Introduction to Immunology and Serology

Immunology Defined as the study of the reactions of a host when foreign substances are introduced into the body. The study of molecules, cells, organs and systems responsible for the recognition and disposal of foreign material and how the body components respond and interact. Antigen These are foreign substances/material that can induce immune response It can be harmful/harmless Antibody Serum factors in the blood formed in response to foreign substance exposure Also known as immunoglobulins Serology Study of antigen-antibody reactions that can be utilized in diagnosing wide array of diseases that may range from infectious diseases, malignancies, hypersensitivity reactions, organ transplantation and autoimmunity History and Milestones in Immunology Voltaire (1773)- reported on Chinese practice of variolation. Edward Jenner (1798)- smallpox vaccination Haeckel (1862)- phagocytosis Pasteur (1880-1881)- live,attenuated chicken cholera and anthrax vaccines; (1885)-live attenuated vaccine for rabies Elie Metchnikoff (1883-1905)- cellular theory of immunity through phagocytosis Emil Von Behring, Kitasato (1890)- Humoral theory of immunity proposed Robert Koch (1891)- Demonstration of cutaneous hypersensitivity Pfeiffer (1894-1895), Buchner- complement mediated cytolysis Gruber and Durham (1896)- discover agglutination reactions Ferdinand Widal (1896)- devised an agglutination reaction for the diagnosis of typhoid fever. Paul Ehrlich (1900)- Antibody formation theory Karl Landsteiner (1900)- discovery of the ABO Blood Group P. Portier and Charles Richet (1902)- Immediate hypersensitivity anaphylaxis Almoth Wright , Stephen Douglas, Joseph Denys (1903)- discovered opsonins and describe its relation to phagocytosis George Snell (1903-)- worked out the genetics of the murine major histocompatibility complex and generated the congenic strains needed for its biologic analysis. Von Pirquet and Schick (1906)- describe the relationship of immunity and hypersensitivity Jean Dausset (1906-)- an early pioneer in the study of MHC or HLA. Niels Jerne (1911-)- developed the hemolytic plaque assay and several important immunological theories including an early version of clonal selection Peter Medawar (1915-1987)- made studies on acquired immunologic tolerance. Jules Bordet (1920)- received Nobel Prize for his pioneering works on complement

Salk, Sabin- development of polio vaccine Baruj Benacerraf (1920-)- discovered immune response genes and collaborated in the first demonstration of MHC restriction. Rodney Porter (1920-1985)- worked out the polypeptide structure of the antibody molecule, laying out the groundwork of its analysis by protein sequencing. Rosalyn Yalow (1921)- developed RIA of peptide hormones Albert Calmette and Camille Guerin (1921)- 1st successful vaccine against tuberculosis. Alexander Flemming (1922)- described the action of lysozymes James Gowan (1924-)- discovered that adaptive immunity is mediated by lymphocytes Cesar Milstein(1927-) and Georges Kohler (1946)developed the technique of monoclonal antibody formation. Gerald Edelman (1929-)- made crucial discoveries about the structure of Ig, including the first complete sequence of Ab molecule. Michael Heidelberger (1888-1991) developed the quantitative precipitin assay. In 1930-1935, collaborated with Kendall in conducting quantitative precipitin assay studies on antigen-antibody reactions. Max Theiler (late 1930)- developed a vaccine against yellow fever Susumu Tonegawa (1939-)- discovered the somatic recombination of immunological receptor genes that underlies the generation of diversity in human and murine antibodies and T cell receptors Alice Isaacs and Jean Lindemann (1957)discovered interferon Luc Montaigner (1980)- isolated a retrovirus from a non-immune deficient homosexual man with lymphadenopathy and called the virus lymphadenopathy associated virus (LAV). Robert Gallo (1980)- renamed the retrovirus as Human Immunodeficiency Virus Mosmann (1986)- Th1 versus Th2 model of Thelper function E.Dounal Thomas and Joseph Murray (1991)introduced the concepts of Transplantation 1996-1998- identification of Toll-Like Receptors Peter Doherty and Rolf Zinkernagel (1996)- work on the mechanism of cellular immune response mediated by T-cells towards virally infected cells. 2001- discovery of FOX3p, the gene directing regulatory -T-cell development Frazer (2005)- discovery of the Human HPV vaccine

