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Introduction to Immunology Milestones of Immunology Immune system – an overview Antigen M. Buc 1 Definition of the subject Immunology is a scientific branch that studies defence of an organism against germs, cancer cells, toxins etc. Doan et al., 2008 M. Buc 2 Definition of the subject Immunology is a scientific branch that studies immunity, its cellular and molecular processes that proceed after a foreign substance, an antigen, enters our body M. Buc 3 Origin of the term The term „immunity“ originates from Latin word „immunitas“, what implies exemption from various civic duties, juridical procedures, etc. from which benefited senators of the Roman empire “Immunitas“ in immunology: an exemption from contracting an infectious disease M. Buc 4 Milestones of Immunology Personalities who substantially contributed to the development of Immunology Milestones of immunology Ancient China (the 11th century) – vaccination against smallpox: children were let to sniff a powder prepared from crusts of patients suffering from a mild form of variola = VARIOLATION www.google.sk It was a dangerous procedure, however it was used as no other possibility existed M. Buc 6 Milestones of immunology • In 1798 Edward Jenner, a physician, observed that that milkmaids who had contracted cowpox were subsequently immune to smallpox • Jenner reasoned that introducing fluid from a cowpox pustule into people might protect them from smallpox M. Buc 7 Milestones of immunology Jenner inoculated an eight-year– old boy with fluid from a cowpox pustule and later intentionally infected the child with smallpox viruses. As he predicted, the child did not develop smallpox www.google.sk Jenner technique rapidly replaced variolation as the preferred method for protecting humans against smallpox M. Buc 8 Milestones of immunology In 1958 the WHO decided to eradicate smallpox by means of a mass vaccination It was so effective that it had become the first infectious disease eradicated from the earth M. Buc 9 Louis PASTEUR (1822-1895) L. Pasteur recognised that aging of bacterial (anthrax) colonies weakened a virulence of the pathogen and that such an attenuated (weakened) strain could be administered to protect (sheep) against the disease www.google.sk M. Buc 10 Louis PASTEUR He called this attenuated strain a vaccine (from the Latin vacca, meaning “cow”), in honour of Jenner´s work with cowpox inoculation M. Buc 11 Louis PASTEUR In 1885 L. Pasteur prepared a vaccine for rabies by drying the spinal cord of infected rabbits The vaccine was administered to a young boy who had been bitten repeatedly by a rabic dog; his life was saved The Pasteur work marked the beginning of the discipline of immunology and L. Pasteur can therefore be considered its founder, the father of immunology M. Buc 12 Emil von Behring (1854 - 1917) He demonstrated that the protection induced by vaccination was associated with the appearance of protective factors in the blood He called these factors antibodies www.google.sk M. Buc 13 Ilja Metchnikov (1845 - 1916) The discoverer of phagocytosis Laureate of the Nobel prize (1908) www.google.sk M. Buc 14 Robert KOCH (1843 - 1910) The discoverer of the etiological agent of tuberculosis, cholera, and anthrax The discoverer of the tuberculin reaction, a cell mediated inflammatory skin inflammation Laureate of the Nobel prize in 1905 www.google.sk M. Buc 15 Rodney Porter (1917 - 1985) R. Porter discovered the biochemical structure of antibodies He was awarded the Nobel prize in 1972 www.google.sk M. Buc 16 Jacques MILLER (1931- ) J. M. discovered a role of the thymus in immunity (1961) The specific cellular immunity is mediated by cells derived from the thymus, i.e. T-lymphocytes www.google.sk M. Buc 17 Jean DAUSSET (1916 - 2009) The discoverer of the major histocompatibility complex in man Nobel prize award: 1980 www.google.sk M. Buc 18 Georges J. F. Köhler (1946 - 1998) The co-discoverer (with C. Milstein), of the hybridoma technique for the production of monoclonal antibodies www.google.sk Both: Nobel prize in 1984 M. Buc 19 Cesar Milstein (1927 - 2002) www.google.sk 20 Commentary All mentioned scientists represent the top of all others, more or less renown personalities All of them contributed to the fact that immunology belongs to the one of the most developing scientific subjects Knowledge of immunology is indispensable in many scientific and medicine branches M. Buc 21 THE IMMUNE SYSTEM An overview of its structure and function The immune system (IS) From the morphological point of view, the immune system is a diffuse organ; it weights app. 1 kg in adults Primary and secondary lymphoid organs Numerous