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INNATE IMMUNITY I Innate immunity •Cells, components and their functions •Recognition •Killing •Other effector functions Innate immunity •Cells, components and their functions • Monocytes/ Macrophages • Dendritic cells • Granulocytes • NK cells • Mast cells • Complement components •Recognition •Killing •Other effector functions WHITE BLOOD CELLS IN THE SMEAR OF HUMAN PERIPHERAL BLOOD neutrophil granulocyte eosinophil granulocyte MONOCYTE neutrophil granulocyte LYMPHOCYTE basophil granulocyte LYMPHOCYTE MONOCYTES - origin: pluripotent cells of the bone marrow myeloid progenitors -size: 10-15 µm - nucleus: bean-shaped -localization: circulation out of circulation: macrophage TISSUE - VENTRICLE MACROPHAGES - phagocytic cells antigen presenting cells (APC) main types (based on tissue localization): a) microglia (brain) b) Kuppfer-cells (liver) c) histiocytes (connective tissue) d) osteoclasts (bone) e) alveolar macrophages (lung) - function: in cellular and humoral immun response One of the cells which initiate the immune response DENDRITIC CELLS - origin: myeloid or lymphoid progenitors - localization: the immature dendritic cell migrates from the circulation into the tissues and upon pathogen uptake it differentiates to a mature dendritic cell and migrates to the draining lymph node and transports the antigen from the periphery to the secondary lymphatic organs - DCs are professional antigen presenting cells (APC) - One of the cells which initiate the immune response - types : a) myeloid DCs: - Langerhans cells (mucosa, skin) - intersticial DCs (liver, spleen, etc.) b) lymphoid DCs: - thymic DCs - plasmacytoid DCs (pDC) NEUTROPHIL GRANULOCYTES - highest number in blood (68% of circulating leukocytes, 99% of circulating granulocytes) - phagocyting cells - They are not present in healthy tissues, only in the blood circulation - tissue damage, migration, elimination of pathogens (enzymes, reactive oxygen intermediers) - main participants in inflammatory processes BASOPHIL GRANULOCYTES -1% of circulating leukocytes - large granules in the cytoplasm - nucleus with 2 lobes - mast cells, histamin, allergic reactions - high affinity IgE receptors - against parasites EOSINOPHIL GRANULOCYTES - against parasites - 2-3% of leukocytes - allergic reactions MAST CELLS -origin: pluripotent cells of the bone marrow myeloid progenitors localization: - absent in circulation - differentiate in tissues - especially around small vessels - function: - upon activation they regulate the permeability of the vessels with their secreted molecules - native and adaptive immunity - allergic reactions, - IgE receptors (cell surface) -against parasites -histamin production NK CELLS (natural killer) - origin: - pluripotent cells of the bone marrow lymphoid progenitors - bigger than lymphocytes - several granules in their cytoplasm - have no antigen binding receptors („null cells”) - participants of native immunity Professional phagocytic cells macrophages neutrophyl granulocytes dendritic cells • the phagocytosed cells or molecules may modify the functions of the cell • phagocytosis followed by enzymatic degradation Professional antigen presenting cells macrophages B lymphocytes dendritic cells • they express MHCII molecules • the protein degradation products (peptides) can be presented to T lymphocytes by MHC molecules The localization of blood cells NK cells Macrophage, dendritic cell – act as TISSUE SENSORS Neutrophil granulocytes, complement, NK cells – migrate from the blood to the SITE OF INFECTION Cells of the innate immune system: Macrophages: Macrophages are constitutively present in tissues and recognize microbes that enter these tissues and respond rapidly to these microbes. They initiate the immune response. •These cells are phagocytes (eliminate the pathogens) •Activate the innate immune response (by secreted proteins, called cytokines) •Activate the adaptive immune system. Macrophages serve as APCs that display antigens and activate T lymphocytes •Dendritic cells are constitutively present in tissues and recognize rapidly microbes that enter these tissues. Initiate the immune response. •They have phagocytic capabilities, migrate to lymph nodes, and display microbial antigens to T lymphocytes,professional antigen presenting cells (APC) Neutrophil granulocytes are phagocytes, their main function is to eliminate the pathogens They appear only in the circulation under normal condition. Main actors in inflammatory processes. THE TWO ARMS OF THE IMMUNE SYSTEM Monocytes, Macrophages, Monocytes, Macrophages, Dendritic cells, Granulocytes, NK Dendritic cells, Granulocytes, NK cells and Complement components cells and Complement components B and T cells Innate immunity •Cells, components and their functions •Recognition •Pattern recognition (PAMP) •Danger signal (DAMP) •NK