Lecture 02_Properties of Natural Immunity PDF

Properties of natural immunity and its cellular components, its mode of action Gulyás Marcell [email protected]  Minimum: Cell Natural immunity  Main fuctions of the immun system: Recognition Communication Elim...

Properties of natural immunity and its cellular components, its mode of action Gulyás Marcell [email protected]  Minimum: Cell Natural immunity  Main fuctions of the immun system: Recognition Communication Elimination (effector functions)  Natural immun system Cells, main functions Recognition mechanisms Killing mechanisms Other effector functions  Cells, main functions Monocytes/macrophages Dendritic cells Granulocytes NK cells Mast cells Complement system  Monocytes origin: bone marrow pluripotent progenitors myeloid progenitor (progenitor) size: 10-15umnucleus: bean-shaped localization: in the circulation exiting the circulation: macrophage  MACROPHAGES their main types (based on tissue localisation): microglia (brain) Kuppfer cells (liver) Function: histiocytes (connective tissue) 1. Recognition osteoclasts (bone) 2. Destroy alveolar macrophages (lung) 3. Communication 4. Restoration phagocytic cells professional antigen-presenting cells (APC) one of the first cell types to recognise the pathogen  DENDRITIC CELLS origin: myeloid or lymphoid progenitor cells localisation: the immature dendritic cell migrates from the bloodstream to the tissues where, after pathogen uptake (phagocytosis), it becomes a mature dendritic cell and migrates to the lymph node. Its main task is to transport pathogens to the lymph nodes from the point of entry professional antigen presenting cells (APCs) One of the first cell types to recognise a pathogen  NEUTROPHIL GRANULOCYTE Most abundant in blood (68% of circulating leukocytes and 99% of circulating granulocytes) They are capable of phagocytosis, In the event of tissue injury, they invade tissues where they participate in the destruction of pathogens Not present in normal healthy tissue, only in the circulation Major cellular participant in inflammatory processes, but not an initiator of inflammation  BASOPHIL GRANULOCYTE 1% of circulating leukocytes large granules in the cytoplasm 2 lobed nucleus tissue mast cells, histamine, allergic reactions high affinity IgE receptors defence against parasites EOSINOPHIL GRANULOCYTE 2-3% of leukocytes Protection against parasites allergic reactions  MAST CELLS Origin: myeloid progenitor cells localisation: absent in the circulation, differentiating in the tissue, localising mainly around small blood vessels Function: during activation, substances released from them regulate vascular permeability in both natural and adaptive immune responses main effector cells of allergic processes (FcЕRI on the surface) histamine production One of the first cell types to recognise the pathogen  NK CELLS (NATURAL KILLER) origin: bone marrow pluripotent progenitors lymphoid progenitor in circulation 5-10% higher in lymphocytes numerous granules in their cytoplasm lack antigen-binding cell membrane receptors cells of natural immunity Destruction of infected or tumour cells Professional antigen-presenting cells Cells capable of phagocytosis Macrophages Macrophages Dendritic cells Dendritic cells B lymphocytes Neutrophil granulocytes  Recognition mechanisms The aim is to identify structures and/or danger signals that are as common as possible in pathogens but are not specific to human cells; e.g. bacterial cell wall components, flagellin, double-stranded RNA Recognition cannot be avoided Detection covers all groups of pathogens, targeting their most characteristic structures Pattern recognition receptors - PPR (Pattern Recognition Receptor) o PAMP - pathogen-associated molecular pattern o DAMP - threat-associated molecular pattern  Felismerő receptor típusok TLR RIG like receptors NOD Scavanger receptors C type lektin receptors Mannose recognition receptors  Danger signal The natural immune system also recognises molecules from damaged or necrotic cells (damage associated molecular patterns (DAMPs).E.g. extracellular ATP, actin  Recognition mechanisms of NK cells Basic NK cell activity is enhanced by cytokines, activating receptors Inhibitory receptors on own cells prevent lysis of the own cell KIR - receptors that inhibit NK cells MHC I binding Target Target KAR - NK cell activating receptors MHC- MHC+ KAR KIR KIR KAR NK NK  OPSONISATION Opsonisation makes it easier for the natural immune cells to recognise the pathogen. Although the natural immune cells can recognise pathogens on their own, recognition is simplified and the response is accelerated in the presence of opsonins. The opsonins bind to the surface of the pathogen, labelling it. Many receptors on different cells are specialised to recognise opsonins, as the opsonin binds to the pathogen at the same time, ultimately the opsonin forms a bridge, connecting the pathogen and the recognising cell. Several molecules such as antibodies, some complement fragments and acute phase proteins can also be involved as opsonin in the immune response. Major opsonins: antibodies, complement fragments, acute phase proteins  