Medical Immunology

medical checkup IMMUNOLOGY & SEROLOGY Terence L. Eday, RMT, MT(ASCPi), MPH College of Medical Technology / Medical Laboratory Science University of Perpetual Help scheme DALTA diachronic Perspective 1773, Voltaire reported on an ancient Chinese custom where dried and powdered small pox scabs were inhaled 1798, Edward Anthony Jenner, Smallpox vaccination 1862, Ernst Haekel, Recognition of phagocytosis 1877, Paul Erlich, acknowledgment of mast stallular telephones historical Perspective 1879, Louis Pasteur, Attennuated chicken cholera vaccinum development 1883, Ellie Metchnikoff developed the cellular scheme of immunity through phagocytosis phagocytic speculation cellular theory of vaccination 1885, Pasteur discovered therapeutic vaccination first report of live attenuated vaccine for lunacy diachronic Perspective 1888, Pierre Roux & Alexander Yersin, Bacterial toxins (Yersinia pestis) 1888, George Nuttall, Bactericidal action of blood 1890, Emil von Behring and Ki tasata introduced passive immunisation into modern medicine humoral theory of immunity 1891, Robert Koch demonstrated the cutaneous (delayed-type) hypersensitivity 1894, Richard Pfeiffer, Bacteriolysis Historical Perspective (1 of 6 ) 1895, Jules Bordet, Complement and antibody application in bacteriolysis 1900, Paul Ehrlich, responsible for the antibody formation theory 1901, Karl Landsteiner, A, B, and O 1901-8, Carl Jensen & Leo Loeb, transplantable tumors 1902, Paul Portier & Charles Richet, Anaphylaxis Historical Perspective (1 of 6 ) 1903, Nicolas Maurice Arthus, discovered the Arthus chemical reaction of intermediate hypersensitivity 1903, Almroth Wright and Stewart Douglas observed the humoral component, opsonin 1906, Clemens von Pirquet, coined the word allergy 1907, Svante Arrhenius, coined the term immunochemistryHistorical Perspective 1910, Emil von Dungern, & Ludwik Hirszfeld, Inheritance of ABO blood groups 1910, Peyton Rous, Viral immunology theory 191 4, Cl bence Little, Genetics theory of tumor transplantation 1915-20, Leonll Strong & Cl arnce Little, Inbred mouse strains Historical Perspective 1917, Karl Landsteiner, Haptens 1921, Carl Prausnitz & Heinz Kustner, Cutaneous reactions 1924, L. Aschoff, Reticuloendothelial establishment 1926, Loyd Felton & GH Bailey, isolation of pure antibody preparation 1938, John Marrack, Antigen-antibody binding hypothesis Historical Perspective 1936, Peter Gorer, Identification of the H2 antigen in mice 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 Chase, Cellular transfer of sensitivity in guinea pigs (anaphylaxis) Historical Perspective 1944, Peter Medwar, Immunological hypothesis of allograft rejection 1948, Astrid Fagraeus, Demonstration of antibody output in plasma B cells 1948, George Snell, Congenic mouse line s 1949, Macfarlane Burnet & Frank Fenner, Immunological tolerance hypothesisHistorical Perspective 1950, Richard Gershon and K Kondo, Discovery of supressor T cells 1952, Ogden and Bruton, discovery of agammaglobulinemia (antibody immunodeficiency) 1953, Morton Simonsen and WJ Dempster, Graft-versus-host reaction 1953, James Riley & Geoffrey West, Discovery of histamine in mast cells Historical Perspective 1953, Rupert Billingham, Leslie Brent, Peter Medwar, & Milan Hasek, Immunological tolerance hypothesis 1955-1959, Niels Jerne, David Talmage, Macfarlane Burnet, clonal Selection Theory 1957, Ernest Witebsky et all. Induction of autoimmunity in animals 1957, Alik Isaacs & Jean Lindemann, Discovery of interferon (cytokine) Historical Perspective 1958-62, Jean Dausset et al. , serviceman leukocyte antigens 1959-62, Rodney Porter et al. , Discovery of antibody structure 1959, James Gowans, Lympocyte circulation 1961-62, Jaques Miller et al. , Discovery of thymus involvem ent in cellular immunity 1961-62, Noel Warner et al. , Disctinction of cellular and humoral resistant retort Historical Perspective 1963, Jacques Oudin et al. Antibody isotypes 1964-68, Anthony Davis et al. , T and B cell cooperation in immune response 1965, Thomas Tomasi et al. , Secretory immunoglobulin antibodies 1967, Kimishige Ishizaka et al. , Identification of IgE as the reaginic antibody Historical Perspective 1971, Donald Bailey, Recombinant inbred mouse strains 1972, Gerald