Innate Immunity PDF

INNATE IMMUNITY Dr Geraldine O’Connor [email protected] HA210  Innate immune cell recognition of pathogen (PAMPs) The role of complement Lesson Plan The role of cytokines in immunity...

INNATE IMMUNITY Dr Geraldine O’Connor [email protected] HA210  Innate immune cell recognition of pathogen (PAMPs) The role of complement Lesson Plan The role of cytokines in immunity The inflammatory response and innate cell recruitment INNATE CELL RECOGNITION Innate Cell Recognition of Pathogen The innate and adaptive immune system use different strategies for Innate Receptor Adaptive Receptor the recognition of pathogen Limited number Huge number, generated encoded in genome by gene re-arrangement Clonally distributed Recognises broad Recognises very specific group of pathogen of pathogen Interacts with a range Ability to discriminate of molecular structures between closely related of a given type structures Triggers immediate Triggers slower response response (days – weeks) Abbas, A. K., Lichtman, A. H., & Pillai, S. (2014). Cellular and molecular immunology E-book. Elsevier Health Sciences.  Pathogen Associated Molecular Patterns Pattern Recognition Receptors (PRR) are receptors on innate cells, capable of recognising Pathogen Associated Molecular Patterns (PAMPs) PRR may be located on cell surface, endosomal membranes, in the cytosol etc. We will focus on the Toll- Like Receptors (TLRs) Abbas, A. K., Lichtman, A. H., & Pillai, S. (2014). Cellular and molecular immunology E-book. Elsevier Health Sciences. TLRs: Location ,8 Murphy, K., & Weaver, C. (2016). Janeway's immunobiology. Garland Science.  TLRs: Specificity Murphy, K., & Weaver, C. (2016). Janeway's immunobiology. Garland Science. PRRs : Consequences Detection of PAMPs by PRRs can initiate innate immune responses Aids phagocytosis Activates innate cells Promotes inflammatory mediators Delves, P. J., Martin, S. J., Burton, D. R., & Roitt, I. M. (2017). Essential immunology. John Wiley & Sons. DAMPs Danger Associated Molecular Pattern (DAMPs) are host proteins that are released during cell injury. These also activate the immune system Delves, P. J., Martin, S. J., Burton, D. R., & Roitt, I. M. (2017). Essential immunology. John Wiley & Sons. SOLUBLE MEDIATORS: COMPLEMENT  Complement is a collection of soluble proteins that upon activation can aid in the immune system by 1. Promoting phagocytosis through opsonisation 2. Induce inflammatory responses Complement 3. Directly kill pathogens A number of complement proteins are proteases that are themselves activated by proteolytic cleavage. Activation of one component triggers an enzyme cascade Complement: Cascade of Activation You do NOT need to memorise this level of detail of complement Overview of Complement Abbas, A. K., Lichtman, A. H., & Pillai, S. (2014). Cellular and molecular immunology E-book. Elsevier Health Sciences.  1. Classical Pathway Triggered by the presence of an antibody- antigen complex 2. Alternative pathway Activation of Triggered by microbial surface structures e.g. LPS Complement 3. Lectin pathway Triggered by mannose residues on pathogen glycoproteins binding to host lectins A common feature is the activation of C3 convertase which converts C3 into C3a and C3b  Complement: Inflammation C3a and C5a are powerful anaphylatoxins which cause mast cell degranulation and promote vasodilation and increase vascular permeability. C5a is chemotactic factor (causes directed movement of leukocytes up a gradient concentration). Murphy, K., & Weaver, C. (2016). Janeway's immunobiology. Garland Science.  Complement: Opsonisation C3b becomes attached to the outside of the microbe. This is recognised by complement receptor 1 (CR1) on phagocytes and promotes phagocytosis and destruction of the pathogen Murphy, K., & Weaver, C. (2016). Janeway's immunobiology. Garland Science.  Complement: Membrane Attack Complex C5b triggers the formation of membrane attack complex (MAC; C5b6789) can result in the lysis of bacterial, virus-infected or tumour cells. Contains multiple copies of C9. Murphy, K., & Weaver, C. (2016). Janeway's immunobiology. Garland Science. SOLUBLE MEDIATORS: CYTOKINES Cytokines Cytokines are soluble proteins produced by a wide variety of cell types and are critical for both innate and adaptive immune responses. Their expression may be perturbed in most immune, inflammatory, and infectious disease states. The action of cytokines may be autocrine, paracrine or endocrine Cytokines may be generally proinflammatory (IL-1, IL-6, TNF-α, IFNγ); anti-inflammatory (TGF-β, IL-10); involved in cell growth and differentiation (colony-stimulating factors (CSFs) and stem cell factor); involved in cell movement and recruitment or chemotaxis (chemokines e.g. CCL3 (MIP-1α), CXCL1) Owen, J. A., Punt, J., & Stranford, S. A. (2013). Kuby immunology (p. 692). New York: WH Freeman.  Do not need to memorise the specific cytokines here Cytokines Pleiotropic: Having more than one effect Redundancy: Several cytokines can have the same effect Synergy: the effect of two cytokines may be greater than the sum of each effect Antagonism: one cytokine may inhibit the response to another cytokine Cytokine Networks: cytokines enhance or suppress the production of others generating complex cytokine networks Owen, J. A., Punt, J., & Stranford, S. A. (2013). Kuby immunology (p. 692). New York: WH Freeman.  Do need to know these cytokines – we Cytokines will meet them again Produced by macrophages/dendritic cells upon stimulation TNF, IL-1: Induce inflammation, by acting on the endothelial cell IL-6: induced acute phase proteins from the liver, promotes adaptive immune responses IL-12: Promotes IFN-γ production and Th1 polarisation of helper T cells. Stimulates NK cell activity IL-23 Promotes survival and function of Th17 cells Produced in response to virus Type 1 Interferon (IFN-α, β) Inhibits viral replication, promotes MHC class I expression and cytotoxic T cells.  