leucocytes, macrophages, dendritic cells etc., altogether are there app. 1012 cells Billions of molecules (antibodies, cytokines, regulatory, anti-microbial, transport molecules, etc.) – 1020 M. Buc 23 Forms of immunity Inherent – species, strain, individual Acquired: - active - natural (post-infectious) - artificial (post-vaccine) - passive - natural (mother - foetus) - artificial (antisera, gamma globulin) M. Buc 24 Biological functions of the immune system The immune system supervises integrity and individuality of an organism Discriminatory Surveillance Effector It cooperates with other systems of the body, esp. nervous and endocrine. They form integrity system Memory Pathogenetic M. Buc 25 Forms of immunity Non specific (natural, innate) Specific (adaptive) M. Buc 26 Cells of the innate immunity Phagocytes Cytotoxic cells Mediator cells Neutrophils Eosinophils Monocytes Macrophages NK-cells Basophils Mast cells M. Buc 27 Neutrophils www.google.sk M. Buc 28 Eosinophils www.google.sk M. Buc 29 Basophils www.google.sk M. Buc 30 M. Buc Doan et al., 2008 31 Mast cells www.google.sk M. Buc 32 Monocytes www.google.sk M. Buc 33 M. Buc 34 Macrophages www.google.sk M. Buc Tizard, 1995 35 Dendritic cells (DC) Myeloid DC (antigen processing) Plasmacytoid DC (production of IFN-I) Folicular DC (capture of immune complexes, i.e. complexes of antigens bound to its antibodies) M. Buc 36 Myeloid dendritic cell www.google.sk M. Buc 37 Foliclar dendritic cells www.google.sk M. Buc 38 LGL/NK cells LGL – „large granular lymphocytes“ NK – „natural killer cells“ www.google.sk M. Buc 39 Specific (adaptive) immunity Antibody mediated Cell mediated M. Buc 41 Organs of the immune system • Primary lymphoid organs Bone marrow, thymus • Secondary lymphoid organs Lymph nodes, tonsils, spleen, Peyers patches, appendix M. Buc 42 M. Buc 43 Goldsby et al. 2000 Cells of the adaptive immunity Antigen presenting cells Dendritic cells Monocytes Macrophages Effector cells T lymphocytes B lymphocytes Plasma cells M. Buc 44 Lymphocytes Lymphocytes are principal cells of the specific immune response B lymphocytes (bursa Fabricii dependent lymphocytes) T lymphocytes (thymus dependent lymphocytes) www.google.sk M. Buc 45 M. Buc 46 M. Buc 47 M. Buc 48 M. Buc 49 The spleen www.google.sk M. Buc 50 M. Buc 51 Goldsby et al. 2000 Nature Rev Immunol M. Buc 52 Recirculation M. Buc 53 M. Buc 54 Tizard 1995 M. Buc 55 M. Buc 56 The number of cells in the peripheral blood in adults Erythrocytes 5 . 106/mm3 Leucocytes 5 – 10 . 103/mm3 Neutrophils 60% Lymphocytes 35% Monocytes 3% Eosinophils 1% Basophils 1% Platelets 150–200.103/mm3 M. Buc 57 Doan et al. 2008 M. Buc 58 M. Buc 59 Mechanisms of non- and specific immuinities Characteristics of the mechanisms of natural immunity They are already present before the first encounter of an antigen They do not make any differences among antigens, the reaction to each one is the same The re-exposition of an organism with the same antigen does not elicit any quantitative or qualitative response compared to the first encounter M. Buc 61 Characteristics of mechanisms of the specific immunity Specificity - The immune response is directed to one particular antigen only, not to any other Diversity - The immune system is able to distinguish the enormous number of different antigens (109 – 1012) M. Buc 62 Characteristics of mechanisms of the specific immunity • Self limitation: The immune response • Memory: The immunity remembers an • Tolerance: The immune system declines some time after fulfilment its role antigen which elicited its induction. The reexposition to the antigen induces a prompt and higher amplitude of the response to him distinguishes self molecules from non self M. Buc 63 oan et al. 2008 • The innate immune system reacts to a given stimulus with a constant intensity, regardless of how many times it has been exposed to that stimulus M. Buc • The specific immune system can adapt and modify its response after each exposure to a given stimulus64 A comparison of the non-specific and specific immunity Mechanisms of the specific immunity are not superior over the non-specific, on the contrary, they help them to identify an intruder of the integrity of the organism and to eliminate it more efficiently M. Buc 65 Mechanisms of innate immunity 1. Mechanisms of the first line of defence (A constitutional make up of an organism) 2. Mechanisms of the second line of defence M. Buc 66 The first line of defence • Skin (pH, fatty acids, epithelial cell desquamation) • Mucosa of the upper respiratory tract (ciliated epithelium, cough, sneezing) • Eye, oral cavity (lysozyme) M. Buc 67 The first line of defence • Stomach (HCl) • Normal intestinal flora (Escherichia coli) • Vagina (Lactobacilus Döderleini) • Urine (acidic pH) M. Buc 68 Doan et al. 2008 M. Buc 69 The first line of defence Kirkwood E and Lewis C 1983 M. Buc 70 The first line of defence Kirkwood E and Lewis C 1983 M. Buc 71 Mechanisms of the second line of defence • Cellular components - Phagocytes - NK and NKT cells • Humoral components - Antibacterial proteins of the plasma - Complement - Carrier and inflammatory proteins M. Buc 72 Goldsy et al. 2000 73 Mechanisms of specific immunity Antibody mediated Antibodies by themselves or by help of some other components of IS destroy or neutralise antigens Cell mediated T cells are responsible for. They destroy targets foreing cells by themselves or they „call“ other cells to help them M. Buc 74 ANTIGEN Antigen An antigen is a substance that is able to induce an immune response Antigens: - microbes - chemical substances (proteins, saccharides, ..) - transplanted organs and tissues - modified self molecules and cells M. Buc 76 Basic properties of antigens Foreignness and phylogeny distance Biochemical structure Relative molecular mass Degradability A dosage and the way of introduction into the body M. Buc 77 Foreignness of an antigen Antigen must be foreign, i.e. an organism has never met it before The greater phylogeny distance between an antigen and the body, the more immunogenic the antigen is M. Buc 78 Biochemical structure The best antigens Proteins, polypeptides Polysaccharides Glycoproteins, peptidoglycans Glycolipids Lipids and native nucleic acids are not antigenic M. Buc 79 Mass relative The higher Mr, the better induction of the immune response is The cut-off value: 5 000 M. Buc Goldsy et al. 2000 80 Degradability Antigen has to be degradable by enzymes into smaller parts, fragments; if not, the immune response cannot be induced, e.g. steel nails used in surgery at repositions of broken bones, plastic material (shams) in orthopaedics, etc. On the contrary, if antigen is degraded too quickly, too easily, is not antigenic too, e.g. gelatine M. Buc 81 Antigen dosage Low doses of an antigen do not induce an immune response as they do not stimulate sufficient numbers of cells of the immune system – low zone tolerance High doses of antigen do not induce an immune response as cells of the immune system do not cope with its processing: immunologic paralysis or high zone tolerance M. Buc 82 Ways of antigen introduction to the body Blood borne antigens – they enter the spleen I.m., s.c, mucosal ways – antigens enter regional lymph nodes Antigens elicit either antibody mediated or cell mediated immune responses in dependence of their structure M. Buc 83 Biological factors in response to antigens Early childhood (till two years of the life) • Children do not respond to polysaccharide antigens • Some bacteria (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae) possess in their capsules polysaccharide antigens • Infections caused by these bacteria result to pneumonias and meningitis – a life threatening events M. Buc 84 Biological factors in response to antigens Old age (> 75) Elderly persons do not produce antibodies to polysaccharide antigens Elderly persons are therefore also more susceptible to infections by bacteria possessing polysaccharides in their capsules (S. pneumoniae, N. meningitidis and H. influenzae) M. Buc 85 Biological factors Women compared to men: are generally more resistant to infections their response to an antigen is more intensive the levels of IgG a IgM as well as the numbers of T cells are higher leptin levels are higher in women than in men (leptin stimulates T cells) M. Buc 86 Properties of an antigen Immunogeneicity – an ability to induce the immune response Specificity – an ability to react with effector mechanisms of the immune system (i.e. antibodies and lymphocytes) M. Buc 87 Epitope An epitope (determinant) is a part of the antigen to which an antibody or a lymphocyte is directedds Doan et al. 2008 88 Virella 2001 M. Buc 89 Affinity Doan et al. 2008 M. Buc 90 Epitope versus Hapten The epitope is an integral part of the antigen A hapten is an external part of the antigen, bound to it; it can exist independently of the antigen, however is unable to elicit the immune response When hapten is bound to a carrier, it induces the immune response and is able to react with induced antibodies or lymphocytes Hapten is able to react with induced antibodies or lymphocytes also without carrier M. Buc 91 Doan et al. 2008 M. Buc 92 Tizard 1995 M. Buc 93 Kindt, 2007 94 Heterophile antigens Heterophile antigens are molecules present in absolutely unrelated species that crossreact, i.e. if one antigen induces antibodies production, these will react with