The Innate Immune Response PDF - UAG School of Medicine

WE MAKE DOCTORS THE INNATE IMMUNE RESPONSE By Sergio Ramirez-Perez, PhD MSc Modified from Arnulfo Hernan Nava Zavala MD PhD WE MAKE DOCTORS Learning objectives a. Describe the basic mechanisms involved in the innate immune response and the consequences of s...

WE MAKE DOCTORS THE INNATE IMMUNE RESPONSE By Sergio Ramirez-Perez, PhD MSc Modified from Arnulfo Hernan Nava Zavala MD PhD WE MAKE DOCTORS Learning objectives a. Describe the basic mechanisms involved in the innate immune response and the consequences of such activation. b.Recognize the cellular components of the innate immune system. c. Identify the sequential events driving the inflammatory response. d.Define the basics of the antiviral response.  Introduction Innate immunity is the first line of defense Exists before the encounter with pathogens Natural immunity Activates rapidly Identifies threats & stimulates AIR DIALOGUE How does the IIS recognize pathogens or damaged cells? How is the IIS eliciting recruitment of other leukocytes? How and where does the IIS triggering activation of the adaptive immune response? Pattern Recognition Receptors We make Doctors Components of the innate immune system Components Principal functions Barriers Epithelial layers Prevent microbial entry Defensins Microbial killing Intraepithelial lymphocytes Microbial killing Circulating effector cells Neutrophils Early phagocytosis and killing of microbes Macrophages Efficient phagocytosis and killing of microbes, secretion of cytokines that stimulate inflammation NK cells Lysis of infected cells, activation of macrophages Circulating effector proteins Complement Killing of microbes, opsonization of microbes, activation of leukocytes Mannose-binding lectin Opsonization of microbes, activation of complement C-reactive protein Opsonization of microbes, activation of complement Coagulation factors Walling off infected tissues Identification of antigens The IIS uses germline-encoded receptors to respond to structures that are characteristic of various classes of microbes (PAMPs) and products of dead cells (DAMPs) TLRs are expressed on plasma membranes and endosomal membranes of many cell types → represent a major class of PRRs Main components of the IIS include epithelial barriers in the skin, GI, and respiratory tract; phagocytes; APCs; mast cells & NK cells Cellular locations of pattern recognition receptors (PRRs) Toll-Like Receptors Homologous to a Drosophila protein called Toll Reactions of the innate immune system Inflammation Accumulation and activation of leukocytes and plasma proteins Antiviral defense Mediated by NK cells and type I interferons Signaling pathways and functions of Toll-like receptors Promote the expression of genes whose products mediate inflammation and antiviral defense  The Inflammasome Inflammasome activation causes pyroptosis (programed cell death of macrophages and DCs) Pryoptosis might increase inflammatory responses evident in LPS induced septic shock Inflammasomes are associated with chronic inflammatory diseases  Antiviral State Cytosolic DNA sensors (CDSs) are molecules that detect double-stranded (ds) DNA in the cytosol Type I IFN production and autophagy DNA damage due to various factors, such as radiation, toxins, or mutations, will lead to the delivery of that DNA into the cytoplasm STING is an endoplasmic reticulum–localized transmembrane adaptor protein STING activates the TBK1 kinase, which phosphorylates and activates the IRF3 transcription factor Cellular Components of the Innate Immune System Phagocytic cells Of hematopoietic origin, distributed through lymphoid and non-lymphoid tissues Participate in both: immune response and homeostasis Highly heterogenic and capable of differentiation Two major lineages: Mononuclear phagocytes (macrophages) and polymorphonuclear granulocytes (neutrophils) Maturation of mononuclear phagocytes Macrophages Big eaters Derived from monocytes Phylogenetically the oldest mediators of innate immunity Express several receptor families involved in their activation Macrophages reside in sub-ephitelial connective tissue, in the interstitia of parenchymal organs, in the lining of vascular sinusoids, liver, spleen, and in the lymph nodes. Dominant effector cells of the later stages of the innate immune response (1 or 2 days after infection) Macrophages Functional responses of phagocytes: 1) Active recruitment of cells to the sites of infection 2) Recognition of microbes 3) Phagocytosis 4) Destruction of ingested microbes 5) Production of cytokines (inflammatory response) 6) Clearence of apoptotic cells 7) Resolution of inflammation  Cytokine-Producing Innate Lymphoid Cells Cells with lymphocyte morphology that were discovered as cells that produced cytokines similar to those made by helper T cells but lacked TCRs Three subsets of ILCs, called ILC1, ILC2, and ILC3, produce different cytokines and express different transcription factors, analogous to the Th1, Th2, and Th17 subsets of CD4 + T lymphocytes Natural Killer Cells NK cell-mediated cytotoxicity is essentially the same as that of CD8 + CTLs Perforin and granzyme production NK cell-derived IFN-γ increases the capacity of macrophages to kill phagocytosed bacteria Acute inflammatory response We make Doctors Cytokines of the IIR Conclusions Activation of the IIR is required to begin with our defense against pathogens Cellular activation occurs after the identification of PAMPs and DAMPS by PRRs Cellular activation culminates in protein synthesis (type I IFNs, inflammatory cytokines, and inflammatory mediators) APCs activation culminates in presentation & activation of T cells References Abbas, A. K., Lichtman, A. H., & Pillai, S. (2022). Cellular and Molecular Immunology E-Book. Elsevier Health Sciences. 10th Edition, Chapter 4. Innate Immunity.