IMS- Prelims PDF

Preview

Summary

HISTORY OF IMMUNOLOGY NAME OF THE SCIENTISTS VOLTAIRE EDWARD JENNER LOUIS PASTEUR ALBERT CALMETTE CAMILLE GUERIN JONAS SALK ALBERT SABIN MAX THEILER IAN FRAZER ERNST HAECKEL ALMOTH WRIGHT, STEPHEN DOUGLAS, JOSEPH DENYS ELIE METCHNIKOFF EMIL VON BEHRING KITASATO JAMES GOWAN KARL LANDSTEINER ALIC ISAA...

Description

HISTORY OF IMMUNOLOGY NAME OF THE SCIENTISTS VOLTAIRE EDWARD JENNER LOUIS PASTEUR ALBERT CALMETTE & CAMILLE GUERIN JONAS SALK & ALBERT SABIN MAX THEILER IAN FRAZER ERNST HAECKEL ALMOTH WRIGHT, STEPHEN DOUGLAS, & JOSEPH DENYS ELIE METCHNIKOFF EMIL VON BEHRING & KITASATO JAMES GOWAN KARL LANDSTEINER ALIC ISAACS & JEAN LINDEMANN ALEXANDER FLEMMING E. DOUNAL THOMAS & JOSEPH MURRAY ROBERT KOTCH P. PORTIER & CHARLES RICHET VON PIRQUET & SCHICK GRUBER & DURHAM FERDINAND WIDAL PFEIFFER & BUCHNER JULES BORDET

YEAR 1773 1798 1880-1881 1921

reported on Chinese practice of Variolation discovered Smallpox vaccine by using Cowpox virus discovered live, attenuated vaccine against Chicken cholera, Anthrax, & Rabies developed 1st successful vaccine against Tuberculosis

Late 1930 2005 1862

developed Polio vaccine developed Yellow fever vaccine discovered Human Papilloma Virus (HPV) vaccine Phagocytosis

1903 1883-1905 1890 1924 1900 1957 1996-1998 1922 1991 1891 1902 1906 1896 1896 1894-1895 1920

GEORGE SNELL

1903

JEAN DAUSSET

1906

BARUJ BENACERRAF

1920

PAUL ERHLICH

1900

RODNEY PORTER

1920-1985

GERALD EDELMAN

1929

PETER MEDAWAR CESAR MILSTEIN & GEORGES KOHLER

1915-1987 1927 1946

NIEL JERNE ROSALYN YALOW MICHAEL HEIDELBERGER KENDALL SUSUMU TONEGAWA MOSMANN

DISCOVERY

1911 1921 1888-1991 1930-1935 1939 1986 2001

PETER DOHERTY & ROLF ZINKERNAGEL

1996

LUC MOTAIGNER

1980

ROBERT GALLO

1980

discovered Opsonins & describe its relation to Phagocytosis Cellular theory of Immunity through Phagocytosis Humoral theory of Immunity discovered that Adaptive Immunity is mediated by Lymphocytes discovered the ABO Blood group discovered Interferons identified the Toll-like receptors Discovered Penicillin & described the action of Lysozymes introduced the concepts of Transplantation demonstration of Cutaneous Hypersensitivity Immediate Hypersensitivity—Anaphylaxis describe the relationship of Immunity & Hypersensitivity discovered Agglutination reactions devised an agglutination reaction for the diagnosis of Typhoid fever Complement mediated Cytolysis received Nobel Prize for his pioneering works on Complement worked out the genetics of the Murine Major Histocompatibility Complex (MHC) & generated the congenic strains needed for its biologic analysis an early pioneer in the study of MHC or HLA discovered Immune response genes & collaborated in the first demonstration of MHC restrictions Antibody formation theory worked out the polypeptide structure of the antibody molecule, laying out the groundwork of its analysis by protein sequencing made crucial discoveries about the structure of Immunoglobulin, including the first complete sequence of Ab molecule made studies on Acquired Immunologic Tolerance developed the Hybridoma technique of Monoclonal Antibody formation developed the Hemolyic Plaque Assay & several important immunological theories including an early version of Clonal selection developed Radioimmunologic Assay (RIA) of peptide hormones developed the Quantitative Precipitin Assay conducted Quantitative Precipitin Assay studies on Antigen-Antibody molecules Discovered Antibody diversity & TCR diversity Th1 vs. Th2 model of T-helper function discovered the FOX3p, the gene directing regulatory T-cell development work on the mechanism of cellular immune response mediated by T-cells towards virally infected cells isolated a retrovirus from a non-immune deficient homosexual man with Lymphadenopathy & called it as “Virus Lymphadenopathy Associated Virus” (LAV) renamed the retrovirus as “Human Immunodeficiency Virus” (HIV)

