Innate Immunity 1 2023 PDF

Immunology: The basics and Innate Immunity Dr Sarah Aynsley [email protected] What is the immune system? A collection of different cells and tissues of the body which work to protect us from disease. Tonsils...

Immunology: The basics and Innate Immunity Dr Sarah Aynsley [email protected] What is the immune system? A collection of different cells and tissues of the body which work to protect us from disease. Tonsils Thymus Lymph Nodes Spleen The immune cells (leukocytes) are produced in the bone marrow. Some circulate in the blood whilst most reside in Payers Patches tissues or immune organs Bone Marrow The Immune Cells Granulocytes Lymphocytes Monocyte Circulating precursor to Dendritic cells and Neutrophil T Lymphocytes macrophages Circulating cell, Helper and cytotoxic. highly phagocytic Recirculate through granulocyte lymph nodes. Activated by dendritic cells. Macrophage Tissue resident Eosinophil around the body. Circulating cell, Natural Killer Phagocytic and responds to IgE. Can Cells antigen presenting degranulate to Innate immune cells remove parasites which kill infected cells using their granule contents Dendritic Cell B Lymphocytes Differentiate in Basophil Produce antibodies the tissues. Circulating as a defence. Phagocytic and granulocyte in very Activated by T Cells antigen low numbers to produce high presenting. affinity antibodies. Travel to the Become antibody lymph nodes to secreting plasma activate T cells cells. Mast Cell Tissue resident, source of cytokines and can degranulate e is a coordinated response of innate and adaptive immunity Innate Immunity Adaptive Immunity B Lymphocytes Antibodies Epithelial barriers Complement Phagocytes NK cells T Lymphocytes Effector T Cells Dendritic Cells 0hrs 6hrs 12hrs 1day 4days 7days Time after infection Physical barriers protect the entrances to our body Eyes Respiratory tract Skin Gastrointesti nal Tract These entrances and surfaces have tight epithelial layers, Fungi fluid or air Genitourina passing over ry Tract them and various secretions to protect them at defences do we have at these barriers? Normal Enzymes Flow of air or Microbiota Defensi Fatty Secretions fluid Outcompete Tight ns potentially harmful Low pH acids Secreted contain Reduces the chance organisms Restricts which antimicrobial of microorganisms Epithelial Contained in antimicrobial enzymes e.g. pathogens can sebum they settling layers destabilise peptides; lysozyme in survive transit if Often renewed and disrupt cell tears ingested bacterial cell membranes restrict the membranes pH movement of things and virus causing direct envelopes between cells and indirect inhibition All Respiratory Gastrointestinal Epithelium Goblet Ciliated cells Ski Move mucus along n Cells Produce Mucus; acts as a sticky Tissue barrier Resident Immune cells Recognise and ‘eat’ (phagocytose) pathogens Tissue resident phagocytes – Skin = Langerhans cells, Liver = Kupffer Cells, Lung = Alveolar Macrophages, Spleen = Red pulp macrophages at happens if these barriers are breached? A simple knock or cut causing damage can initiate the inflammatory response even without the presence of a pathogen 1. Fragments of cells particularly intracellular proteins and nuclear 1 material are released through damage 2 Danger-associated molecular pattern molecules = DAMPS Include: DNA, RNA, Nuclear proteins 3 2. They bind to receptors 3. This then induces inflammation through inflammatory cytokine release What is Inflammation? “…a localized physical condition in which part of the body becomes reddened, swollen, hot, and often painful, especially as a reaction to injury or infection.” We see this as symptoms known as the four cardinal signs of inflammation Redness – Rubor Heat – Calor Swelling – Tumor Pain - Dolor Inflammation is part of the body’s response to damage and is a way to protect itself It progresses through a series of stages and involves the Immune system Pro-inflammatory cytokines In the immune system cells ‘talk’ to each other by releasing small proteins called cytokines The pro-inflammatory cytokines are three which are released in response to damage and TNFα IL-1β inflammation Activates vascular