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IMMUNOLOGY COURSE 26 LECTURES 11 SZEMINARS/PRACTICALS 2 lectures/week Weeks 1-13 1 class/week Weeks 1-11 BASIC IMMUNOLOGY and PATHOLOGY DEMO 1. BASIC + SEMINARS 2. PATHOLOGY + PRACTICALS BOOKS Peter Parham: The immune system (Garland Science) 2nd Edition 2005 Janeway C.A. Jr., Travers P., Walport M., Shlomchik M.: Immunbiology (Garland Publishing) 5th Edition 2001 Rosen F., Geha R.: Case Studies in Immunology (Garland Publishing) 5th Edition 2001 Abbas A.K., Lichtman A.H., Pober J.S.: Cellular and Molecular Immunology (W.B. Saunders Company) 4th Edition 2000 www.immunology.unideb.hu Username: student PASSWORD: download TESTS IMMUNOLOGY MICROBIOLOGY EPIDEMIOLOGY IMMUNOLOGY BASIC CLINICAL ALLERGOLOGY CELL BIOLOGY GENETICS BIOCHEMISTRY BIOPHYSICS IMMUNOGENETICS IMMUNOGENOMICS MOLECULAR BIOLOGY ENVIRONMENTAL GENOMICS IMMUNE DEFICIENCIES HYPERSENSITIVITY REACTIONS INFECTIOUS DISEASES AUTOIMMUNITY TUMOR IMMUNOLOGY TRANSPLANTATION IMMUNOLOGY HISTORY OF IMMUNOLOGY Babylonian Epic of Gilgamesh (2000 B.C.) diseases, pestilence Egypt older dynasties severe epidemics Phobus Apolló plague in the Greek army Old testament God’s punishment 1880 – First World War study of disases, vaccines 1920 – 1960 scientific revolution, chemistry and biology Immunological memory Thucydides, historian, Athen 430 i.e. plague „yet it was with those who recovered from the disease that the sick and the dying found most compassion……. No fear for themselves; as no man was never attacked twice – never at least fatally” Immunity Depletion theories Immunitas (latin) – excemption from taxes First infection depletes nutrients required for the propagation of the pathogen Variolation Smallpox live, wild-type virus inoculated (from China) but practiced in Europe too FIRST VACCINATION Edward Jenner 1796 Immunity (protection) can be induced (cowpox - smallpox) Louis Pasteur 1880 rabies, 1888 Pastuer Institute 1884 Ilya Mechnikoff Phagocytosis Immunization with attenuated pathogens CELLULAR IMMUNOLOGY Koch Laboratory Berlin 1890, Diphteria and Tetanus toxin Antibodies in serum – bound to relevant pathogens Humoral factors HUMORAL IMMUNE RESPONSE Emil Behring Shimbasaru Kitasato 1. Many disease occurs only once (natural protection) 2. Some diseases can be prevented by vaccination 3. The blood contains anti-bacterial activity (anti-toxins, serum therapy) MILESTONES OF IMMUNOLOGY RESEARCH I. YEAR NAME DISCOVERY NOBEL PRIZE 1890 Emil von Behring Anti-toxins Serotherapy (diphteria) 1901 1890 Robert Koch Tuberculosis, anthrax Cellular immunity, tuberculin reaction 1905 1883 Elie Mecsnyikov 1908 1900 Paul Ehrlich Phagocytosis, inflammation Cellular protection Side chain theory 1902 Charles Richet (Paul Portier) Anaphylaxis 1913 1894 Jules Bordet Complement Antibodies/bacteriolysis 1919 1900 Karl Landsteiner A/B/0 blood groups - serology 1930 1940 Max Theiler Vaccine against yellow fever 1951 Daniel Bovet Anti-histamines, treatment of allergy 1957 MILE STONES OF IMMUNOLOGY RESEARCH II. 1944 Peter Medawar Macfarlane Burnet Acquired tolerance Clonal selection theory 1960 1959 Rodney Porter Gerald Edelman Antibody structure 1972 Rosalyn Yalow Roger Guillemin Andrew Schally Radioimmunoassay Peptide hormon production in brain 1977 1958 Baruj Benacerraf Jean Dausset, George Snell Histocompatibility antigens 1980 1975 George Köhler Cesar Milstein Niels Jerne Monoclonal antibody 1984 Susumi Tonegawa Gene rearrangement 1987 E. Donnall Thomas Joseph Murray Transplantation immunology 1990 Rolf Zinkernagel, Peter Doherty MHC restriction 1996 1979 1974 Network theory GENERAL CHARACTERIZATION OF THE IMMUNE SYSTEM GENERAL FEATURES OF THE IMMUNE