IMMUNITY * IMMUNOLOGY - the study of a host’s reactions when foreign substances are introduced into the body * IMMUNITY - the state of being resistant to infection - all those physiological mechanisms that endow the animal with the capacity to recognize materials as foreign to itself & to neutralize, eliminate, or metabolize them with or without injury to its own tissue - complex reaction involving any different cells, molecules, & 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 body’s ability to resist foreign organisms & toxins (poisons) that damage tissues & organs TYPES OF IMMUNITY: NATURAL 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

1. NATURAL / INNATE IMMUNITY (NON-SPECIFIC / NON-ADAPTIVE) - present since birth - ability of an individual to resist infections by means of normally present body functions - has standardized response to all invading antigen (no memory cells) TWO KINDS OF NATURAL / INNATE IMMUNITY: a. EXTERNAL DEFENSE MECHANISM: structural barriers that prevents the penetration of microorganisms in the body I. PHYSICAL BARRIERS: • Intact skin • Mucous membranes of Respiratory, GI, & GU tract • Ciliated Epithelium • Lacrimal Apparatus • Sweat & Sebaceous glands II. MECHANICAL BARRIERS: • Peristaltic movement of intestine • Shedding of cells • Coughing & sneezing • Flushing action of urine III. CHEMICAL BARRIERS: • Acidic pH: lactic acids & fatty acids, HCl, Lactobacillus acidophilus in intestine & vagina • Lysozyme: attacks cell wall of microorganisms & rendered it osmotically sensitive • Lactoferrin: present in human milk

b. INTERNAL DEFENSE MECHANISM- includes both cells and soluble factors play essential parts designed to recognize molecules that are unique to infectious organisms I. PHYSIOLOGIC FACTORS: • Body temperature • Oxygen tension • Hormonal balance II. BASIC POLYPEPTIDES: • Spermin: pH dependent polyamine found in semen & inhibits growth of g(+) bacteria • Defensin: catanionic proteins present in human neutrophil that kill microbes by interacting with microbial membrane to form channels through which important metabolites escape III. INTERFERONS: group of molecules that limit the spread of viral Infections by blocking translation of viral CHONS • Alpha IFN: produced in WBC infected with virus • Beta IFN: produced in fibroblast infected with virus • Gamma IFN: produced in T-cytotoxic cells infected with virus IV. COMPLEMENT: principal soluble mediator of inflammatory response V. ACUTE-PHASE PROTEINS: • C-Reactive Protein TWO ARMS OF ADAPTIVE IMMUNITY: • Mannose Binding Protein HUMORAL CELL-MEDIATED MECHANISM Antibody mediated Cell mediated • Haptoglobin CELL TYPE B-Lymphocytes T-Lymphocytes • Fibrinogen Antibodies in biologic MODE OF Direct cell-to-cell contact • Ceruloplasmin fluid ACTION Defense against viral & fungal • Serum Amyloid-A Primary defense infections, intracellular organisms, • Alpha-1-Antitrypsin against bacterial FUNCTION tumor antigens, & graft infection, infections • Apha-1-Acid Glycoprotein parasites NATURE OF • Engogenous pyrogens Circulating INFECTING Intracellular organism Extracellular antigen VI. CELLULAR DEFENSE MECHANISM: ANTIGEN TYPE OF • Neutrophils Acute pyogenic Chronic, granulomatous infection, INFECTION infection neoplasm, fungal, parasitic disease • Basophils Contact sensitivity, DTH, Allograft Ab-mediated • Eosinophils rejection, GVH response, elimination VARIANTS hypersensitivities, of tumors, formation of chronic • Monocytes/Macrophages Autoimmunity granulomas • Mast cells • Dendritic cells 2. ACQUIRED / ADAPTIVE IMMUNITY (SPECIFIC) - not active until there is an invasion of microorganism - a reaction resulting from the invasion of a foreign substance - has greater response to secondary infection/exposure (with memory cells) TWO TYPES OF ADAPTIVE IMMUNITY: 1. ACTIVE IMMUNITY: produces his own antibody a. NATURAL ACTIVE: antigens enter the body naturally during infections & diseases b. ARTIFICIAL ACTIVE: antigens (Ag) are introduced in vaccines 2. PASSIVE IMMUNITY: receives antigen from others a. NATURAL PASSIVE: antibodies pass from mother to fetus via placenta or via colostrum on mother’s milk b. ARTIFICIAL PASSIVE: antibodies (Ab) are introduced by vaccines

