by binding and cleavage of an additional complement factor C3 C3 BINDING C3 CLEAVAGE hydrolysis extra factor cleavage CONVERTASE Figure 2.6  Next, opsonized C3b is used to form membrane bound C3 convertase C3 CONVERTASE 29 Figure 2.8 CBI 2023 IMM1 PART II  The lectin pathway activates C3 convertase after binding of MBL 2. L E C T I N PAT H W AY  First, a protein specifically recognizing sugars on the pathogen surface will bind  Mannose Binding Lectin (MBL)  Second, sequential cleavage of two complement factors by MBL forms C3 convertase C3 BINDING C3 CLEAVAGE INFLAMMATION & RECRUITMENT OPSONIZATION C3 CONVERTASE Figure 3.37 30 CBI 2023 IMM1 PART II  The classical pathway activates C3 convertase after binding of CRP and C1 3. C L A S S I C A L PAT H W AY  First, C-Reactive Protein (CRP) binds to the pathogen surface  Second, the complement factor C1 binds CRP  Third, sequential cleavage of two complement factors by C1 forms C3 convertase C3 BINDING C3 CLEAVAGE INFLAMMATION & RECRUITMENT OPSONIZATION Figure 3.40 31 CBI 2023 IMM1 PART II  C3b is also important for formation of the membrane attack complex (MAC) and pathogen lysis Figure 2.12 Cleavage of C5 by the alternative C5 convertase C3b can also bind C3 convertase on pathogen surface C5b initiates formation of the Membrane Attack Complex (MAC) forming a new convertase which cleaves C5 for bacterial perforation (lysis) C3b NEW Figure 2.13 (Part 1) Assembly of the membrane-attack complex produces a pore in the CONVERTASE pathogen’s membrane [C3 convertase + C3b] Inflammation lysis & recruitment 32 CBI 2023 IMM1 PART II  Three complement pathways sequentially leading to C3 cleavage for Figure 2.5 Three pathways of complement activation enhanced inflammation and pathogen destruction C1 CRP © UpToDate, Inc. and/or its affiliates. All Rights Reserved. 33 CBI 2023 IMM1 PART II  The complement factor C3 A. is active upon cleavage by C3 convertase B. has three subunits with effector functions C. is always pathogen membrane bound D. initiates inflammation upon bacterial infection 34 CBI 2023 IMM1 PART II  What is the effector function of anaphylatoxins (C3a/C5a)? A. Complement fixation and induction of phagocytosis B. Inducing inflammation and recruitment of phagocytes C. Induction of the Membrane Attack Complex (MAC) D. Killing pathogens via toxin release thereby inducing lysis 35 CBI 2023 IMM1 PART II  the complement system o The complement system consists of plasma proteins with enzymatic function o C3 is the most important factor and is cleaved into C3a ad C3b for effector functions C3a is an anaphylatoxin  Induction of inflammation and phagocyte recruitment C3b induces complement fixation  Opsonization of pathogen and phagocytosis via complement receptors  Bacterial lysis via MAC formation o Three pathways lead to activation of C3 convertase for C3 cleavage into C3a and C3b 1. Alternative pathway spontaneous activation (hydrolysis) 2. Lectin pathway protein induced activation  MBL binds sugar residues on pathogen surface  MBL sequentially cleaves complement factors for C3 convertase formation 3. Classical pathway protein induced activation (C1)  CRP binds pathogen surface followed by C1  C1 sequentially cleaves complement factors for C3 convertase formation 36 CBI 2023 IMM1 PART II  IMMUNOLOGY PART I Intro: immune system & defense PART II The complement system Innate cellular responses 37 CBI 2023 Overview lecture  PATHOGEN DICTATES IMMUNE RESPONSE NEEDED Innate immune cells battling infection BACTERIA VIRUS Figure 2.2 Pathogens are present on the outside and the inside of human cells. 38 CBI 2023 IMM1 PART III  Macrophages are the “big eaters” of the innate immune system and alert upon tissue infection Figure 1.16 In responding to pathogens, different macrophage receptors are used to induce phagocytosis and cytokine secretion. Figure 1.11 MACROPHAGES  Are “big (macro) eaters (phagocytosis)”  Present in tissue  Alert upon tissue damage and infection PHAGOCYTOSIS AND D E S T R U C T I O N ACTIVATION AND C Y T O K I N E PRODUCTION  Two main modes of action 39 CBI 2023 IMM1 PART III  Specific pathogen recognition receptors are used for the detection and response to infection C-TYPE LECTIN TOLL-LIKE RECEPTORS RECEPTORS (CLR) PATHOGEN DETECTION (self vs non-self) (TLR)  CLR pathogen specific sugar (carbohydrate) residues  Family of Scavenger Receptors (SR)  Extracellular  TLR pathogen specific structures (peptides, RNA, DNA)  Intra- and extracellular  Ligands are highly preserved and essential to pathogen Figure 3.10 survival RESPONSE  CLR phagocytosis and degradation  TLR activation and cytokine secretion Tissue macrophage detects pathogen and responds by production of cytokines and Figure 3.2 chemokines to activate appropriate immunity 40 CBI 2023 IMM1 PART III  Macrophages induce immunity upon bacterial infection by activation of complement and neutrophils CYTOKINE complement & neutrophils signaling molecule for activation CHEMOKINE signaling molecule for Figure 1.6 migration Figure 3.22 Resident macrophages in an infected tissue respond to infection by making and secreting inflammatory cytokines. 