Immunity All those physiological mechanisms that endow the animal with the capacity to recognize materials as foreign to itself and to neutralize, eliminate or metabolize them with or without injury to its own tissues. Complex reaction involving many different cells, molecules and genes aimed essentially in maintaining the genetic integrity of an individual, protecting it from invasion of substances that can bear the imprint of a foreign genetic code. The bodys ability to resist foreign organisms and toxins (poisons) that damage tissues & organs It is a part of a complex system of defense reactions of the body which can be classified as either innate or acquired. Types of Immunity NATURAL IMMUNITY- ability of an individual to resist infections by means of normally present body functions.

ACQUIRED IMMUNITY- a reaction resulting from the invasion of a foreign substance. HALLMARK FEATURES INNATE IMMUNITY 1.Mechanisms involved are non-specific 2.Mechanisms that pre-exist the invasion of foreign agents. 3.Components are pre-formed. 4.They are non-adaptive, has a standardized magnitude of response. 5.Lacks immunologic memory. ADAPTIVE IMMUNITY 1.Reinforcement 2.Inducibility 3.Specificity 4.Diversity 5.Memory 6.Specialization 7.Self-Limitation 8.Discrimination

Natural Immunity EXTERNAL DEFENSE MECHANISM composed of structural barriers that prevent most infectious agents from entering the body. Structural/Physical Barriers Intact Skin Mucous membranes of the respiratory and GI tract Ciliated Epithelium Lacrimal apparatus Sweat, sebaceous glands Mechanical Barriers Peristaltic movement of intestine Shedding of cells Coughing and sneezing Flushing action of urine Chemical Barriers Acid pH- lactic acids and fatty acids, HCl, Lactobacillus acidophilus in intestine and vagina Lysozyme- attacks cell wall of microorganisms and rendered it osmotically sensitive. Lactoferrin- in human milk INTERNAL DEFENSE MECHANISM Both cells and soluble factors Recognize molecules that are unique to infectious organisms Physiologic Factors Body temperature Oxygen tension Hormonal balance Basic polypeptides Spermin- pH dependent polyamine found in semen; inhibits the growth of gram-postive bacteria Defensin- present in human neutrophil, are cationic proteins that kill microbes by interacting with microbial membrane to form channels through which important metabolites escapes. Cathelicidin mucosal secretions Interferons - group of molecules that limit the spread of viral infections by blocking translation of viral proteins. Types: Alpha IFN Beta IFN Gamma IFN Complement - principal soluble mediator of inflammatory response. Acute phase proteins- serum molecules in which concentrations increase rapidly at the onset of inflammatory disease CRP Serum amyloid A Mannose Binding Protein Alpha-1-antitrypsin Haptoglobin Fibrinogen Ceruloplasmin Alpha-1-acid glycoprotein Engogenous pyrogens CELLULAR DEFENSE MECHANISM Neutrophils 50-70% of circulating WBCs Primary granules contain myeloperoxidase, elastase, proteinase 3, lysozyme, cathepsin G, defensins

2 TYPES OF ADAPTIVE IMMUNITY ACTIVE 1.Natural Active 2.Artificial Active PASSIVE 1. Natural Passive 2.Artificial Passive

2 ARMS OF ADAPTIVE IMMUNITY HUMORAL 1. Mechanism Antibody mediated 2. Cell type B-lymphocytes 3. Mode of Action Antibodies in biologic fluid 4. Function Primary defense against bacterial infections CELL MEDIATED Cell mediated T-lymphocytes Direct cell-to-cell contact or soluble products secreted by cells Defense against viral and fungal infections, intracellular organisms, tumor antigens, and graft rejection, parasites Intracellular organism Chronic, granulomatous infection, neoplasm, fungal, parasitic diseases Contact sensitivity, DTH, Allograft rejection, GVH response, elimination of tumors, formation of chronic granulomas.