PHAGOCYTOSIS & INFLAMMATION * PHAGOCYTOSIS: engulfment of cells & particulate matter by leukocyte, macrophage, & other cells TYPES OF PHAGOCYTOSIS: 1. INDIRECT PHAGOCYTOSIS - via opsonin receptors that recognize opsonins such as IgG, CRP, & C3 bound to microorganism 2. DIRECT PHAGOCYTOSIS - via Pattern Receptors (PRR) & Pathogen Associated Molecular Pattern (PAMP) that recognize lipid & carbohydrates sequences on microorganisms

STEPS IN PHAGOCYTOSIS: 1. Physical Contact between the WBC & the Antigen 2. Engulfment of the Antigen via “Endocytosis” forming “Phagosome” 3. Fusion with Lysosome, forming “Phagolysosome” 4. Digestion & Release of debris to the outside via “Exocytosis”

PATHWAYS OF KILLING PATHOGENS BY PHAGOCYTES: 1. OXYGEN DEPENDENT: *RESPIRATORY BURST: occurs when the Cytoplasmic Pseudopods enclosed the particle within a vacuole 2. OXYGEN INDEPENDENT: production of Nitric Oxide from oxidation of L-Arginine by NO synthase which is produced by IFN-gamma activated cells

* INFLAMMATION: the overall reaction of the body to injury or invasion by an infectious agent MAJOR EVENTS IN INFLAMMATION: 1. Vasodilation due to vasodilating substance produced like—Histamine, Kinin, Prostaglandin, & Leukotriene 2. Increase in Blood flow 3. Increase in Vascular permeability 4. Diapedesis & Chemotaxis occur 5. Destruction of Pathogens by Phagocytes 6. Tissue repair

LYMPHOID SYSTEM * IMMUNE SYSTEM - includes Lymphoid system as its vital part - computerized war machine - “defense department” of the body MAJOR FUNCTIONS OF THE IMMUNE SYSTEM: • Block harmful agents • Seek-out invasive pathogens • Isolate & Neutralize activity of that antigen CELLS OF THE IMMUNE SYSTEM: 1. MYELOID LINEAGE: Monocytes & Granulocytes 2. LYMPHOID LINEAGE: Lymphocytes * ACQUIRED / SPECIFIC IMMUNITY - type of resistance that is characterized by specificity for each individual pathogen & the ability to remember prior exposure, which results in an increased response upon repeated exposure * LYMPHOCYTES - the key cell involved in the Adaptive immunity - represent between 20-40% of the circulating WBCs - Size: between 7-10 µm in diameter - Nucleus: large, round, & indented - Chromatin: dense & stains deep blue - Cytoplasm: sparse, stains light blue, containing few organelles but no specific granules * LYMPHOPOIESIS - production of Lymphocytes STAGES OF LYMPHOCYTE DEVELOPMENT: 1. ANTIGEN INDEPENDENT STAGE OF LYMPHOPOIESIS - occurs on the Primary lymphoid organs - without the involvement of Antigens 2. ANTIGEN DEPENDENT STAGE OF LYMPHOPOIESIS - occurs on the Secondary lymphoid organs - with the involvement of Antigens