41 CBI 2023 IMM1 PART III  Macrophages recruit neutrophils from the bone marrow to collaborate and clear bacterial infection using phagocytosis Figure 1.15 Neutrophils are stored in the bone marrow and move in large numbers to infected tissue. NEUTROPHILS  Recruited to infection site from bone marrow  Signature multi-lobular nucleus  Express scavenger receptors  Efficient killers with a short life-span Figure 3.26 Recognition, phagocytosis, and elimination of a bacterium by a neutrophil. 42 CBI 2023 IMM1 PART III  Neutrophils efficiently kill bacteria following phagocytosis, die and are cleared by macrophages Figure 3.28 Neutrophil killing of bacteria involves fusion of the phagosome 43 CBI 2023 IMM1 PART III  Macrophages induce the acute phase response upon bacterial infection for systemic responses Figure 3.22 Resident macrophages in an infected tissue respond to infection by making and secreting inflammatory cytokines. 44 CBI 2023 IMM1 PART III  The acute phase response induces production of a.o. MBL and CRP: Lectin and classical complement pathways COMPLEMENT ACTIVATION C3 BINDING C3 CLEAVAGE C1 CRP Figure 3.36 45 CBI 2023 IMM1 PART III  VIRUS Macrophages recruit NK cells upon viral infection for killing of infected cells Figure 3.22 Resident macrophages in an infected tissue respond to infection by making and secreting Figure 3.2 Cell-surface receptors on NK inflammatory cytokines. cells detect the differences between 46 self and altered-self. CBI 2023 IMM1 PART III  The interferon response initiated by virally infected cells ensures activation of recruited NK cells 47 CBI 2023 IMM1 PART III  NK cells express receptors which can distinguish “self ” from “altered-self ” INFECTED CELL HEALTHY CELL LIGANDS  Expressed by the “target” cell  Inhibitory ligands are always expressed  Activating ligands are expressed during stress KILLING  Induced by viral infection ACTIVATION NO ACTIVATION  IFN response RECEPTORS  Expressed by the NK cell  detect healthy versus unhealthy cells  Combination of inhibitory and activating receptors are continuesly expressed 48 CBI 2023 IMM1 PART III  After NK cell recruitment the interferon response enhances NK cell killing of infected cells Figure 3.45 Activation by type I interferon induces NK-cell proliferation and differentiation into cytotoxic effector cells. 49 CBI 2023 IMM1 PART III  What is true about neutrophils? Neutrophils… A. phagocytose bacteria using Toll-like receptors (TLR) B. enter the tissue in large numbers upon viral infection C. have a short-life span and are cleared by macrophages D. initiate inflammation upon bacterial infection 50 CBI 2023 IMM1 PART III  Why is the interferon response important during viral infection? A. To stop viral replication and activate NK cells B. To enhance expression of activating receptors on NK cells C. To enhance expression of inhibitory ligands on virally infected cells D. To ensure NK cells differentiate into cytotoxic T cells 51 CBI 2023 IMM1 PART III  innate cellular response o Macrophages are the big eaters of our immune system and reside in tissue to alert upon damage and infection Express receptors to detect pathogens and induce two main modes of action  C-type lectin receptors (CLR): pathogen phagocytosis and destruction  Toll-like Receptors (TLR): activation and cytokine secretion Secrete cytokines (activation) and chemokines (migration) to induce local and systemic immune activation, depended on the type of pathogen  Recruitment of neutrophils for bacterial phagocytosis  Activation of acute phase response and complement pathways  Recruitment of NK cells for killing of virally infected cells o NK cells are recruited upon viral infection Express receptors to distinguish self (inhibitory) from altered-self (activating) Virally infected cells secrete type I interferons to induce the interferon response  Expression of activating ligands on infected (target) cells  Activation and proliferation of NK cells for killing 52 CBI 2023 IMM1 PART III  Graphical summary response to bacterial infection CLR TLR classical 1 lectin C1 (MBL) 5 (CRP) 4 2 alternative MBL & CRP complement 3 53 CBI 2023 IMM1 PART III