Do need to know these cytokines – we Cytokines will meet them again Produced by helper T cells IL-2 Clonal expansion of antigen-stimulated T cells, maintenance of regulatory T cells (Treg) IFN-γ Product of Th1 cells (and NK cells), promotes activation of macrophage to be better killers of intracellular bacteria, increased MHC class I expression IL-4 Th2 cytokine, includes class switching to IgE IL-5 Activates eosinophils IL-17 Th17 cytokine, promotes neutrophil-based inflammation in defense against extracellular pathogens  Do need to know these cytokines – we Cytokines will meet them again Anti-inflammatory cytokines IL-10 inhibits the production of pro-inflammatory cytokine by dendritic cells; produced by Treg, DC and macrophages (later response) TGF-β promotes differentiation to Treg, inhibitor effector T cell function; produced by Treg and other cells. Can promote wound healing (if chronic fibrosis). But, in presence of inflammatory cytokine, can promote Th17. INFLAMMATION  Inflammation Non specific, localised, protective tissue response to injury e.g. infection, trauma, heat, etc. intended to eliminate, or wall off, the cause of injury as well as any resulting necrotic cells and promote tissue repair. Denoted by suffix “-itis” Cardinal signs of inflammation Redness Heat Swelling Pain Functional Impairment https://socratic.org/questions/what-are-the-four-cardinal-signs-of-inflammatory-response  Inflammation Steps Detection of pathogens or danger (PAMPs, DAMPs) by innate cells results in the release of mediators that cause vascular and cellular responses Vasodilation and increased vascular permeability Recruitment of additional immune cells (neutrophils, then monocytes, then lymphocyte) Elimination of trigger Resolution Kumar, V., Abbas, A. K., & Aster, J. C. (2017). Robbins basic pathology e-book. Elsevier Health Sciences. Inflammation: Vascular Changes 1. Vasodilation increases blood flow (red, warm) 2. Increased permeability leads to exudation of protein-rich fluid (swelling) 3. Reduced blood velocity 4. Accumulation of immune cells Prchal, J. T., & Levi, M. M. (2010). Williams hematology. Recruitment of Effector Cells Recruitment of effector to the site of infection is an important step in control of infection. Murphy, K., & Weaver, C. (2016). Janeway's immunobiology. Garland Science. Steps in Cell Recruitment Time: Neutrophils < Monocytes < Lymphocytes Modified from Clark, M. L. (Ed.). (2009). Kumar & Clark's clinical medicine. Elsevier health sciences.  Neutrophil/Monocyte recruitment may seem complicated – focus on the overall process. You do not need to memorise Neutrophil Rolling the specific receptors or ligands involved – expect for CXCL8 Neutrophils are often the first cell recruited. Activation by inflammatory cytokines (e.g. TNFα, IL- 1) induces expression of E-selectin on the endothelium. Weak interactions with carbohydrate ligands on the neutrophils, slows the movement, causing rolling. Murphy, K., & Weaver, C. (2016). Janeway's immunobiology. Garland Science. Neutrophil Adhesion Chemokines induce conformation changes in integrins (e.g. LFA-1), allowing the leukocyte to adhere tightly to the endothelial cells via interactions with their ligands (e.g. ICAM-1, also upregulated by inflammatory cytokines like TNF). Cells cross the blood vessel walls (extravasation). The chemokine CXCL8 (aka IL-8) direct the migration of neutrophils along the its concentration gradient. Murphy, K., & Weaver, C. (2016). Janeway's immunobiology. Garland Science. Neutrophil Recruitment In Action Monocyte Recruitment Monocytes are typically recruited (hours) later than neutrophils. CCL2 and CCL7 both bind to CCR2 chemokine receptor and recruit monocytes Murphy, K., & Weaver, C. (2016). Janeway's immunobiology. Garland Science. Inflammation Ideally the inflammatory response remains confined to a localised area but in some cases local injury can result in prominent systemic manifestations as inflammatory mediators are released into the circulation. The most prominent systemic manifestations of inflammation are: The acute phase response: a group of physiologic processes occurring soon after the onset of inflammation. The most prominent change is a dramatic increase of acute phase proteins in the serum. Alterations in white blood cell count (leukocytosis or leukopenia) Fever Sepsis and septic shock, also called the systemic inflammatory response, represent the severe systemic manifestations of inflammation Inflammation Chemical mediators of inflammation impact vasodilation vascular permeability chemotaxis IL-1 and fever TNF are considered pain the “master cytokines tissue damage Often the target of anti- inflammatory drugs Kumar, V., Abbas, A. K., & Aster, J. C. (2017). Robbins basic pathology e-book. Elsevier Health Sciences.  Systemic Effects of Inflammation Abbas, A. K., Lichtman, A. H., & Pillai, S. (2014). Cellular and molecular immunology E-book. Elsevier Health Sciences. MBBS Learning Outcomes Over the first three sessions, we will address: Recognise the role of the immune system in defence against invasion by foreign matter and list individual components of the immune system Distinguish the function of immune cell types and other arms of the immune system Distinguish the role of immune response in disease prevention Distinguish the components of the lymphatic system and describe their role in host defence Reading List Both available via Clinical Key