SYSTEM 1. STRUCTURE – various cell types, diffuse Cell communication Th Partners Mode macrophage – direct B pathogen – soluble factors extracellular matrix macrophage Cell – to – cell communication 2. ACTION – dynamic Homeostasis – environmental factors Replacement vs death Adhesion Homing Migration neutrophil Activation vs differentiation Endothelial cell 3. FUNCTION Inflammed tissue 4. SPECIAL FEATURES Recognition – self - antigen - danger Defense against pathogens Recognize, prevent spread, clear from the body Signal processing and transduction Signal storage – learning, memory Protection of self SIMILARITIES TO THE NERVOUS SYSTEM WHY IS THE IMMUNE SYSTEM SO IMPORTANT? Species have been evolved in the presence of pathogens PATHOGENS Virus Bacteria 3 hours Viruses 3 hours DIVERSITY VARIABILITY Multicellular parazites (helminths) Cells of human body: 90% microbes, 10% human Monocellular parazites 1012 (1.5kg) bacteria in the gut Human population: 7x109 (7 billion) Biomass: 90% microbes Animal mass < 5 – 25x microbes TWO LINES OF IMMUNE DEFENSE TWO TYPES OF IMMUNE RESPONSES INNATE/NATURAL IMMUNITY Innate immunity constitutes those components that protect against infection without any requirement for prior activation or clonal expansion First line of defense Inherited It is always present Rapid response Short term protection ACQUIRED/ADAPTIVE IMMUNITY Requires the activation and clonal expansion of cell to protect against pathogens PHYSICAL BARRIERS PROTECTING OUR BODY FROM THE ENVIRONMENT HAIR BRONCHIAL TRACT EYES GASTROINTESTINAL SYSTEM Sinuses Trachea Lungs Oral cavity esophagus Stomach Intestines NAILS SKIN Damage Kidney Bladder Vagina UROGENITAL SYSTEM Infection WALDEYER RING Tonsils, adenoids Palatinal, pharyngeal lingual and tubar tonsils Mucus glycoproteins, proteoglycanes, enzymes EPITELIAL SURFACES ARE IMPORTANT IN THE FIRST LINE OF DEFENSE DEFENSE LINES OF NATURAL IMMUNITY ANATOMIC BORDERS Skin Inhibits entry of pathogens, pH3 – 5 inhibits growth Mucosa Normal bacterial flora competes for binding sites and nutrients Mucus keeps away pathogens from the surface Cilia remove pathogens PHYSIOLOGICAL BORDERS Temperature Physiological body temperature and fever inhibits growth of certain pathogens Low pH Most pathogens are destroyed in the stomach Chemical Lysosym 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 damage 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 PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS Toll receptor CR3 (LPS) Toll receptor (fungi) PHAGOCYTES (macrophages, dendritic cells, neutrophil granulocytes) RECOGNIZE PATHOGENS BY PATTERN RECOGNITION RECEPTORS RECOGNITION IS UNAVOIDABLE Macrophage, dendritic cell – ACT AS TISSUE SENSORS Neutrophil granulocytes – MIGRATE FROM THE BLOOD TO THE SITE OF INFLAMMATION WHAT IS RECOGNIZED BY INNATE AND ACQUIRED IMMUNITY? HOW DO THEY RECOGNIZE PATHOGENS? RECEPTORS 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 Innate immunity Ancient Unique structural elements Antigenic determinant Recognition by highly specific antigen receptors B cell receptor BCR (sIg) T cell receptor TCR Several millions antigen receptors Acquired immunity 450 million years TOLL RECEPTORS RECOGNIZE VARIOUS MICROBIAL STRUCTURES Bacteria Virus CpG DNA ssRNS dsRNA Peptidoglycane Gram+ TLR3 IFN TLR7 TLR8 TLR2 Interferon producing cell pDC Flagellin LPS Gram- TLR4 TLR6 TLR9 TLR5 Macrophage/Dendritic cell ALL STRUCTURES ARE ESSENTIAL FOR THE SURVIVAL OR REPLICATION OF THE PATHOGEN GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES Prokariotic cells Eukariotic cells Mannose Glucoseamin Mannose Galactose Neuraminidase PATTERN RECOGNITION BY MANNAN BINDING LECTIN