TWO ARMS OF THE IMMUNE SYSTEM INNATE IMMUNITY ACQUIRED IMMUNITY

MIKROBES 90% PATHOGENICPATHOGENIC COMMENSAALCOMMENSAAL PEOPLE 7 BILLION INDIVIDUALS GENETIC POLIMORPHISM MHC GENES Recognition of common & variable structures VARIABILITY RAPID MULTIPLICATION CHANGES Földrajzi határok Populáció sűrűség Biodiverzitás Életforma BIOMASSENVIRONMENTMANKIND v v v v v v v v v v v v vvv v v v v v v v v v EPIDEMY LIFE AMONG MICROBES

Bakteria Víruses Multicellular parazites (worms) Unicellular parazites VARIABILITY Rapid evolution AdaptationSelectionENVIRONMENT Microbial and other effects Animals total mass< 5x – 25x Microbes Vírus 3 óra év

Sinuses Trachea Lungs AIRWAY SYSTEM EYE Oral cavity Esophagus Stomach Alimentary tract GASTROINTESTINAL SYSTEM Demage Infection Mucus glycoproteins, proteoglycanes, enzymes Kidney Bladder Vagina UROGENITAL SYSTEM WALDEYER RING Tonsils, adenoids Palatinal, pharyngeal lingual and tubar tonsils SKIN CONTACT SURFACES Physical, chemical, biological borders

MICROBES WITHIN OUR BODY 90% of the cells is microbe 10% human cell (1.5kg) bacteria in the gut Special microbial environment at the mucosal epithelial surface Integrated phylogeny of metabolism and immunity Required for survival Paralel development or organ systems and signaling pathways Drosophila fat body – liver, fat tissue, lymph nodes Nutrient sensingNutrient sensing Energy efficiency Energy storage Energy surplus Metabolic syndrome Pathogen sensingPathogen sensing Food deprivation Defense against pathogens High energy expenditure Impaired immune responses Chronic inflammation METABOLIC HOMEOSTASIS – PROPER IMMUNE SYSTEM Hotamisligil & Erbay NRI 2008

IMMUNE RESPONSE ReproductionThermoregulationLactation HIGHEST ENERGY CONSUMING SYSTEMS Loss of apetite – induction of leptin synthesis Usage of local energy and nutrient stores Chronic nutrient deficiency or overnutrition lead to pathological relationships Pre-adipocytes – Macrophages – Adipocytes – Dendritic cells SHARED GENES IN PHYSIOLOGICAL CONDITIONS & METABOLIC DISEASE STATES

SENSINGRECOGNITION SIGNAL TRANSDUCTION RESPONSE INNATE IMMUNITY CellsReceptors Signaling pathways Cell-to-cell collaboration Effector mechanisms DEFENCE SYSTEMS

ORGANIZATION OF IMMUNE CELLS UNDER EPITHELIAL SURFACES DC Epithelial cells Stroma cells TISSUE SPECIFIC CELL – TO – CELL COMMUNICATION NETWORKS Granulocyte Macrophage NK cell NKT cell

PHYSIOLOGICAL BORDERS TemperaturePhysiological body temperature and fever inhibits growth of certain pathogens Low pHMost pathogens are destroyed in the stomach Chemical Lysosyme degrades bacterial cell wall Type I interferons induce anti-viral resistance The complement system is able to lyse bacteria and promotes phagocytosis PHAGOCYTOSIS/ENDOCYTOSIS Many cells can take up microorganisms by receptor-mediated internalization Special professional phagocytes (monocyte, neutrophil, macrophage) are able to internalize, kill and degrade microorganisms INFLAMMATION Tissue demage and infection results in the leakage of anti-bacterial proteins and peptides to the affected tissue Phagocytic cells leave the blood stream and enter inflammed tissues ANATOMICAL BORDERS SkinInhibits entry of pathogens, pH3 – 5 inhibits growth MucosaNormal bacterial flora competes for binding sites and nutrients Mucus keeps away pathogens from the surface Cilia remove pathogens DEFENSE LINES OF NATURAL IMMUNITY

FAGOCYTE SYSTEM GRANULOCYTES MONOCYTE – MACROPHAGE – DENDRITIC CELL Defence against infectious diseases Elimination of tumor cells Transplantation Gatekeeper function Sensing commensals and pathogens Rapid activation of innate immunity Priming adaptive immune responses Maintenance of self tolerance

RECOGNITION BY THE INNATE IMMUNE SYSTEM

INNATE/NATURAL IMMUNITY RECOGNITION ENDOTOXIN Richard Pfeiffer, a student of Robert Koch – ENDOTOXIN There must be a receptor that recognizes endotoxin Lipopolysaccharide (LPS) receptor remained elusive The Dorsoventral Regulatory Gene Cassette Spätzle/Toll/Cactus controls the potent antifungal response in Drosophila adults Bruno Lemaitre, A Hoffmann et al, Cell, 1996 Spätzle: Toll ligand Toll: Receptor Cactus:I-kB Dorsal:NF-kB Drosomycin is not synthesized

PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS Toll receptor- mediated signaling Toll receptor PHAGOCYTES (macrophages, dendritic cells, neutrophil granulocytes) RECOGNIZE PATHOGENS BY PATTERN RECOGNITION RECEPTORS RECOGNITION IS ESSENTIAL Macrophage, dendritic cell – ACT AS TISSUE SENSORS (GATE KEEPERS) Neutrophil granulocytes – MIGRATE FROM THE BLOOD TO THE SITE OF INFLAMMATION

Multicellular (Metazoa) Sea urchin 600 million years complement C. elegans Toll-receptors Drosophila 700 million years INNATE (NATURAL) IMMUNITY RECOGNIZING RECEPTORSPROTECTIVE MECHANISMS Enzyme systems IN PLANTS

A SZÖVETI MAKROFÁGOK ÉS DENDRITIKUS SEJTEK OLDATOK ÉS RÉSZECSKÉK FELVÉTELÉRE KÉPESEK C-TÍPUSÚ LEKTINEK MMR/CD206 DC-SIGN/209 Langerin/CD207 SZÉNHIDRÁTOK SCAVENGER RECEPTOROK CD36, SR-A LIPID RECEPTOROK LDL-R, CD91LIPIDEK OPSZONIZÁLÓ RECEPTOROK FcR, CR FEHÉRJÉK FERTŐZÖTT ELHALT SEJTEK FELVÉTELMakcropinocitózis Receptor-közvetítette endocitózis Fagocitózis KÖRNYEZETI INFORMÁCIÓK ÖSSZEGYŰJTÉSE, KONCENTRÁLÁSA ION CSATORNÁK ABC TRANSPORTEREK

RECOGNITION BY THE INNATE IMMUNE SYSTEM

Macrophage/Dendritic cell TLR5 Flagellin Virus TLR3 dsRNA TOLL RECEPTORS RECOGNIZE VARIOUS MICROBIAL STRUCTURESTLR2 Peptidoglycane Gram+ TLR4 LPS TLR6 Gram- Interferon producing cell PC/DC IFN  Bacteria CpG DNA TLR9 TLR7TLR8ssRNS ALL STRUCTURES ARE ESSENTIAL FOR THE SURVIVAL OR REPLICATION OF THE PATHOGEN

Conventional DC Plasmacytoid DC NLR=NOD/NALP (IL-1β) RLH=RIG-1/MDA5 (IFN) NLR IL-1β IL-12/23 IL-10 Th1/Th17/Th2 IFNαβ NK/DC RLH RLH DANGER SIGNALS ARE TRANSLATED TO CYTOKINE SECRETION THROUGH VARIOUS MOLECULAR SENSORS IN DC SUBTYPES TLR1 – bacterial lipoprotein (together with TLR2) TLR2 – bacterial lipoprotein, peptidoglycane, lipoteicholic acid (heteromer with TLR1 and TLR6) TLR3 –viral dsRNS, polyI:C TLR4 – bacterial LPS TLR5 – bacterial flagellin TLR6 – bacterial lipoprotein (with TLR2) TLR7 – viral ssRNA TLR8 – GU rich viral ssRNS, imidazoquinolin (antiviral drug) TLR9 – unmethylated CpG DNA TLR10 – mdified viral nucleotides

TLR CONSERVED RECEPTORS/SENSORS THAT DETECT DANGER SIGNALS MEMBRANETLR3Fibroblast Epithelial cell DC CELL MEMBRANEBacteria MEMBRANES OF INTRACELLULAR VESICLES vírus

SIGNALING IN INNATE IMMUNITY

Bacterium CD14 TLR4 LPSNFkBMyD88 IRAK LPB IL-6 Fungus Toll Cactus Tube Spätzel Peptid Protease Pelle Relish TOLL RECEPTORS ACTIVATE PHYLOGENETICALLY CONSERVED SIGNAL TRANSDUCTION PATHWAYS Inflammation Acute phase response Danger signal Macrophage Drosophila CD14 TLR4 TRIF IRF3 STAT1 IFN  TLR3 IL-1R associated Kinase

Liver C-reactive protein COMPLEMENT Serum Amyloid Protein (SAP) Mannose/galactose binding Chromatin, DNA, Influenza Fibrinogen Mannose binding lectin/protein MBL/MBP COMPLEMENT IL- 6 THE ACUTE PHASE RESPONSE IL-6 induces the production of acute phase protiens

Figure 3 The 'hourglass' shape of the innate immune response. Although microbial stimuli are chemically complex and although the innate immune response ultimately involves the activation of thousands of host genes, innate immune signals traverse a channel of low complexity. Ten Toll-like receptors (TLRs), four TIR (Toll/interleukin-1 receptor homologous region) adaptors and two protein kinases are required for most microbial perception. This circumstance lends itself to effective pharmacotherapeutic intervention. NF-  B, nuclear factor-  B; STAT1, signal transducer and activator of transcription 1. TOLL RECEPTOR MEDIATED SIGNALLING NEW THERAPEUTIC TARGET

WHAT IS RECOGNIZED BY INNATE AND ACQUIRED IMMUNITY? HOW DO THEY RECOGNIZE PATHOGENS? Common pattern of groups of pathogens Pathogen Associated Molecular Pattern PAMP Recognition by receptors Pattern Recognition Receptor PRR 9-13 various Toll-receptors TLR family RECEPTORS Innate immunity Ancient