Activates endothelium and IL = interleukin vascular increases vascular TNF = tumour necrosis factor endothelium IL-6 permeability Upregulating Signalling to the TNF adhesion receptor causes nitric molecules Early warning signal oxide release from of danger endothelial cells Local tissue Increases chemokine destruction production Activates macrophages Has important systemic effects on the liver increasing acute phase effect do pro-inflammatory cytokines have on the tissue? MAYV 1. Pro-inflammatory cytokines are released into 4 the surrounding tissue 2. They can act on the endothelial cells of blood vessels to weaken the tight junctions between 3 cells. This causes the vessel to become more permeable and fluid to leak into the tissue  Tumour/Swelling (Oedema ) 1 3. They also cause the blood vessels to increase in diameter, increasing and slowing blood flow to the area.  Rubor/redness and Calor/Heat 2 4. The swelling in the tissue and bradykinins released by the activated vascular endothelial cells can sensitise nerve endings in the skin causing pain  Dolor/Pain ow are pathogens recognised? As well as damage we can recognise things which are foreign to our body Pathogen surfaces and nuclear material are different to our body Pathogen Associated Molecular Patterns (PAMPs) These are recognised by tissue and immune cells through their Pattern Recognition Receptors (PRRs) There are immune cells resident in Fungi the barrier tissues of our body attern recognition receptors Receptors recognise the same shape on different microbes. Our innate immune system is the oldest part and has evolved alongside the pathogens we’re infected by. Same response for all three pathogens hat receptors do our cells have? External Internal Cytoplasmic Endosomal NFκB NFκB IRF Result in changes Induce Result in changes Result in changes to transcription and internalisation to transcription and to transcription and cytokine release (phagocytosis) of cytokine release type I interferon the pathogen and release Toll Like Receptors destroy it NOD and RIG-like receptors Toll Like Receptors Complement, Toll- Like Receptors TLR 2 Lipopeptides Lipomannans (mycobacteria) TLR 1 TLR 6 TLR 2 Lipoproteins Lipoteichoic acids (Gram +ve) Cell-wall β-glucans (bacteria and fungi) 1 Zymosan (fungi) Flagel TLR 5 TLR 4 LPS (gram –ve) lin Co (bacteri Lipoteichoic stimulatory acids (Gram +ve) molecules a) (CD80, CD86) NFκB 1. Recognition of a pathogen transmits a signal to 3 the nucleus 2 2. A protein called NFκB assembles and binds the DNA this instructs the cells to produce new Cytokines proteins 3. These include pro-inflammatory cytokines and cell surface molecules Phagocytic receptors C-type lectin Scavenger Mannose receptors receptors Receptor e.g Dectin-1 Bacterial Recognise bacterial Fungal β-glucan Lipoproteins which mannose on the component of fungal make up the cell surface of some cell walls walls of bacteria bacteria These receptors are expressed on Fc receptors Complement phagocytic cells Recognises antibody receptor and allow them to bound (CR1) to pathogen surfaces Recognises C3b recognise a complement pathogen and protein bound to engulf if. pathogen On macrophages, dendritic cells, neutrophils and B Cells surfaces w do the macrophages kill the pathogen? 1. The pathogen is recognised by receptors and phagocytosis is induced 2. The pathogen is internalised in a phagosome which fuses with a lysosome which contains antimicrobial peptides, lysozyme and nitric oxide. 3. The pathogen is broken down and destroyed 1 3 2 Phagocytosis Videos https://www.youtube.com/watch?v=BDr44vLNnP Y https://www.youtube.com/watch?v=ygkvXT1Bm aA Complement Proteins Complement is a C3 C3a C1 collection of small Mannose proteins produced by Alternative pathway C3b Binding Lectin Lectin pathway the liver which Spontaneous Recognise mannose circulate in the blood. They become active Classical pathway Antibody driven when they enter the tissue C4 Factor D C 4a Binding of complement C 5a Factor B to the surface of the C 4b pathogens makes it Phagocytosis Membrane Attack visible to the Phagocytes C 5b Complex C3b sets off a recognise C3b pathway of cleavage complement through resulting in