* LYMPHOID SYSTEM - a system in the body which consist of lymph vessels, lymph nodes, & lymph fluids. Its primary function is to transport lymph, a colorless fluid containing lymphocytes that help rid the body toxins, waste, & other unwanted materials COMPARTMENTS OF LYMPHOID SYSTEM: 1. STEM CELL DEVELOPMENT 2. PRIMARY / CENTRAL LYMPHOID SYSTEM - serves as the developmental sites a. BONE MARROW - largest primary lymphoid organ - Weight: 1,300-1,500g (adult) - it is where B-cell maturation occurs - main source of hematopoietic stem cells - center for Antigen-Independent Lymphopoiesis b. THYMUS - small, flat bilobe organ found in thorax or chest cavity right below thyroid gland & overlaying the heart - Weight: 30g (birth), 35g (puberty) then atrophies - it is where T-cell maturation occurs - produces “Thymosin” which promotes maturation of T-cell - although it diminishes in size, it is still capable of producing T-Lymphocytes until at least the 5th or 6th decade of life - T-cell progenitors appear in the fetus as early as 8 weeks in gestational period PARTS OF THYMUS: * CORTEX: where Thymocytes can be found * MEDULLA: where mature T-cell can be found * THYMIC STROMAL CELLS: include epi cells, macrophages, & dedritic cells which serves as APC & MHC 3. SECONDARY / PERIPHERAL LYMPHOID SYSTEM - serves as the activation sites I. ENCAPSULATED ORGANS a. SPLEEN - largest secondary lymphoid organ - Weight: 150 g – Length: 12 cm - located in the upper-left quadrant of the abdomen, just below the diaphragm & surrounded by thin connective tissue capsule - characterized as “large discriminating filter” as it removes old, damaged cells & foreign antigens - Lymphocytes enter this area via Specialized Capillaries on Marginal Sinus & via Trabecular Artery - an adult’s blood volume passes through spleen for about 4 times each day

TYPES OF SPLENIC TISSUE: * WHITE PULP - comprises 20% of the total weight - contains the lymphoid tissue, which is arranged around arterioles in a PERIARTERIOLAR LYMPHOID SHEATH (PALS) where T-cells can be found PARTS OF WHITE PULP: * CENTRAL ARTERIOLE: where T-cells are found * PRIMARY FOLLICLES: Naïve/Virgin/ Resting B-cells are found * SECONDARY FOLLICLES: Activated B-cells are found * MARGINAL ZONE: contains macrophages & APC * GERMINAL CENTER: indicator that cells are actively multiplying & dividing * RED PULP - makes up 80% of the total weight - involved in the culling, pitting, & platelet sequestration b. LYMPH NODES - the “junctional filter” of the lymphoid system - Size: 1mm-25mm - located along lymphatic ducts - especially numerous in joints, arms, & legs of the body - the central collecting points for lymph fluid from adjacent tissues - Filtration & generation of memory B-cell is its main function - Lymph fluid flows slowly through spaces called “ SINUSES” which are lined with macrophages, creating an ideal location for Phagocytosis to take place - Lymphocytes enter this area via Afferent Lymphatic vessels & by Specialized venules called “HIGH ENDOTHELIAL VENULES” located in Paracortical areas & exits via Efferent Lymphatic vessels - Particulate antigens are removed as the fluid travels across the node from Cortex to Medulla within 18hrs - If contact with antigen takes place, the Lymphocyte traffic shuts down due to proliferation of activated cells LAYERS OF LYMPH NODES: * CORTEX - B-cell area - has Macrophages & Specialized cells called “FOLLICULAR DENDRITIC CELL” - contains Primary follicles with small amounts of T-cell & Secondary follicles that has interior called “GERMINAL CENTER” where blast transformation of B-cell takes place * PARACORTEX - T-cell area - the region between follicles & medulla - T-Lymphocytes are in close proximity to antigen-presenting cells called “INTERDIGITATING CELLS” * MEDULLA - less densely populated but contains some T-cells, Macrophages, & Plasma cells

II. NON-ENCAPSULATED LYMPHOID ORGANS 1. MUCOSAL-ASSOCIATED LYMPHOID TISSUE (MALT) - found in intestinal, genitourinary, & respiratory tract 2. BRONCHUS-ASSOCIATED LYMPHOID TISSUE (BALT) - found in tonsils & adenoids 3. GUT-ASSOCIATED LYMPHOID TISSUE (GALT) - includes Peyer’s Patches & Appendix 4. CUTANEOUS-ASSOCIATED LYMPHOID TISSUE (CALT) - includes Intra-epidermal lymphocytes * LYMPHOCYTE TRAFFIC / RECIRCULATION: movement of lymphocytes from blood to lymphoid organs & back to blood HOW WILL T-CELLS & B-CELLS FIND ITS WAY TO THE LYMPH NODE??? - through POST CAPPILARY TRAFFIC ENDOTHELIAL VENULE / HIGH-WALLED ENDOTHELIAL VENULE (HEV) * has ADDRESINS, which composed of CD-32 & CD-102 together with other adhesion molecules * T-cells & B-cells have Homing rececptors which is called “LEUKOCYTE ADHESION MOLECULE” (LAM) or L-SELECTIN STAGES OF B-CELL DIFFERENTIATION:

1. PRO-B CELLS - rearrangement of genes that code for the heavy chains & light chains of an antibody molecule - has transcription/growth factors such as: * E2A necessary to differentiate common lymphoid precursors against pro-B cells * EARLY B-CELL FACTOR (EBF) * PAIRED BOX PROTEIN-5 (PAX) - has intracellular proteins such as: * Terminal Deoxyribonucleotide Transferase (TdT): attach the DNA fragment to another one * Recombination-Activating Genes (RAG-1) & (RAG-2): cleaves the DNA at possible recombination sites - has distinctive markers such as: * CD19: acts as coreceptor that helps regulate further B-cell development & activation * CD24: * CD45R: largest form of CD45 found on B-cells * CD43: * C-KIT: interacts with a Stem cell factor which is found on stromal cells which triggers the activation process - Interleukin-7 (IL-7) is also necessary at this early developmental stage

PARTS OF B-CELL’S SURFACE ANTIBODY: composed of 4 polypeptide chain * 2 identical HEAVY CHAIN - coded on Chromosome 14 - has 5 types: Alpha, Beta, Gamma, Epsilon, & Mu * 2 identical LIGHT CHAIN - has 2 types: Kappa (Chromosome 2) & Lambda (Chromosome 22) 2. PRE-B CELLS - begins when the heavy chain part of the Ab molecule are formed - it starts to lose CD43, TdT, & C-Kit - Mu chains are the first heavy chain to be synthesized are accompanied by unusual light chain called “SURROGATE LIGHT CHAIN” & “VERY SHORT CHAINS Ig-α/Ig-β” forms the PRE-B CELL RECEPTOR, which adheres to bone marrow stromal cell membranes & transmits a signal to prevent rearrangement of heavy chain genes - only existing B-cells expressing the Mu chains & Surrogate light chains survive & proceed to further differentiation 3. IMMATURE B-CELLS - earliest stage to predict the Ag specificity of the B-cell (by VARIABLE REGION) - B-cells capable of producing Ab to self-Ag are deleted in the bone marrow through APOPTOSIS - distinguished by the appreance of complete IgM molecules which indicates that rearrangement of the genetic sequence coding for light chains on either Ch2 or Ch22 has taken place - include surface markers for Complement Component such as: * CD3: receptor for Epstein-Barr Virus (EBV) * CD21: acts as receptor for a breakdown product of Complement Component C3 /C3d * CD40 Important for the interaction of B-cells & T-cells * MHC Class II 4. MATURE B-CELLS - mature B-cells exhibit both IgM & IgD on their cell surface * MARGINAL ZONE B-CELLS: remain in the spleen in order to respond quickly to any blood-borne pathogens * FOLLICULAR B-CELLS: found constantly recirculating to secondary lymphoid organs 5. ACTIVATED B-CELLS - exhibit CD25 & acts as a coreceptor to IL-2, responsible for the proliferation & multiplication - Antigen-dependent activation takes place in the primary follicles of Peripheral Lymphoid tissue - it occurs when Ag cross-link several surface Ab on the B-cells, causing it to transform into blast, which will give rise either to plasma cells or memory cell 6.1 PLASMA CELLS - spherical, ellipsoidal cells that contain abundant cytoplasmic Ig & little to no surface Ig - Size: 10-20 um - Nucleus: eccentric or oval with - Chromatin: heavily clumped that stains darkly - Cytoplasmic: has abundant Endoplasmic Reticulum (ER) & clear well-defined Golgi zone - considered as the “most fully differentiated lymphocyte” - its main function is to produce antibodies - not normally found in the blood but located in germinal centers in the peripheral lymphoid organs - they are non-dividing, has short life-span, & after days of producing antibodies, they die without further proliferation 6.2 MEMORY CELLS - also found in the germinal centers in the peripheral lymphoid organs - represent the progeny of antigen-stimulated B-cells that are capable of responding to Ag w/ increase speed & intensity - they are similar to the appearance to unstimulated B-cells, but they have longer life-span

STAGES OF T-CELL DIFFERENTIATION: 1. PRO-THYMOCYTE - include surface markers CD44 & CD25 - they go through gene rearrangement same as with B-cell which takes up to 3 weeks - has intracellular proteins such as: * Terminal Deoxyribonucleotide Transferase (TdT): attach the DNA fragment to another one * Recombination-Activating Genes (RAG-1) & (RAG-2): cleaves the DNA at possible recombination sites - Interleukin-7 (IL-7) i...