cell •Opsonization •Killing •Other effector functions Innate immunity •Cells, components and their functions •Recognition •Pattern recognition (PAMP) •Danger signal (DAMP) •NK cell •Opsonization •Killing •Other effector functions Innate immunity as a first line of defense Innate immune cells recognize frequently found structures of pathogens, these are not found in human cells! Examples: duple stranded RNA bacterial cell wall components bacterial flagellin…. Recognition is inevitable monocytes, macrophages, dendritic cells, granulocytes (NK cells, T cells, B cells, somatic cells) PAMP Pathogen-associated molecular patterns PRR Pattern recognition receptors PAMPs- Pathogen associated molecular patters Structures on pathogens recognized by the innate cells Recognition is mediated by several PRR receptor families with overlapping functions PRR types TOLL RIG like receptors NOD Scavenger receptors C-type lectin receptors Mannose recognizing receptors Intracellular and extracellular receptors Some type of PRRs: Protein glycosilation is highly differnt in species Eukaryotes Prokaryotes Mannose Glucosamine Galactose Siallic acid Mannose Phagocytes express mannose receptors Mannose Bacterium Mannose receptors Macrophage / Dendritic cell Innate immunity •Cells, components and their functions •Recognition •Pattern recognition (PAMP) •Danger signal (DAMP) •NK cell •Opsonization •Killing •Other effector functions Danger signal Danger signal! The innate immune system also recognizes molecules that are released from damaged or necrotic cells. Such molecules are called damage-associated molecular patterns (DAMPs). Innate immunity •Cells, components and their functions •Recognition •Pattern recognition (PAMP) •Danger signal (DAMP) •NK cell •Opsonization •Killing •Other effector functions Killing of the cells infected with intracellular pathogens 1. The activity of NK cells is enhanced by activatory receptors 2. Inhibitory receptors block NK cell activity. Self cells lysis are protected by inhibitory receptors. KAR 3. Infection or tumors may increase the amount of activation and/or decrease the efficacy of inhibition Target MHC+ Target MHC- Inhibition of lysis KIR NK KAR KIR NK KIR –Inhibitory Receptor of NK cells, association to MHC I KAR –Activatory Receptor of NK cells Innate immunity •Cells, components and their functions •Recognition •Pattern recognition (PAMP) •Danger signal (DAMP) •NK cell •Opsonization •Killing •Other effector functions OPSONIZATION Opsonization facilitates and accelerates the recognition of the pathogen by phagocytes. Opsonins form a bridge and connect the pathogen with the phagocyte. Main opsonins: • Antibodies • Complement fragments • Acute-phase proteins Pathogen recognition by innate immune system 1. Directly via PRR 2. Indirectly via opsonization Innate immunity •Cells, components and their functions •Recognition •Killing •Phagocytosis •Soluble mediators •Complement system •NK cells •Other effector functions Professional phagocytic cells MACROPHAGES DENDRITIC CELLS NEUTROPHILS PHAGOCYTOSIS MACROPHAGE – killing, antigen presentation DENDRITIC CELLS – antigen presentation NEUTROPHIL GRANULOCYTE – killing PRR Degradation ACTIVATION Bacterium Phagocyte Uptake Intracellular killing 0.5 - 1 hours The amount of internalized particles is limited Antigen presentation T cell ACQUIRED IMMUNITY Innate immunity •Cells, components and their functions •Recognition •Killing •Phagocytosis •Soluble mediators •Complement system •NK cells •Other effector functions Soluble mediators • are released mainly from macrophages and granulocytes • are responsible for killing of extracellular pathogens • ROS - reactive oxigen species • NO - nitric oxide • destructive enzymes • antimicrobial substances Innate immunity •Cells, components and their functions •Recognition •Killing •Phagocytosis •Soluble mediators •Complement system •activation •function •NK cells •Other effector functions Initiation of complement response 1.Alternative pathway - constitutively active - inhibited by self structures 2.Classical patway - activated by antibodies/immuncomplexes 3.Lectin pathway - mannose binding lektin (MBL) or – acute-phase protein activates it THE FUNCTION of COMPLEMENT SYSTEM • The complement system is a set of plasma proteins that act in a cascade • • • • to attack and kill extracellular pathogens to recruit inflammatory cells to opsonizate pathogens to remove immunecomplexes Human cells are protected by several cell surface and soluble complement inhibitors Immunocomplex Complement proteins ACTIVATION OF THE COMPLEMENT SYSTEM COMPLEMENT SYSTEM CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY COMPLEMENT ACTIVATION RECRUITMENT OF INFLAMMATORY CELLS OPSONIZATION OF PATHOGENS DIRECT KILLING OF PATHOGENS FACILITATING PHAGOCYTOSIS Immunecomplex removal MEMBRANE ATTACK COMPLEX (MAC) MAC in the cell membrane live