M. Edelman & Rodney Porter, Identification of antibody molecule 1974, Rolf Zinkernagel & Peter Doherty, MHC restriction 1975, Kohler and Milstein, First monoclonal antibodies apply in elementtic analysisHistorical Perspective 1984, Robert Good, Failed treatment of severe combined immunodeficiency (SCID, David the bubble boy) by bone total grafting 1985, Tonegawa, Hood et al. , Identification of immunoglobulin genes 1985-1987, Leroy Hood et al. , Identification of genes for the T cell re ceptor 1986, monoclonal hepatitis B vaccine Historical Perspective 1986, Mosmann, Th1 versus Th2 model of T-helper-cell region 1990, Yamamoto et al. Molecular differences between the genes for blood groups O and A and between those for A and B 1990, NIH team, Gene therapy for SCID using cultured T cells 1993, NIH team, interposition of SCID using genetically altered umbilical cord cells Historical Perspective 1996-1998, Identification of toll-like receptors 2001, FOXP3, the gene directing regulatory-T-cell development 2005, Frazer, Development of human papilloma-virus vaccine The tolerant SYTEM What is Immunology? Study of the molecules, cells, organs, and establishments responsible for the recognition and governing of foreign (nonself) material ow body components respond and interact desirable and undesirable consequences of immune interactions ways in which the immune system can be advantageously manipulated to protect against or treat disease What is opposition ? Latin word immunitas, freedom from It refers to all mechanisms used by the body as protection against env urge onmental agents that are foreign to the body. Can be either natural ( native or inborn) or acquired (adaptive) Function of the insubordinate System Recognize self from nonself Defend the body against nonself Physiologic function is to prevent contagious disease and to reverse established infections (sterilizing immunity) Key Characteristics of the resistant System indwelling immunity Primary response Secondary response and immunologic memory resistant response is super specific repellent system is tolerant of self-antigens Immune responses against self-antigens can result in autoimmune diseases Immune responses against infectious agents do not always conduce to elimination of the pathogen (HIV/AIDS) Major Principles of Immunity (immune response) Elimination of many microbial agents through the nonspecific protective mechanisms of the innate immune syste m. Cues from the innate immune system inform the cells of the adaptive immune system as to whether it is sequester to make a response and what type of response to make. Major Principles of Immunity (immune response) Cells of the adaptive immune system display exquisitely specific recognition of foreign antigens and mobilize potent mechanisms for elimination of microbes bearing such antigens. The immune system displays memory of its previous responses. Tolerance of self-antigens. Cells of the Immune System Lymphocytes occupy the central give determines the specificity of immunity Dendritic cells (DCs) & Langerhan cells Monocyte/macrophages Natural killer (NK) cells Neutrophils Mast cells & Basophils Eosinophils Epithelial and stromal cells provides anatomic env agitatement (secretion of critical factors that regulate migration, offshoot and homeostasis) Lymphoid Tissues and Organs Primary Lymphoid Organs Sites where pre-B and pre-T lymphocytes mature into naive T and B cells in the absence of foreign antigen Fetal Liver, Adult bone marrow, and thymus The INNATE IMMUNE SYTEM INNATE IMMUNE SYSTEM relies on germ line-encoded receptors to detect a limited set of microbial structures that are uniquely associated with microbial infection not a function of a single defined physiologic system rather, it is a carrefour of multiple and diverse demurrer mechanisms Modules of the intrinsic Immune System Surface epithelium The phagocyte system critical for the defense against both intracellular and extracellular bacterium as tumesce as fungal pathogens aided by opsonins Acute phase response and complement variety of secreted proteins that function in the circulation and in tissue fluids secreted by the hepatocytes in response to the inflammatory cytokines IL1 and IL-6 Modules of the Innate Immune