Killing mechanisms Phagocytosis production of soluble mediators complement system NK cells  Phagocytosis MACROPHAGE- Digestion, cell killing function, antigen presentation DENDRITIC CELL - Digestion, antigen presentation NEUTROPHIL GRANULOCYTE - Degradation, cell killing function  Production of soluble mediators ROS - Reactive oxygen radical NO - Nitric oxide proteolytic enzymes antimicrobial peptides  Complement system A cooperative chain of proteins (protease cascade) in the blood plasma. The protection of the own cells is provided by a large number of complement inhibitors expressed on the cell surface or soluble. Activation: 1. Alternative pathway - continuously active - inhibited by own cell surface structures 2. Classical pathway - activated by antibody molecule 3. Lectin pathway - activated by mannose binding lectin (MBL - acute phase protein)  Complement system functions 1. Destroys the pathogen 2. Opsonises 3. Chemotactic, attracts phagocytes to the location of the infection 4. Involved in the clearance of immune complexes  NK Cells NK cells destroy infected or tumour cells by secreting cytotoxic granules and/or activating cell death receptors. Components of the adaptive immune system can also activate NK cells (Antibody Dependent Cellular Cytotoxicity, ADCC) Fc receptors on NK cells can bind to antibody molecules that recognise the antigens of the pathogen  Other effector functions Antiviral response Inflammation Opsonisation Antigen presentation  Antiviral response Type I interferons (α and β) NK cells Cytotoxic T cells Neutralising antibodies  VIRUS INDUCATED INTERFERON α AND β PRODUCTION Intracellular PRR detects the virus - IFN-beta expression - IFN I production Autocrine and paracrine action. Any of our (nucleated) cells can be infected, all our cells contain intracellular PRR and all our cells can produce type I IFN! Plasmacytoid dendritic cells produce 1000 times more type I interferon than any other cell They cluster in the T cell zone of lymph nodes following viral infection  The function of type I interferons: Anti-viral mechanisms: o Inhibition of RNA synthesis o RNA degradation o Inhibition of protein synthesis o Degradation of viral proteins Induction of apoptosis Activation of NK cells Activation of cytotoxic T cells (activation of DC cells)  ACUTE INFLAMMATION The body's rapid response to some kind of tissue damage. It aims to deliver important elements of the defence (leukocytes and plasma proteins) to the site of damage. The three main components of acute inflammation are: increased diameter of the affected blood vessels, resulting in increased blood flow Increased permeability (patency) of the vessel wall migration of leukocytes out of the small vessels, their accumulation and activation in the area of damage  Acute inflammation Local inflammation of tissues is essential in the fight against microbes. They facilitate the control of infections and promote the development of an effective immune response. Pattern-recognition receptors can efficiently activate cells, causing them to produce hormone-like substances - cytokines, chemokines - that activate, for example, other immune cells and attract them to the site.  Acute inflammation In inflamed tissue, the permeability of the capillaries is increased, which helps to allow large amounts of antimicrobial substances in the blood plasma, such as complement system proteins, to be released into the tissue cells. This also increases the amount of lymph that is released into the lymphatic system, which carries some of the antigens to the surrounding lymph nodes, where antigen-specific lymphocytes that are camped there can be activated. The chemokines and other cytokines produced by the activated cells also activate cells in the endothelium of the capillaries. The activated endothelial cells have increased adhesion molecules, which, together with the chemokines produced, promote the migration of additional immune cells, mainly neutrophil granulocytes specialised in pathogen killing, to the site of inflammation.  Acute inflammation It also activates the blood coagulation system, which isolates heavily infected areas, helping to prevent pathogenic microbes from entering the bloodstream. During inflammation, cytokines are also produced that act as growth factors to help regenerate tissue, for example by stimulating fibroblasts to divide or by helping new vascular branches to grow in damaged areas to replace damaged ones. In addition to triggering the immune response at the site of infection, IL-6, TNF, IL-1 cytokines produced by macrophages or their induced responses may also have endocrine effects. In the brain they increase hypotension. In the liver, their effects increase antimicrobial protein production, and intense white blood cell formation in the bone marrow.  Opsonisation Facilitates pathogen recognition by natural immune cellsInfluences the response reaction Main opsonins: Antibody Complement fragments Acute phase proteins  Antigen presentation Professional antigen-presenting cells: Macrophages B lymphocytes Dendritic cells MHCII expression T-helper and naive T cell activation Thank you for your attention!