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MEDICAL IMMUNOLOGY , SEROLOGY Terence L. Eday, RMT, MT(ASCPi), ADVISE College of Medical Technology / Medical Laboratory Scientific research University of Perpetual Help System DALTA Historical Point of view • 1773, Voltaire reported on an historic Chinese customized where dried up and powder small pox scabs had been inhaled • 1798, Edward cullen Anthony Jenner, Smallpox vaccination • 1862, Ernst Haekel, Recognition of phagocytosis 1877, Paul Erlich, recognition of mast cells Historical Perspective • 1879, Louis Pasteur, Attennuated chicken breast cholera vaccine development • 1883, Ellie Metchnikoff created the cellular theory of immunity through phagocytosis, phagocytic theory, mobile theory of vaccination • 1885, Pasteur discovered restorative vaccination, initially report of live “attenuated” vaccine for rabies Historic Perspective 1888, Pierre Roux , Alexander Yersin, Bacterial toxins (Yersinia pestis) • 1888, George Nuttall, Bactericidal action of blood • 1890, Emil von Behring and Kitasata introduced unaggressive immunization into modern medicine, humoral theory of defenses • 1891, Robert Koch demonstrated the cutaneous (delayed-type) hypersensitivity • 1894, Rich Pfeiffer, Bacteriolysis Historical Point of view (1 of 6 ) 1895, Jules Bordet, Enhance and antibody activity in bacteriolysis • 1900, Paul Ehrlich, responsible for the antibody formation theory • 1901, Karl Landsteiner, A, B, and Um • 1901-8, Carl Jensen , Leo Loeb, Transplantable tumors • 1902, Paul Portier , Charles Richet, Anaphylaxis Historical Perspective (1 of 6th ) • 1903, Nicolas Maurice Arthus, discovered the Arthus reaction of intermediate hypersensitivity • 1903, Almroth Wright and Stewart Douglas seen the humoral component, opsonin • 1906, Clemens von Pirquet, coined the word allergy or intolerance • 1907, Svante Arrhenius, coined the definition of immunochemistry

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Traditional Perspective • 1910, Emil von Dungern, , Ludwik Hirszfeld, Gift of money of ABO blood groupings • 1910, Peyton Rous, Viral immunology theory • 1914, Clarence Little, Genes theory of tumor hair transplant • 1915-20, Leonll Strong , Clarence Little, Inbred mouse strains Historical Point of view • 1917, Karl Landsteiner, Haptens • 1921, Carl Prausnitz , Heinz Kustner, Cutaneous reactions • 1924, L. Aschoff, Reticuloendothelial program • 1926, Loyd Felton , GH Bailey, Seclusion of real antibody planning • 38, John Marrack, Antigen-antibody binding hypothesis Historical Perspective 1936, Peter Gorer, Identification in the H2 antigen in rodents • 1940, Karl Landsteiner , Alexander Weiner, Identification of the Rh Antigens • 1941, Albert Coons, Immunofluorescence technique • 1942, Jules Freund , Katherine McDermott, Adjuvants • 1942, Karl Landsteiner , Merill Pursue, Cellular transfer of tenderness in guinea pigs (anaphylaxis) Historical Point of view • 1944, Peter Medwar, Immunological speculation of allograft rejection • 1948, Astrid Fagraeus, Demo of antibody production in plasma W cells • 1948, George Snell, Congenic mouse lines • 49, Macfarlane Burnet , Outspoken Fenner, Immunological tolerance hypothesis

Historical Point of view • 1950, Richard Gershon and E Kondo, Breakthrough of supressor T cellular material • 1952, Ogden and Bruton, finding of agammaglobulinemia (antibody immunodeficiency) • 1953, Morton Simonsen and WJ Dempster, Graft-versus-host reaction • 1953, Wayne Riley , Geoffrey Western world, Discovery of histamine in mast skin cells Historical Point of view • 1953, Rupert Billingham, Leslie Brent, Peter Medwar, , Milan Hasek, Immunological tolerance speculation • 1955-1959, Niels Jerne, David Talmage, Macfarlane Burnet, Clonal Variety Theory • 1957, Ernest Witebsky ou all.

