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2ND SEMINAR BASIC CONCEPTS OF INNATE IMMUNITY, INFLAMMATION CONTACT SURFACES Physical, chemical, microbiological barriers EYE SKIN AIRWAY SYSTEM WALDEYER RING Tonsils, adenoids Palatinal, pharyngeal lingual and tubar tonsils Sinuses Trachea Lungs GASTROINTESTINAL SYSTEM Oral cavity Esophagus Stomach Alimentary tract UROGENITAL SYSTEM Kidney Bladder Vagina DAMAGE TO ANY OF THESE BARRIERS MAY LEAD TO INFECTION FIRST LINE OF DEFENSE PHYSICAL, CHEMICAL AND MICROBIOLOGICAL BARRIERS GI tract Stomach: pH of 3-4; small intestine: pH of 6-8 Digestive enzymes Mucus Antibacterial peptides e.g. defensins, cryptidins Peristalsis, diarrhoea, vomiting Normal flora H. pylori – making basic pH Skin Tight junctions Keratin layer Antibacterial peptides e.g. defensins pH of 5.5 Fatty acids Normal flora Burns susceptibility to infections Eye Tear film (oils, lactoferrin, mucin and lysozyme) Urogenital tract Flushing out Vagina: pH of 3.8-4.5, normal flora (Lactobacillus lactic acid) Respiratory tract Ciliary movement – constant outward flow Coughing, sneezing CF - impaired cilia movement MICROBIOLOGICAL BARRIERS The normal flora SKIN, NASO-ORO-PHARYNGS, GUT, VAGINA Symbiotic, non-pathogenic microbes, living in „peaceful” commensalisms Beneficial features: • Digesting non absorbable food compounds e.g. cellulose • Producing vitamines, antimicrobial molecules, regulating pH • Compete with pathogenic microbes – survival of the fittest • Providing constant low-dose antigen exposure • Helping the development of the immune system • Maintainig tolerance BALANCE! (antibiotics – probiotics) Some facts about the normal flora: • • • • There are 100-times more bacterial genes than eukaryotic genes Cells of human body: 90% microbes, 10% human Gut bacteria: 1014 - more than 500 microbial species (approx. 1.5 kgs) Human cell population: 1013 Gut normal flora play an important role in: - Development of mucosal and systemic immunity - Normal development of peripheral lymphoid organs - Maintenance of basic level of immunity ORGANIZATION OF IMMUNE CELLS UNDER EPITHELIAL SURFACES Epithelial cells Stroma cells Dendritic cell NK cell NKT cell DC Granulocyte Macrophage PERIFÉRIÁS TISSUE–SPECIFIC CELLULAR COMMUNICATION NETWORKS SZÖVETEK RECOGNITION BY THE INNATE IMMUNE SYSTEM DEFENSE SYSTEMS ADAPTIVE IMMUNITY INNATE IMMUNITY SENSING Cells SENSING RECOGNITION Receptors RECOGNITION SIGNALING Signaling pathways SIGNALING Cell-Cell collaboration RESPONSE Effector functions RESPONSE RECOGNITION RECEPTORS OF INNATE IMMUNITY • Pattern Recognition Receptors (PRRs) – recognise molecular patterns as danger signals – can be classified as PRR families: • • • • • Lectins Toll-Like Receptors (TLRs) Nod-Like Receptors (NLRs) RIG-Like Receptors (RLRs) Scavenger receptors • molecular pattern: characteristic molecules that are expressed in high amounts by cells or microbes – Patogen-Associated Molecular Patterns (PAMPs): molecules that are expressed unlike human cells, usually essential for the survival or replication of pathogens – Damage-Assoiated Molecular Patterns (DAMPs): molecules released after cellular damage TOLL-LIKE RECEPTOR FAMILY DANGER SIGNALS ARE TRANSLATED TO CYTOKINE SECRETION THROUGH VARIOUS MOLECULAR SENSORS IN DC SUBTYPES 4 2 5 3 1 6 6 1 7 NLR 8 7 9 10 RLR RLR Conventional DC IL-1β IL-12/23 IL-10 Plasmacytoid DC TLR1 – bacterial lipoprotein (together with TLR2) TLR2 – bacterial lipoprotein, peptidoglycane, lipoteicholic acid (heteromer with TLR1 and TLR6) TLR3 – viral dsRNA TLR4 – bacterial LPS TLR5 – bacterial flagellin TLR6 – bacterial lipoprotein (together with TLR2) TLR7 – viral ssRNA TLR8 – viral ssRNA TLR9 – unmethylated CpG DNA TLR10 – modified viral nucleotides NLRs – microbial products, DAMPs RLRs – viral ssRNA IFNα IFNβ EFFECTOR MECHANISMS OF INNATE IMMUNITY KILLER CELLS PHAGOCYTIC CELLS COMPLEMENT SYSTEM PHAGOCYTIC SYSTEM NEUTROPHIL - MACROPHAGE - DENDRITIC CELL Gatekeeper function Sensing commensals and pathogens Rapid activation of innate immunity Priming adaptive immune responses Maintenance of self-tolerance Defense against infectious diseases Elimination of tumor cells Transplantation rejection RECEPTORS ON MACROPHAGES Scavanger receptor Mannose receptor FcRI (CD64) Ag + Ab complex TLR4 + CD14 MHCI TLRs – PAMPs FcRII (CD32) MHCII FcRIII (CD16) LFA1 (CD11a/CD18) Cell adhesion molecules CR1 (CD35) CR3 (CD11b/CD18) Complement receptors GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES Prokaryotic cells Eukaryotic cells Mannose Glucoseamin Mannose Galactose Sialic acid MANNOSE RECEPTORS ON PHAGOCYTES Bacterium Mannose Mannose Receptor Macrophage/dendritic cells PHAGOCYTOSIS, RECOGNITION RECEPTORS, SIGNAL TRANSDUCTION, EFFECTOR MECHANISM Pattern recognition Receptors (PRR) UPTAKE Macropinocytosis Receptor-mediated endocytosis Phagocytosis COLLECTION OF ENVIRONMENTAL INFORMATON Engagement of PRR triggers phagocytosis and cytokine production PHAGOCYTOSIS INNATE IMMUNITY Pathogen recognition PRRs (TLRs, lectins, NLRs, RLRs, scavenger receptors) Cell activation Increased phagocytic activity, intracellular killing (reactive oxygen species (ROS), lysosomal enzymes), chemokine and cytokine secretion Antigen processing Phagocytosis/endocytosis degradation in phagolysosomes Antigen presentation (later) ACUTE INFLAMMATION & ACUTE-PHASE RESPONSE 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 THE CLASSIC SYMPTOMS OF INFLAMMATION: • • • • • Redness (rubor) Swelling (tumor) Heat (calor) Pain (dolor) Loss of function (functio laesa) Resident phagocytes get activated by PRR signalization upon recognition of danger signals • Production of cytokines and chemokines, • Intracellular killing, • Antigen presentation (activation of adaptive responses) ORDER OF INNATE CELLS APPEARANCE IN THE INFLAMED SITE NEUTROPHIL GRANULOCYTES • 68% of circulating leukocytes, 99% of circulating granulocytes • Phagocytic cells • Are not present in healthy tissues • Migration elimination of pathogens (enzymes, reactive oxygen intermediates) • Main participants in acute inflammatory processes NEUTROPHIL CHEMOTAXIS MIGRATION OF NEUTROPHILS Neutrophil Transendothelial Migration (Diapedesis) Pathogens activate macrophages to release cytokines and are then phagocytized and digested in phagolysosomes CHEMICAL MEDIATORS Local effect & systemic effect CHEMICAL MEDIATORS Vasodilation – Prostaglandins (PG), nitric oxide (NO) Increased vascular permeability – vasoactive amines (histamine, serotonin), C3a and C5a (complement system), bradykinin, leukotrienes (LT), PAF Chemotactic leukocyte activation – C3a, C5a, LTB4, chemokines (e.g. IL-8) Fever • IL-1, IL-6, TNFα, PGE2 Pain • Prostaglandins, bradykinin Tissue damage • Neutrophil and Macrophage products – lysosomal enzymes – Reactive oxygen species (ROS) – NO NSAIDs and Paracetamol: inhibiting COX-1 and COX-2 preventing the synthesis of prostaglandins ACUTE-PHASE RESPONSE PROTEINS Pentraxin family: CRP – opsonization, complement activation SAP – opsonization, complement activation, binding of mannose/galactose Collectin family: SP-A/D – collectins of lungs MBL – part of complement system During an APR their concentration increases up to x1000 Complement proteins (C1-C9) Fibrinogen – blood clotting RESOLUTION OF ACUTE INFLAMMATION