and bacteria dead Innate immunity •Cells, components and their functions •Recognition •Killing •Phagocytosis •Soluble mediators •Complement system •NK cells •Other effector functions ACTIVATION OF NATURAL KILLER CELLS NK-CELLS PRR Virus-infected cell RECOGNITION ACTIVATION Lysis of infected cell RECOGNITION OF ALTERED HOST CELLS NK cell kill infected cells or tumors by secreted toxic garnules or by activation of death receptors Killing of the cells infected with intracellular pathogens 1. The activity of NK cells is enhanced by activatory receptors 2. Inhibitory receptors block NK cell activity. Self cells lysis are protected by inhibitory receptors. KAR 3. Infection or tumors may increase the amount of activation and/or decrease the efficacy of inhibition Target MHC+ Target MHC- Inhibition of lysis KIR NK KAR KIR NK KIR –Inhibitory Receptor , association to MHC I KAR –Activatory Receptor Adaptive components are also able to activate NK cells ADCC-Antibody Dependent Cell Cytotoxicity Activating NK cells through FcR on NK cells recognizing pathogen-bound Antibodies Innate immunity •Cells, components and their functions •Recognition •Killing •Other effector functions • Acute inflammation • Localized effects • Systemic effects •anti-viral response (interferons) •opsonization •antigen prezentation ACUTE INFLAMMATION A rapid response to an injurious agent that serves to deliver leukocytes and plasma proteins to the site of injury. TRIGGERS OF ACUTE INFLAMMATION: Infections Trauma Physical and Chemical agents (thermal injury, irradiation, chemicals) Tissue necrosis Foreign bodies (splinters, dirt, sutures) Hypersensitivity or autoimmune reactions MAJOR COMPONENTS OF INFLAMMATION: 1. Vascular response: Increased vascular diameter Increased flood flow. Endothelial cell activation increased permeability that permits plasma proteins and leukocytes to leave the circulation and enter the tissue edema increased expression of cell adhesion molecules e.g. E-selectin, ICAM 2. Cellular response: Migration of leukocytes (diapedesis/extravasation), accumulation, effector functions Recognition of PAMP or DAMP induce inflammation Autocrine and paracrne effect: Vasodialtion Increased vascular permeability extravasation Endocrine effect: Brain---fever Liver---acute phase reaction Bone marrow– more intense cell production Innate immunity •Cells, components and their functions •Recognition •Killing •Other effector functions •acute inflammation •anti-viral response (interferons) •opsonization •antigen prezentation Crucial factors of anti-viral response 1. Type I. Interferons 2. NK cells 3. Cytotoxic T cells 4. Neutralizing antibodies VIRUS INDUCED TYPE I INTERFERON PRODUCTION Type I IFN receptor IFN response Virus IFN- IRF-3 NFB AP-1 IRF-3 IFN- paracrine IFN- IRF-7 autocrine Infected cell IFN response IFN- subtypes IRF: interferon regulatory factor Induction of interferons virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses. are produced by different (~all) cell types usually in response to the entry of a virus, which has the property of inhibiting virus replication Az anti-virális válasz legfőbb összetevői: 1. I-es típusú interferonok 2. NK sejtek 3. Citotoxikus T-sejtek 4. Neutralizáló ellenanyagok Crucial factors of anti-viral response 1. Type I. Interferons • Inhibition of RNA Synthesis • Inhibition of protein synthesis • RNA degradation • degradation of viral proteins 1. NK cells 2. Cytotoxic T cells 3. Neutralizing antibodies EFFECTS OF TYPE I INTERFERONS vírus Plasmacytoid dendritic cells produce 1000x more type I interferon than other cells NATURAL INTERFERON PRODUCING CELLS – IPC After viral infection they are accumulated at the T cell zone of the lymph nodes Crucial factors of anti-viral response 1. Type I. Interferons 2. NK cells 3. Cytotoxic T cells 4. Neutralizing antibodies Most important cytocines: • Inflammatory cytokines: IL1, IL6, TNFα, IL12, IL8 (chemokine) • Anti-viral cytokine: IFNα, IFNβ Innate immunity •Cells, components and their functions •Recognition •Killing •Other effector functions •acute inflammation •anti-viral response (interferons) •opsonization •antigen presentation OPSONIZATION Opsonization facilitates and accelerates the recognition of the pathogen by phagocytes. Opsonins form a bridge and connect the pathogen with the phagocyte. Main opsonins: • Antibodies • Complement fragments • Acute-phase proteins Innate immunity •Cells, components and their functions •Recognition •Killing •Other effector functions •Acute inflammation •Anti-viral response (interferons) •Opsonization •Antigen presentation Professional phagocytic cells macrophages neutrophyl granulocytes dendritic cells Professional antigen presenting cells macrophages B lymphocytes dendritic cells they express MHCII molecules the protein degradation products (peptides) can be presented to T lymphocytes by MHC molecules