antigens in other individual of different species M. Buc 95 Weil Felix reaction in the laboratory diagnosis of epidemic typhus Antibodies produced against Rickettsia prowasekii react also with Proteus vulgaris, strain OX19 We detect antibodies against etiological agent of the disease in a patients serum, i.e. non pathogenic P. vulgaris and not R. prowasekii, is used as antigen in this serological in vitro reaction A laboratory worker is protected from being infected M. Buc 96 Paul Bunnel reaction Antibodies characteristic for infectious mononucleosis, of which Epstein-Barr virus (EBV) is the etiological agent, react also with sheep or cow erythrocytes M. Buc 97 ABO blood groups Discovered by K. Landsteiner and J. Jansky in 1900 and 1907, respectively They discovered A, B, and O; the group AB was added to them by A. von Decastello a A. Stürli in 1902 How should the blood group „O“ be called? - should it be called „zero“ (0)? - should it be called according to the letter „O“? The correct nomenclature: „O“ = „ohne (without) A“ „ohne (without) B“ M. Buc 98 Biochemical structure of ABO antigens The basis structure for all three ABO antigens: H-substance = oligosaccharide + fucose Blood group A: H-substance + N-acetylglucosamine Blood group B: H-substance + galactose M. Buc 99 M. Buc 100 M. Buc 101 ABO blood groups Imunogenetic relationships Phenotype Genotype Antigens AB A/B A, B A A/A, A/H A B B/B B/H B O H/H H/H M. Buc 102 Antibodies against A- Bantigens are called isohaemaglutinins Phenotype Antibodies AB No A Anti-B B Anti-A O Anti-A, anti-B Newborns are born without them; the first antibodies appear between the moths 3 till 6 of their life Antibodies are induced by immunisation of the child when colonised by bacteria belonging to a normal bacterial flora M. Buc 103 Natural isohaemaglutinins A blood group A child when colonised by Escherichia coli, strain O86, develops anti-B antibodies A blood group B child when colonised by Streptococcus pneumoniae, strain 14, develops anti-A antibodies Isohaemaglutinins are of IgM class and are present in the plasma only, not in other body fluids M. Buc 104 ABO antigens - distribution ABO antigens are regarded blood groups because of their paramount importance in blood transfusions In reality, they are tissue antigens as they are present also in membranes of epithelial and endothelial cells of many tissues and organs App. 75% individuals contain ABO blood groups in their tissue fluids = secretors M. Buc 105 Rhesus system Rh-system was discovered by K. Landsteiner and A. S. Wiener, resp., in 1940 Rh-systemm is very complex, so far we recognise app. 45 different antigens The most significant Rh-antigens are: C or c, E or e, and D or d M. Buc 106 Rh-system Rh-antigens are in reality epitopes of proteins crossing the cell membrane 12-times and are responsible for ammonium transfer There are no natural anti-Rh antibodies in our plasma Rh-system is of a great importance in a possible immunisation of RhD-negative mother by RhD-positive erythrocytes of her child M. Buc 107 Rh system 108 Rh-isoimmunisation When a mother is RhDnegative (d/d) and her partner is either RhDhomozygous (D/D) or heterozygous (D/d) their child can be RhDpositive (DD or Dd) M. Buc 109 Rh-isoimmunisation Imumunisation of the mother usu. happens during the delivery when the placenta is being detached from the body of the uterus what enables transfer of child's erythrocytes to enter the blood stream of the mother M. Buc 110 Rh-isoimmunisation Rh-negative mother is sensitised by Rh-positive erythrocytes of her child Formation of antibodies follows Antibodies are of IgG class and are able to cross the placenta pregnancies that follow M. Buc 111 Rh-isoimmunisation Reactions of anti-RhD antibodies with foetal erythrocytes results in their lysis Haemolytic diesease of newborns subsequently develops: Easy forms: Haemolytic anaemia Heavy f.: Erythroblastosis fetalis (hydrocephalus). Bilirubin that results from haemoglobin, dissolves in fat and in this from can cross haemo-encephalic barrier and damage the developing brain M. Buc 112 M. Buc Kindt 2007 113 References Doan, T., et al. Lippicotts Illustrates Reviews: Immunology. Philadelphia: Wolters Kluwer 2008, 200 pp. Goldsby, RA, Kindt TJ, Osborne BA. Kuby Immunology. 6. New York: WH Freeman Comp 2000, 670 pp. Kindt TJ, Goldsby, RA, Osborne BA. Kuby Immunology. 6. New York: WH Freeman Comp, 2007, 574 s. Kirkwood, E, Lewis C. Understanding Medical Immunol. New York: Jon Wiley 1989, 179 pp. Tizard IR. 1995. Immunology. 4. Philadelphia, New York, London, Sydney, Tokyo: Saunders Coll Publ 1995, 544 s. Virella G (Ed). Medical Immunology. 5. New York, Basel: Marcel Dekker, 2001, 656 s. M. Buc 114