BOH1 - 2024-05-21 Innate Immunity Ashik Srinivasan.pdf

Innate Immunity Dr Ashik Srinivasan School of Medical Sciences Thank You: Dr Belal Chami, author of the previous version of this lecture Last update: 2024-05-20 Learning objectives List the physical barriers wh...

Innate Immunity Dr Ashik Srinivasan School of Medical Sciences Thank You: Dr Belal Chami, author of the previous version of this lecture Last update: 2024-05-20 Learning objectives List the physical barriers which comprise the innate immune response Describe acute inflammatory events resultant from bacterial infections Describe the pathogenesis of Porphyromonas gingivalis oral infections Understand the sensory mechanism of antigen detection via TLR and PAMPS Understand the mechanism of neutrophil and macrophage bactericidal activity  Innate Responses – Barriers Barriers - First Line of Defence Physical (epithelial surfaces) Skin, mucous membranes (mouth, eyes, respiratory tract, GI tract, UT, vagina) Chemical (low pH or antimicrobial molecules) Physiological Probiotic  Innate Responses – Barriers Barriers - First Line of Defence Physical (epithelial surfaces) Chemical (low pH or antimicrobial molecules) Skin (pH 5.5); Gastric acid (pH 1-3); Vagina (pH 4.4) Mucosal immunoglobins (IgA), lysozyme (sebum, perspiration, urine), mucus, beta-defensins (epithelia and most leukocytes), pepsin (GI) Physiological Probiotic  Innate Responses – Barriers Barriers - First Line of Defence Physical (epithelial surfaces) Chemical (low pH or antimicrobial molecules) Physiological Diarrhoea, Vomiting, Coughing, Sneezing Probiotic  Innate Responses – Barriers Barriers - First Line of Defence Physical (epithelial surfaces) Chemical (low pH or antimicrobial molecules) Physiological Probiotic Competition for nutrients, blocking adhesion sites, immune stimulation, direct antagonism Innate Responses – barriers in the oral cavity In the oral cavity saliva washes the mucosal surfaces Epithelial cells also release anti-microbial peptides Local blood vessels respond to alarm signals by releasing migrating phagocytic white blood cells These move in a directional manner toward the microbial threat and attempt to engulf and destroy microbes Lining epithelia have junctional complexes and express Toll-like Receptors (TLRs) for detection of microorganisms connected to an inflammasome system that releases mediators of inflammation Epithelial adhesion complexes E-cadherin in adherens junctions The pathogen Porphyromonas gingivalis attacks the epithelial barrier Bacterial toxins can disrupt the protective adhesion complexes P. gingivalis produces a toxin with structural similarity to intercellular adhesion molecules. The toxin corrupts adhesion complexes allowing access of microbial products to the underlying tissue (evidenced by red dye). Innate Responses Innate Responses Cells Antigen Presenting Cells (APCs) Relatively longer lived than granulocytes Dendritic cells (DC), macrophages, B cells Phagocytic Oxygen independent pathway (lysosomal enzymes) collagenase, gelatinase, phospholipases or serine proteases Important for presenting antigens (APCs) Oxygen-dependent pathway (oxidative burst) Reactive oxygen and nitrogen species (RONS) Neutrophils, macrophages (Pathogen associated Molecular Patterns)  Effects of activating TLRs PAMP = Pathogen Associated Molecular Pattern PRR = Pattern Recognition Receptor  Effects of activating TLRs PAMP = Pathogen Associated Molecular Pattern PRR = Pattern Recognition Receptor Must know For your interest Effects of activating TLR: Cytokine production --> fever, inflammation IL-1, TNF Chemokine production --> cell recruitment Activation of bacterial killing mechanisms Activation of dendritic cells aka. Neutrophilic PMN (sometimes incorrectly shortened to just “PMN”) Most common WBC Kills bacteria Makes pus Immunity against parasitic infections, especially in intestine Plays role in allergies and asthma aka Monocytic PMN Kill bacteria Eat debris Attacks intracellular pathogens Wide role in immunity Become macrophages Second most common type of WBC Many types of Lymphocytes: T, B, NK Specific immunity Immunity against viruses Tumour protection Rarest variety of WBC in blood Become mast cells Contribute to allergy  Chemotaxis During growth and metabolism bacteria release distinctive low molecular weight products. These include fMLP (a small peptide released during bacterial protein synthesis) and peptidoglycan (a sugar polymer, component of the bacterial cell wall). Neutrophils have surface receptors that not only detect these products but that enable the cell to move towards the source. This directional movement is termed chemotaxis. Products of inflammation assist in the directional locomotion of neutrophils. Chemotaxis  Opsonisation Microorganisms must normally be coated before being bound and engulfed by phagocytic cells. The complement system is a powerful coating agent. Common bacterial products such as cell wall peptidoglycan and surface lipopolysaccharide of gram-negative bacteria can activate complement. These are the same common determinants that are recognised by Toll-like receptors. Complement coats the microorganism and the coating material is recognised by special receptors on the phagocytic cells.  Phagocytosis Phagocytosis is the capture and digestion of foreign particles Chemokines are cytokines that attract macrophages and neutrophils to infected tissues Opsonins at t ac h to microbes to increase the ability of phagocytes to adhere (opsonization) Oxygen independent pathway tinyurl.com/nwvhtyal  Oxygen-dependent pathway (oxidative burst) Myeloperoxidase is produced primarily by neutrophils, monocytes and macrophages tinyurl.com/2bbjlbqn Defective neutrophil function leads to microbial accumulation and inflammation – neutropenia. The most common oral manifestations of neutropenia include ulcer, gingivitis, and periodontitis.  For your interest only Architha Srinivasan, Cambridge University. https://upload.wikimedia.org/wikipedia/commons/a/a9/Innate_immune_system.png  Table of examples of which part of the innate immune system targets which pathogens. For your Pathogen Main examples Phagocytosis complement NK cells interest influenza only mumps Intracellular and yes yes yes cytoplasmic virus measles rhinovirus Listeria https://en.wikipedia.org/wiki/Innate_immune_system monocytogenes yes yes yes Intracellular bacteria Legionella (specifically neutrophils) Mycobacterium Rickettsia no yes no Staphylococcus Streptococcus Extracellular bacteria yes yes no Neisseria Salmonella typhi Plasmodium malariae Intracellular protozoa no no no Leishmania donovani Entamoeba Extracellular protozoa histolytica yes yes no Giardia lamblia Candida Extracellular fungi Histoplasma no yes Yes Cryptococcus