disruption of phagocytic receptors complement the cell membrane receptor Chemotaxis C3a and C5a recruit phagocytic cells and promote inflammation immune response requires further cell recruitment This process is referred to as chemotaxis and is controlled by chemokines. All leukocytes have chemokine receptors which allow them to recognise different chemokines Depending on the tissue and point in infection different chemokines are produced Chemokines- small attractant protein which stimulates migration and activation of cells. Which cell do we need to recruit? How does it reach the tissue? Neutrophil extravasation from blood vessel https://www.youtube.com/watch?v=qRoE 1jSIKxs Neutrophil migration into wound site https://www.youtube.com/watch?v=pqtSuCA 0ZjY  IL-6 IL-1β CXCL8 E - Selectin CXCL8R Proteoglycans ICAM-1 LFA-1 Neutrophil recruitment Pathogen 1. During normal conditions the neutrophils circulate in the blood and bind weakly to E-selectin via their proteoglycans IL-1β 2. When an infection occurs or the tissue is damaged 2 pro-inflammatory cytokines and chemokines are released TNF-α 3. The cytokines IL-1β and TNF-α up-regulate adhesion IL-1β molecules on the blood vessels at the sight of CXCL8 inflammation. CXCL8 adheres to the lumen of the vessel 4 CXCL8R 3 4. The neutrophil attaches to E-Selectin and rolls along E - Selectin ICAM-1 the vessel before being firmly attached via ICAM-1 and LFA-1. The cell also recognises CXCL8 via its receptor Proteoglycans (CXCL8R) and starts to extravasate where the LFA-1 inflammation is occurring. The neutrophils follow the chemokines to the site of infection 1 Remember the complement fragments C5a and C3a also contribute to vascular endothelium activation Neutrophil function Neutrophils have granules containing antimicrobial proteins and peptides which disrupt and digest microbes The formation of NAPDH oxidase by secondary granule binding produces superoxide radicals lowering the pH and activating the peptides within 3mins of phagocytosis H2O2 NAPDH O2 - oxidase Granules Primary (Azurophilic) NO Myeloperoxidase, cathepsins, elastase, protease, defensins Secondary (Specific) Collagenase and heparinase Tertiary (Gelatinase) NAPDH - Nicotinamide adenine dinucleotide phosphate = cofactor Gelatinase and lysizyme eutrophil apoptosis and netosis Neutrophils can preform the respiratory Neutrophil burst. This produces toxic oxygen Extracellular species which diffuse out. Trap O2- Once done the neutrophil cannot O2 replenish and dies either through apoptosis or netosis. NAPDH oxidase During netosis the nucleus swells and bursts extruding chromatin decorated with histones and granule contents - Neutrophil Extracellular Traps. emic effects of the pro-inflammatory cytokines Liver Fat & Muscle Hypothalamus Bone Marrow & Epithelium Predominantly Predominantly IL-6 IL-6 TNFα also IL-6 IL-6 but also IL- 1β and TNFα Induces acute Protein and energy Increase body Neutrophil phase protein mobilisation to temperature by mobilisation Actions production allow increased inducing the synthesis (Broad specificity body temperature of prostaglandin E2. proteins inc C-reactive protein,C1q, Mannose and leukocyte This then acts on binding lectin, production hypothalamus to complement proteins) increase heat production Increased antigen Activation Increased numbers processing, increased Effects of specific immune in the tissue  complemen increased response and cell t. phagocytosis replication Opsonisatio hat if the pathogen isn’t cleared? The early innate responses are non-specific for the pathogen Continued release of pro-inflammatory cytokines can be very damaging. Damaged blood vessels produce bradykinins which increase vascular permeability and can stimulate nerves causing pain. If the infection has not been resolved the immune system needs to recruit more specific cells Summary Barriers initially try to prevent injury or infection When breached the damage and/or presence of a pathogen induces inflammatory cytokine release These cytokines have local and systemic effects to enhance the immune response Tissue resident cells act early to phagocytose the pathogen whilst neutrophils are recruited into the tissue