Bacterium lysis Complement activation LECTIN PATHWAY CR3 Macrophage Phagocytosis Strong binding No binding THE ACUTE PHASE RESPONSE IL- 6 Mannose binding lectin/protein C-reactive protein Complement MBL/MBP Complement Liver Serum Amyloid Protein (SAP) Phagocytosis, ECM stability Fibrinogen IL-6 induces the production of acute phase protiens PHAGOCYTOSIS Macrophages ingest and degrade particulate antigens through the use of long pseudopodia that bind and engulf bacteria. The engulfed bacteria are degraded when the phagosome fuses with a vesicle containing proteolytic enzymes (lysosome), forming the phagolysosome. Specialized compartments also exist in the macrophage to promote antigen processing for presentation to antigenspecific T cells. MACROPHAGES ACTIVATE OTHER MECHANISMS OF INNATE IMMUNITY CELLULAR AND HUMORAL MECHANISMS OF INNATE IMMUNITY PHAGOCYTOSIS Phagocytosis Intracellular killing Phagocyte Bacterium COMPLEMENT Complement proteins Lysis of bacteria Inflammation Bacterium INFLAMMATION Complement-dependent phagocytosis Cytokines IL-12 Bacterium LPS NK-CELLS Virus-infected cell TNF IFN NK-cell Neutrophil NK-cell Macrophage Lysis of infected cell TWO LINES OF IMMUNE DEFENSE TWO TYPES OF IMMUNE RESPONSES INNATE/NATURAL IMMUNITY ACQUIRED/ADAPTIVE IMMUNITY Phagocytes (monocyte/macrophage, neutrophil, dendritic cell) B lymphocytes (B2) Killer cells (NK cell, δ T cell) B1 lymphocytes (CD5+) CELLS T lymphocytes helper T cell Enzymes (lysozyme,transferrin, lactoferrin, spermin, trypsin) Antibacterial peptides Complement system Cytokines, chemokines cytotoxic T cell HUMORAL FACTORS Antibodies CHARACTERISTICS OF INNATE IMMUNITY • • • • • • • NATURAL/INNATE Rapid, prompt response (hours) No variable receptors Limited number of specificities No improvement during the response No memory Not transferable Can be exhausted, saturated • • • • • • • • ADAPTIVE/ACQUIRED Time consuming Variable antigen receptors Many very selective specificities Efficacy is improving during the response Memory Can be transferred Regulated, limited Protects self tissues COMMON EFFECTOR MECHANISMS FOR THE ELIMINATION OF PATHOGENS TWO LINES OF IMMUNE DEFENSE INNATE/NATURAL IMMUNITY Innate immunity constitutes components that protect against infection without any requirement for prior activation or clonal expansion First line of defense Inherited Always present ACQUIRED/ADAPTIVE IMMUNITY Requires the activation and clonal expansion of cells to protect against pathogens Induced by antigen Response is under genetic control Depends on environmental stimuli FUNCTIONAL ATTRIBUTES OF INNATE AND ADAPTIVE IMMUNITY Chapter 1 Elements of the Immune System and their Roles in Defense • The innate immune response causes inflammation at sites of infection • The adaptive immune response adds to an ongoing innate immune response • Potent immune responses require the collaboration of innate and adaptive immune responses © Garland Science 2009 FIRST LINE OF DEFENSE BY INNATE IMMUNITY EPITHELIAL CELLS •Pattern recognition receptors (PRR) •Cytokine, chemokine secretion NEUTROPHIL GRANULOCYTES •Phagocytosis •Intracellular cytotoxicity MONOCYTE – MACROPHAGE – DENDRITIC CELL NETWORK •Pattern recognition receptors (PRR) •Internalizing receptors •Phagocytosis NATURAL KILLER CELLS •Cytoxicity •Cytokine production CELLS & MECHANISMS OF INNATE IMMUNITY Soluble proteins – Defensins Enzymes - Complement system - Chemotaxis Recognition by Pattern Recognition Receptors (PRR) Macrophage & dendritic cell subsets Neutrophils Pro-inflammatory and inflammatory cytokine secretion Local effects Systemic effects Chemokine receptors & ligands – cell recruitment, other functions Cytotoxicity – NK cells