Debut ? initiation ? inauguration ? introduction of autoimmunity in pets or animals • 1957, Alik Isaacs , Jean Lindemann, Discovery of interferon (cytokine) Historic Perspective • 1958-62, Blue jean Dausset ainsi que al., Human being leukocyte antigens • 1959-62, Rodney Porter et ‘s., Discovery of antibody composition • 1959, James Gowans, Lympocyte blood circulation • 1961-62, Jaques Burns et ing., Discovery of thymus participation in cellular immunity • 1961-62, Noel Warner ou al., Disctinction of cellular and humoral immune response Historical Perspective • 1963, Jacques Oudin et al. Antibody isotypes • 1964-68, Anthony Davis et ‘s., T and B cellular cooperation in immune response • 1965, Thomas Tomasi et ‘s., Secretory immunoglobulin antibodies • 1967, Kimishige Ishizaka et al., Recognition of IgE as the reaginic antibody Historical Perspective • 1971, Donald Bailey, Recombinant inbred mouse pressures • 1972, Gerald M. Edelman , Rodney Assurer, Identification of antibody molecule • mid 1970s, Rolf Zinkernagel , Peter Doherty, MHC restriction • 1975, Kohler and Milstein, First monoclonal antibodies found in genetic evaluation

Historical Perspective • 1984, Robert Good, Failed remedying of severe merged immunodeficiency (SCID, David the bubble boy) by cuboid marrow grafting • 85, Tonegawa, Bonnet et ing., Identification of immunoglobulin family genes • 1985-1987, Leroy Bonnet et al., Identification of genes to get the T cell receptor • 1986, Monoclonal hepatitis B shot Historical Point of view • 1986, Mosmann, Th1 versus Th2 model of T-helper-cell function • 1990, Yamamoto et ing. Molecular dissimilarities between the genes for bloodstream groups U and A and among those for A and B • 1990, NIH team, Gene therapy for SCID using cultured T cells • 93, NIH group, Treatment of SCID using genetically altered umbilical cord cellular material Historical Perspective • 1996-1998, Identification of toll-like pain • 2001, FOXP3, the gene directing regulatory-T-cell advancement • 2005, Frazer, Development of human papilloma-virus vaccine The IMMUNE SYTEM What is Immunology? • Study of the molecules, cells, organs, and devices responsible for nice and fingertips of foreign ( nonself ) material • , ow body components respond and interact • …desirable and undesirable consequences of immune connections • …ways in which the disease fighting capability can be better manipulated to protect against or take care of disease What is Immunity? • Latin expression “immunitas”, freedom from • It identifies all components used by the body as protection against environmental providers that are foreign to the human body. • May be either organic (innate or perhaps inborn) or acquired (adaptive) Function in the Immune System • Recognize “self” from ” non-self ” • Protect the body against nonself Physiologic function is always to prevent infection and to get rid of established attacks (sterilizing immunity) Key Features of the Disease fighting capability • Inborn immunity • Primary response • Second response and immunologic storage • Immune response is highly specific • Immune system is tolerant of self-antigens • Immune responses against self-antigens can result in autoimmune diseases • Immune reactions against infectious agents usually do not always lead to elimination with the pathogen (HIV/AIDS) Major Concepts of Defenses (immune response): Elimination of countless microbial real estate agents through the nonspecific protective mechanisms of the innate immune system. • Cues in the innate disease fighting capability inform the cells of the adaptive defense mechanisms as to whether it can be appropriate to generate a response and what type of respond to make. Main Principles of Immunity (immune response): • Cells with the adaptive immune system display remarkably specific reputation of foreign antigens and mobilize potent mechanisms intended for elimination of microbes bearing such antigens. The immune system exhibits memory of its prior responses. • Tolerance of self-antigens. Cellular material of the Immune System • Lymphocytes – occupy the central stage, determines the specificity of immunity • Dendritic cells (DCs) , Langerhan cells • Monocyte/macrophages • Natural great (NK) cellular material • Neutrophils • Mast cells , Basophils • Eosinophils • Epithelial and stromal cells – delivers anatomic environment (secretion of critical factors that regulate migration, development and homeostasis) Lymphoid Damaged tissues and Bodily organs Primary Lymphoid Organs Sites where pre-B and pre-T lymphocytes adult into naive T and B cellular material in the lack of foreign antigen, • Embrionario Liver, Adult bone marrow, and thymus The NATURAL IMMUNE SYTEM INNATE IMMUNE SYSTEM • relies upon germ line-encoded receptors to detect a small set of microbial structures which can be uniquely linked to microbial illness • not just a function of your single defined physiologic system, rather, it is a product of multiple and diverse immunity process Modules from the Innate Immunity process • Surface epithelium The phagocyte program , crucial for the protection against both intracellular and extracellular bacteria as well as fungal pathogens, aided by opsonins • Serious phase response and go with , variety of secreted aminoacids that function in the blood circulation and in tissues fluids, released by the hepatocytes in response for the inflammatory cytokines IL1 and IL-6 Quests of the Natural Immune System • Natural great (NK) cells are specialized in the eradication of afflicted host skin cells and in assisting defense against viral and also other intracellular infections through creation of cytokines(IFN-?, regulated by type We interferons (IFN-? /? ) • Mast cells, eosinophils, and basophils are specializing in defense against multicellular unwanted organisms, such as helminthes, regulated simply by several cytokines, including IL-4, IL-5, IL-9, and IL-13 Strategies of Inborn Immune Recognition 1 . Identification of microbial nonself – referred to as pattern recognition, depending on the recognition of molecular buildings that are one of a kind to microorganisms and not produced by the web host 2 .