System Natural killer (NK) cells are specialized in the elimination of infected host cells and in aiding defense against viral and other intracellula r infections through production of cytokines(IFN-? regulated by type I interferons (IFN-? /? ) Mast cells, eosinophils, and basophils are specialized in defense against multicellular parasites, such as helminthes regulated by several cytokines, including IL-4, IL-5, IL-9, and IL-13 Strategies of Innate Immune Recognition 1. Recognition of microbial nonself referred to as pattern recognition, based on the recognition of molecular structures that are unique to microorganisms and not produced by the host 2.Recognition of missing self based on the recognition of molecules expressed only on normal, uninfected cells of the host Targets of Innate Immune Recognition PAMPs (pathogen-associated molecular patterns) molecular structures produced by microbial pathogens, but not by the host organism PRRs (pattern recognition receptors) receptors of the innate immune system and represents targets of the innate immune system Targets of Innate Immune Recognition Examples of PAMPs include ( 1) LPS of gram-negative bacteria (2) LTA of gram-positive bacteria (3) Peptidoglycans (4) Lipoproteins of bacteria (cell wall) (5) Lipoarabinomannan of mycobacteria (6) dsRNA produced by virus during the infection cycle (7) ? -glucans and mannans found in fungal cell wall Receptors of the Innate Immune System freehanded categories of PRRs (1) PRRs that signal the presence of infection expressed on the cell surface or intracellularly Categories of gene products a. proteins and peptides that have direct antimicrobial effecter functions (antimicrobial peptides and lysozyme) b. nflammatory cytokines and chemokines (TNF, IL-1, IL-8) c. gene products that control activation of the adaptive immune response (MHC, CD80/CD86, IL-12) Receptors of the Innate Immune System Broad categories of PRRs (2) Phagocytic (or endocytic) PRRs expressed on the surface of macrophages, neutrophils, and dendritic cells(DCs) (3) Secreted PRRs (mannan-binding lectin and peptidoglycan-recognition proteins Func tion a. activate complement b. opsonize microbials cells to expedite their phagocytosis c. ccessory proteins for PAMP recognition by trans membrane receptors (TLR) Receptors of the Innate Immune System Toll-like Receptors comprise a family of type 1 transmembrane receptors characterized by leucine rich repeats (LRRs) in the extracellular portion and an intracellular TIR (Toll/IL-1 receptor) domain grouped into two classes (1) TLRs 1, 2, 4, 5, and 6 are expressed on the plasma membrane and detect bacterial and fungal cell wall components (2) TLRs 3, 7, and 9 are expressed in endosomal compartments and recognize viral nucleic acidsToll-like receptor 4 (TLR4) expressed predominantly in the cells of the immune system, including macrophages, DC, neutrophils, mast cells, and B cells also expressed on endothelial cells, fibroblasts, surface epithelial cells, and muscle cell Signal transducing receptor for LPS, heat sensitive protein associated with the cell walls of MTB Together wit h CD14 shown to mediate responsiveness to the fusion (F) protein of RSVToll-like receptor 2 (TLR2) Involved in recognition of LTA and peptidoglycan from gram-positive bacteria, bacterial lipoproteins, mycoplasma lipoprotein, mycobacterial lipoarabinomannan, a phenol-soluble modulin from S. epidermidis, zymosan of yeast cell walls, and lipoglycosylphosphotidylinositol T. cruzi likewise shown to recognize two kinds of atypical LPS L. interrogans and Porphyromonas gingivitis Toll-like receptor 3 (TLR3) Receptor for dsRNA Can mediate responses to poly(IC) explicit on DCs, macrophages, and surface epithelial cells, including instestinal epithelium Also expressed in CD8+ DCs Toll-like receptor 7 (TLR7) Involved in viral recognition and both detect nucleic acids together with TLR9 Recognizes viral ssRNA (derived from RNA viruses) TLR9 (unmethylated DNA derived from DNA viruses) Expressed primarily on plasmacytoid dendritic cells Activated by small antiviral compunds, e. g. imiqu inoid TLR7-mediated recognition takes place interior the late lyso just abouts Toll-like receptor 9 (TLR9) Involved in the antiviral host defense especially on