MD137 Immunology Lecture 2: Innate Immunity PDF

MD137 Immunology Lecture 2: Innate Immunity Dr. Louise Horrigan Physiology [email protected] University ofGalway.ie Learning To learn: Characteristics of innate branch...

MD137 Immunology Lecture 2: Innate Immunity Dr. Louise Horrigan Physiology [email protected] University ofGalway.ie Learning To learn: Characteristics of innate branch of Objectives of immune system Today’s Lecture Pathogen recognition by innate cells Functions of innate system Phagocytosis Complement Natural Killer Cells  Physical barriers Tight junctions at epithelial cells Mucous membranes Innate pH Antimicrobial secretions eg. Lysozyme in tears defenses Internal defenses Phagocytosis Complement Natural Killer Cells Cytokine secretion Humoral immunity B cells Antibodies Adaptive Cell-mediated immunity defenses T cells Cell killing Cytokine secretion  Cells involved in innate and adaptive immunity Yamauchi, T., & Moroishi, T. (2019). Hippo pathway in mammalian adaptive immune system. Cells, 8(5), 398. Image available via license: CC BY Features of innate/natural immunity We are born with it It is always present and functional Can respond immediately Instructs the adaptive immune system Recognises non-self in a non-specific manner Has no ability to remember pathogens or to improve with experience University ofGalway.ie Pathogen recognition by cells of the innate system Proposed by Janeway (1989) Innate cells possess pattern recognition receptors (PRRs) Encoded in germline and have limited diversity Eg: Toll-like receptors, NOD-like receptors PRRs recognise structures shared by classes of microbes Pathogen-associated molecular patterns (PAMPs) such as peptidoglycan, lipopolysaccharide (LPS) etc. University ofGalway.ie Innate immune recognition of bacterial cell wall components Gram-negative bacteria Gram-positive bacteria  Identical Toll-like receptors recognise a common structure on different microbes TLR Innate Cells  Jules Hoffman discovered that Toll receptors in Drosophila are critical for immune defense and later Beutler identified mammalian TLR4 as the LPS More receptor Share of Nobel Prize 2011 on Ten different TLRs in humans Expressed by many types of cells including TLRs…. macrophages and dendritic cells Found on the cell surface and on the membranes of intracellular vesicles Abbas et al: Basic Immunology 4th edition Chapter 02: Innate Immunity 12 Phagocytosis Neutrophils & macrophages are most important phagocytes Following infection, these cells can leave the blood and travel to site of infection Phagocytosis involves Recognition Ingestion Digestion https://www.youtube.com/watch?v=2d1SFqJJeVY University ofGalway.ie Phagocytosis 14 Image from: Phagocytosis and the actin cytoskeleton R.C. May, L.M. Machesky Journal of Cell Science 2001 114: 1061-1077; Image provided for that article by Philippe Montcourrier and Philippe Chavrier.  Complement 30 plasma proteins normally circulating in an inactive state Become activated at sites of infection and trigger a series of inflammatory events C3 is the central component Classical pathway C1q, C1r, C1s, C4, C2 Inflammation C3a Alternative pathway C3 Opsonisation Properdin, Factor B and D C3b Lectin pathway MBL, C4, C2 Terminal pathway (MAC) Classical pathway activation Activators of C1 Mainly activated by immune complexes containing IgM or IgG Also C reactive protein Lipopolysaccharide (LPS) Bacterial porins And others Mol Immunol., 39(7-8)., Arlaud GJ., Gaboriaud C, Thielens NM., Budayova-Spano M., Rossi V., Fontecilla-Camps JC., Structural biology of the C1 complex of complement unveils the mechanisms of its activation and proteolytic activity., 383-94,  Classical Pathway Pathogen C3a C3 C3b C4b2a = C3 convertase Safety Checks: Covalent binding of C4b and C3b to activator ensures that reaction stays on surface of pathogen Inhibitors in plasma and on host cells prevent activation in absence of C3b pathogen Pathogen b Kolev M, Friec GL, and Kemper C. Complement — tapping into new sites and effector systems. Nature C4b2a3b = C5 convertase Reviews Immunology 14: 811, 2014.  C5a C3b C5 Pathogen C5b C5 convertase MAC Kolev M, Friec GL, and Kemper C. Complement — tapping into new sites and effector systems. Nature Reviews Immunology 14: 811, 2014. Membrane Attack Complex Causes disruption of fluid balance leading to lysis of pathogen https://en.wikipedia.org/wi ki/Complement_membran e_attack_complex#/media/ File:Membrane_Attack_Co mplex_(Terminal_Comple ment_Complex_C5b- 9).png https://creativecommons.o rg/licenses/by-sa/3.0/ Functions of Complement 1. Opsonisation may be the most important function  C3b recognised by complement receptor type I (CR1 or CD35) on phagocytes  C5a can activate phagocytosis where C3b is bound to CR1 2. Cell lysis Membrane attack complex 3. Inflammation C3a, C4a and C5a are mediators of inflammation (anaphylotoxins)  Bind to receptors on neutrophils, macrophages, mast cells, basophils, endothelial cells  Recruitment and activation 4. Can stimulate adaptive immunity Some components can B cells to cause B cell activation and antibody production Deficiencies of complement Classical pathway deficiencies Increased susceptibility to autoimmune diseases  88% of c1q-deficient individuals develop systemic lupus erythematosus (SLE) Increased susceptibility to some bacterial infections  Eg. streptoccus pneumoniae, haemophilus influenzae University ofGalway.ie Natural Killer Cells Lymphoid lineage 10-15% of blood lymphocytes Recognise if a cell has been invaded by a virus or if a cell has become cancerous These cells have lost or modified surface structures Kill infected cells through release of Perforin Punches holes in cell membrane Granzyme Enters cells via perforin pore Induces apoptosis pathway University Image from Wikimedia Commons,ofGalway.ie licensed under Creative Commons Attribution 2.0 Generic license. Summary of main points The innate immune system responds rapidly, but it is relatively non-specific, it does not develop and it does not have memory Innate cells differentiate ‘self’ from ‘non-self’ using pattern recognition receptors such as Toll-like receptors Bind to PAMPs on groups of pathogens Innate functions include phagocytosis, complement and direct killing by NK cells Function to kill, or facilitate the killing of pathogens, as well as virally infected and cancerous host cells Innate mechanisms activate and stimulate the adaptive immune response University ofGalway.ie