Identification of absent self – based on nice of substances expressed only on typical, uninfected cellular material of the sponsor Targets of Innate Immune Recognition • PAMPs (pathogen-associated molecular patterns) – molecular structures made by microbial pathogens, but not by the host affected person • PRRs (pattern identification receptors) – receptors of the innate immunity process and represents targets of the innate immune system Goals of Inborn Immune Identification Examples of PAMPs include: (1) LPS of gram-negative bacterias (2) LTA of gram-positive bacteria (3) Peptidoglycans (4) Lipoproteins of bacteria (cell wall) (5) Lipoarabinomannan of mycobacteria (6) dsRNA created by virus through the infection routine (7)? -glucans and mannans found in yeast cell wall structure Receptors with the Innate Immunity process • Extensive categories of PRRs: (1) PRRs that sign the presence of disease, expressed on the cell surface or intracellularly Categories of gene products: a. proteins and peptides which may have direct anti-bacterial effector functions (antimicrobial peptides and lysozyme) b. nflammatory cytokines and chemokines (TNF, IL-1, IL-8) c. gene products that control account activation of the adaptable immune response (MHC, CD80/CD86, IL-12) Pain of the Innate Immune System • Broad types of PRRs: (2) Phagocytic (or endocytic) PRRs, expressed around the surface of macrophages, neutrophils, and dendritic cells(DCs) (3) Secreted PRRs (mannan-binding lectin and peptidoglycan-recognition proteins Function: a. trigger complement b. opsonize microbials cells to facilitate their phagocytosis c. ccessory proteins for PAMP recognition simply by transmembrane pain (TLR) Pain of the Inborn Immune System • Toll-like Receptors – consist of a family of type 1 transmembrane receptors characterized by leucine rich repeats (LRRs) inside the extracellular section and a great intracellular TIR (Toll/IL-1 receptor) domain, grouped into two classes: (1) TLRs 1, 2, four, 5, and 6 will be expressed for the plasma membrane and identify bacterial and fungal cell wall pieces, (2) TLRs 3, 7, and being unfaithful are portrayed in endosomal compartments and recognize viral nucleic acids

Toll-like radio 4 (TLR4) • stated predominantly inside the cells from the immune system, including macrophages, POWER, neutrophils, mast cells, and B skin cells • as well expressed upon endothelial cells, fibroblasts, area epithelial skin cells, and muscle cell • Signal transducing receptor for LPS, heat sensitive healthy proteins associated with the cellular walls of MTB • Together with CD14 shown to mediate responsiveness for the fusion (F) protein of RSV

Toll-like receptor 2 (TLR2) • Involved in acknowledgement of LTA and peptidoglycan from gram-positive bacteria, microbial lipoproteins, mycoplasma lipoprotein, mycobacterial lipoarabinomannan, a phenol-soluble modulin from H. epidermidis, zymosan of yeast cell surfaces, and lipoglycosylphosphotidylinositol T. cruzi • Likewise shown to acknowledge two varieties of atypical LPS: L. interrogans and Porphyromonas gingivitis Toll-like receptor a few (TLR3) Radio for dsRNA • May mediate replies to poly(IC) • Indicated on DCs, macrophages, and surface epithelial cells, which include instestinal epithelium • Likewise expressed in CD8+ DCs Toll-like receptor 7 (TLR7) • Associated with viral identification and equally detect nucleic acids together with TLR9 • Recognizes virus-like ssRNA (derived from RNA viruses), TLR9 (unmethylated GENETICS derived from DNA viruses) • Expressed mostly on plasmacytoid dendritic cellular material • Activated by small antiviral compunds, e. g. imiquinoid •