recognition of DNA viruses (HSV) Expressed in type-I INF-producing plasmacytoid DCs Phagocytic Receptors Scavenger receptors cell-surface glycoproteins that are defined by their aptitude to bind to modified LDL Macrophage Mannose Receptor (MR) type I transmembrane protein expressed primarily in macrophages entangled in phagocytosis of bacterial (MTB, P. eruginosa, K. pneumonia), fungal (S. cerevisae, C. albicans), and protozoan pathogens (P. carinii) Cells of the Innate Immune System Macrophages most central and ingrained functions and have multiple roles in host defense (e. i. housekeeping functions) in red pulp of the spleen, it phagocytose and disengage from circulation senescent RBCs Neutrophils Mast Cells best known effecters of allergic response protective role is by rapid production of TNF-? nd leukotri ene B4 (neutrophil recruitement) Cells of the Innate Immune System Eosinophils found primarily in the respiratory, intestinal, and genitourinary tracts contains cationic effector proteins toxic to parasitic worms poor phagocytes Dendritic Cells immature DCs reside in peripheral tissues and are highly active in macropinocytosis and receptor-mediated endocytosis expresses PRRs and TLRs have roles in the initiation of adaptive immune response Cells of the Innate Immune System Suface Epithelium lines the mucosal surfaces of the intestinal, respiratory, and genitourinary tracts provide an important physical barrier The Effector Mechanisms of the Innate Immune System The Major Categories of Antimicrobial Effector Enzymes that hydrolyze components of microbial cell walls Antimicrobial proteins and petides that decompose the integrity of microbial cell walls Lysozyme Chitinases Phospholipase A2 BPI Defensins Cathelicidins Complement Eosinophil cationic protein Microbicidal ser ine proteasesProteins that sequester iron and zinc Enzymes that generate toxic oxygen and nitrogen derivatives Seprocidins Lactoferrin NRAMP calprotein Phagocytic oxidase Nitric oxide synthase myeloperoxidase The Effector Mechanisms of the Innate Immune System Lysozyme a. k. a. muramidase degrades the peptidoglycan of some gram(+) bacteria highly concentrated in secretions such as tears and saliva Chitinases enzymes that degrade chitin secreted by activated macrophages and presumably play a role in antifungal defenseThe Effector Mechanisms of the Innate Immune System Defensins cationic peptides with a broad spectrum of antimicrobial activities against gram(+) and gram(-) bacteria, fungus kingdom, parasites, and some envelope viruses kill microorganisms by forming pores in the membranes divided into ? and ? defensins ? -defensins presynthesized and stored in granules of neutrophils and Paneth cells of the small intestine ? -defensins produced by epithelial cells an d not stored in cytoplasmic granulesThe Effector Mechanisms of the Innate Immune System Cathelicidins active against gram(+) and gram(-) bacteria and fungi produced in neutrophils and stored as inactive proproteins in the secondary granules Serprocedins comprise a family of cationic serine proteases with antimicrobial activity (neutrophil elastase, proteinase 3, cathepsin G, and azurocidin) exert its antimicrobial activity by either perturbation of microbial membranes or by proteolysisThe Effector Mechanisms of the Innate Immune System Lactoferrin, NRAMP, and Calprotectin antimicrobial activities are due to the ability to sequester iron and zinc Lactoferrin found in the secondary granules of neutrophils, in epithelial secretions (e. i. breast milk), in the intestinal epithelium of infants, and in airway fluids bacteriostatic (iron sequestration) and bacteriocidal (perturbation of microbial membranes) The Effector Mechanisms of the Innate Immune System NRAMP (natural resistan ce-associated macrophage protein) integral membrane protein that functions as an ion pump in the phagocytic vacuoles of macrophage and neutrophils Calprotectin member of the family of calciumbinding proteins microbial activity is by chelation and sequestration of zinc ion ACUTE PHASE REACTANTS Soluble factors which are normal constituents that increase or decrease rapidly as produ Not a function of a single defined physiologic system rather, it is a product of multiple and diverse defense mechanisms