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Nature of infecting antigen Circulating Extracellular Antigen 6. Type of infection Acute pyogenic infection 7. Variants Ab-mediated hypersensitivities Autoimmunity

Secondary granules contain collagenase, lysozyme, lactoferrin, plasminogen activators, ALP, NADPH Tertiary granules contain gelatinase and plasminogen activator capable of the process diapedesis

Eosinophils 1-3% of circulating WBCs increases in allergic reactions and parasitic diseases reddish-orange granules primary granules contain ACP, arylsulfatase secondary granules contain Major Basic Protein, eosinophil cationic protein, eosinophil peroxidase, eosinophil- derived neurotoxin, phospholipase, histaminase, aminopeptidase and ribonuclease. Basophils Less than 1% of circulating WBCs bluish-purple granules contain histamine, eosinophil chemotactic factor of anaphylaxis, and heparin. involved in immediate hypersensitivity reactions Mast cells can be found on connective tissues. Granules contain ACP, ALP, and protease Monocytes largest WBC, constitutes 4-10% of circulating WBCs possess grayish-blue cytoplasm and is ground-glass in appearance granules contain peroxidase, ACP, arylsulfatase other type of granule contains B-glucuronidase, lysozyme and lipase Macrophages larger version of monocytes on tissues. there is increase in the number of ER, lysosomes and mitochondria granules contain no peroxidase at all compared with monocytes. Monocyte-macrophage system functions in microbial killing, tumoricidal activity, killing of intracellular parasites, phagocytosis, secretion of cell mediators and antigen presentation. Dendritic cells function is to phagocytosed antigen and present it to T-helper cells most potent phagocytic cell in the tissues. Toll-like Receptors Protein discovered in the fruit of Drosophila antifungal immunity in the adult fly Highest concentrations are found in monocytes, macrophages, neutrophils 11 slightly different TLRs in humans PHAGOCYTOSIS engulfment of cells and particulate matter by leukocyte, macrophage and other cells. Chemotaxis Cells are attracted to the site of inflammation by chemical substances Positive chemotaxis - towards the stimulus Negative chemotaxis away from the stimulus Ex. C5a, C5b, C6, C7 Opsonization coating of Antibody and/or complement to facilitate phagocytosis ex. of opsonins - C3b, C4b, C5b, fibronectin, leukotrienes, immunoglobulins

Steps 1. Physical contact between the WBC and the foreign particle 2. Formation of phagosome 3. Fusion with lysosome 4. Digestion and release of debris to the outside

Pathways of Killing Pathogens by Phagocytes Oxygen Dependent Respiratory Burst - occurs when the cytoplasmic pseudopods enclosed the particle within a vacuole. Oxygen Independent Production of nitric oxide from oxidation of Larginine by NO synthase which is produced by IFN-gamma activated cells. Types of Phagocytosis Indirect Via opsonin receptors that recognize opsonins such as IgG, CRP and C3b bound to microorganisms. Direct Via Pattern Recognition Receptors that recognize lipid and carbohydrate sequences on microorganisms. INFLAMMATION The overall reaction of the body to injury or invasion by an infectious agent. Tissue damage cause release of vasoactive and chemotactic factors that trigger a local increase in blood flow and capillary permeability. Permeable capillaries allow the influx of fluids and cells. Phagocytes migrate to the site of the inflammation. Phagocytes and anti-bacterial exudates destroy pathogen. Cardinal Signs Rubor - redness Calor - heat Tumor - swelling Dolor - pain Functio Laesa loss of function Events in the Inflammatory Response