TLR7-mediated identification takes place within the late lysosomes Toll-like radio 9 (TLR9) • Active in the antiviral web host defense, especially on reputation of DNA viruses (HSV) • Expressed in type-I INF-producing plasmacytoid DCs Phagocytic Receptors • Scavenger pain – cell-surface glycoproteins which can be defined by way of a ability to situation to modified LDL • Macrophage Mannose Receptor (MR) – type I transmembrane protein expressed primarily in macrophages, involved with phagocytosis of bacterial (MTB, P. eruginosa, K. pneumonia), fungal (S. cerevisae, C. albicans), and protozoan pathogens (P. carinii) Cells with the Innate Defense mechanisms • Macrophages – many central and essential functions and have multiple roles in host defense (e. my spouse and i. “housekeeping functions”), in red pulp with the spleen, this phagocytose and remove from circulation senescent RBCs • Neutrophils • Mast Skin cells – best known effectors of allergic response, protective function is by quick production of TNF-? nd leukotriene B4 (neutrophil recruitement) Cells with the Innate Disease fighting capability • Eosinophils – located primarily in the respiratory, intestinal tract, and genitourinary tracts, contains cationic effector proteins toxic to parasitic worms, poor phagocytes • Dendritic Cellular material – premature DCs stay in peripheral tissue and are very active in macropinocytosis and receptor-mediated endocytosis, expresses PRRs and TLRs, have jobs in the avertissement of adaptable immune response Cells from the Innate Defense mechanisms Suface Epithelium – lines the mucosal surfaces from the intestinal, respiratory system, and genitourinary tracts provide an important physical barrier The Effector Systems of the Innate Immune System Difficulties Categories of Antimicrobial Effector Nutrients that hydrolyze components of microbes cell walls Antimicrobial protein and petides that disturb the integrity of microbial cell wall surfaces • Lysozyme • Chitinases • Phospholipase A2 • • • • • BPI Defensins Cathelicidins Complement Eosinophil cationic protein Microbicidal serine proteases

Proteins that sequester iron and zinc Enzymes that generate harmful oxygen and nitrogen derivatives • Seprocidins • Lactoferrin • NRAMP • calprotein • Phagocytic oxidase • Nitric oxide synthase • myeloperoxidase The Effector Mechanisms of the Inborn Immune System • Lysozyme – a. k. a. muramidase, degrades the peptidoglycan of some gram(+) bacteria, very concentrated in secretions such as tears and saliva • Chitinases – enzymes that degrade chitin, secreted by simply activated macrophages and presumably play a role in antifungal protection

The Effector Mechanisms in the Innate Defense mechanisms • Defensins – cationic peptides having a broad variety of anti-bacterial activities against gram(+) and gram(-) bacteria, fungi, parasitic organisms, and some envelope viruses, destroy microorganisms by forming tiny holes in the walls, divided into? , and? defensins •? -defensins – presynthesized and kept in granules of neutrophils and Paneth cells of the little intestine •? -defensins – produced by epithelial cells but not stored in cytoplasmic granules

The Effector Components of the Innate Immune System • Cathelicidins – active against gram(+) and gram(-) fungi and bacteria, produced in neutrophils and placed as sedentary proproteins inside the secondary lentigo • Serprocedins – comprise a family of cationic serine proteases with antimicrobial activity (neutrophil elastase, proteinase 3, cathepsin G, and azurocidin), exert its antimicrobial activity by both perturbation of microbial walls or by simply proteolysis

The Effector Mechanisms of the Innate Immune System • Lactoferrin, NRAMP, and Calprotectin – antimicrobial activities are due to the ability to sequester straightener and zinc • Lactoferrin – seen in the supplementary granules of neutrophils, in epithelial secretions (e. i. breast milk), in the digestive tract epithelium of infants, and airway liquids, bacteriostatic (iron sequestration) and bacteriocidal (perturbation of microbes membranes) The Effector Systems of the Inborn Immune System NRAMP (natural resistance-associated macrophage protein) – important membrane proteins that capabilities as a great ion pump in the phagocytic vacuoles of macrophage and neutrophils • Calprotectin – member of the family of calciumbinding aminoacids, microbial activity is by chelation and sequestration of zinc ion SERIOUS PHASE REACTANTS • Sencillo factors which can be normal matters that boost or lower rapidly since produ • Not a function of a sole defined physiologic system, somewhat, it is a merchandise of multiple and different defense mechanisms

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