A short History of Immunology

Transcription

1 A short History of Immunology Note: I would like to point out that the doctor explained some theories that are not mentioned in the slides. - The first documented evidence regarding the concept of immunity came about 430 B.C by Thucydides, a Greek historian, who is known for his book (Peloponnesian war). In his book he said that the ones who had recovered from plague ),(الطاعون could nurse the sick without getting the disease a second time, this means those who developed plague were immune against this disease. - During the 15 th century: Chinese and Turks used dried crusts of smallpox to vaccinate the susceptible individuals. This practice was common and it led in many situations to the development of a fatal disease. The procedure was transferred from Turkey by Lady Montague - the wife of the British ambassador in the Turkey - into Britain where the first vaccination against smallpox was discovered by Edward Jenner. - The term "immunity" was first used before Jenner in 1775 by Van Sweiten, a Dutch physician, as "immunitas" to describe the effect induced by an early attempt at variolization. Variolization: is the exposure to the dried crusts of smallpox to induce immunity against the disease, so the state of resistance was described as immunitas. «Edward Jenner» : - Jenner, as a 2 nd year medical student, started immunization against smallpox in Jenner noticed that milkmaids who develop cowpox as a consequence of exposure to cowpox lesions were resistant to smallpox! So, he did this experimentally by injecting an 8-year-old boy (called James Phipps) with cowpox lesions obtained from the milkmaid Sarah Nelmes, and then he exposed the child to smallpox and the child was resistant to this virus as expected. (this experiment is shown in the figure in slide #31) - Since then, smallpox vaccination continues until the eradication of the disease in 1978, and that s why Edward Jenner is credited as being the (Founder of Immunology). - The History of Immunology started slightly more than 100 years in the 19 th century after Jenner - by 3 scientists: Koch, Pasteur and Behring. - However, the real immunology started after the second world war when the first kidney transplantation was made. - In the mid-late 19 th century, Robert Koch, Loius Pasteur, Emil Non Behring and Shibasaburo Kitasato were credited for their different discoveries in the field of immunity. - Emil Von Behring and Shibasaburo Kitasato found, in the serum of immune individuals, a substance bound to the bacteria to which they were immune. Called the substance ANTIBODY. «Loius Pasteur» : - Pasteur, who is the (Father of Immunology), is a stereochemist. He worked on fermentation, silk worker disease, pasteurization and germ theory of disease. - He developed attenuated vaccine for cholera, anthrax and rabies. 1

2 - He was the first to utilize the rabies vaccine, vaccinating a 9-year-old Joseph Meister who was bitten repeatedly by a rabid dog. Pasteur treated him with his attenuated rabies vaccine and Meister survived. «Robert Koch» : - A contemporary scientist of Pasteur is Robert koch, a German physician, who was famous for his postulates. - Our understanding of diseases nowadays (the relationship between organisms and diseases) originates from Koch's postulates. Koch's postulates are 4 criteria designed to establish a causal relationship between causative organisms and diseases: 1) Each disease has a causative agent. 2) That causative agent must be isolated in a pure form in each disease. 3) When that causative agent is reinjected into the individual, the same disease must be reproduced. 4) And then the causative agent must be isolated. - He discovered tubercle bacilli (they were called Koch's bacilli) and tuberculin. Tuberculin skin test: Tuberculin is the culture filtrate of TB which was used in skin testing to identify a tuberculosis infection. Tuberculin is nowadays called the PPD (Purified protein derivative) and is used to test individuals skin to demonstrate their susceptibility to TB (whether they are susceptible or resistant to TB). - For all of these achievements, Robert koch was awarded the Nobel prize. «Emil Behrig» : - Is a student of Koch, and he with Kitasato and Wernike discovered the antitoxin for Diphtheria and Tetanus, and applied as therapy. Diphtheria and Tetanus are deadly diseases, so by discovering the antitoxin, they saved millions of individuals from death. «Paul Ehrlich» : - He is the (Father of chemotherapy). He was a biochemist. - He developed a series of tissue-staining dyes that for tubercle bacillus. - He worked with Koch and developed the antitoxin for Diphtheria. - He proposed the side-chain theory for antibodies formation and the way antigen and Antibody interact "key and lock interaction". «Elie Metchnikoff» : - He is the (Father of cellular immunology) - Metchnikoff discovered phagocytosis and described it. «Sir Frank Macfarlane Burnet» : - He has two major achievements: 1) Clonal selection theory: is the most important theory in immunology 2) Discovery of acquired immunological tolerance. He with Peter Medawar demonstrated tolerance in experimental animal (in mice). If mice are exposed to certain tissues in neonatal period, tolerance 2

3 can be built up. wiki: Aquired tolerance: refers to the immune system's adaptation to external antigen characterized by a specific non-reactivity of the lymphoid tissues to a given antigen that in other circumstances would likely induce cell-mediated or humoral immunity. «Edelman and Porter» : - Edelman and Porter were awarded the Nobel prize in 1972 because they demonstrated the structure of antibodies. «Benacerraf, Jean Dausset and Snell» : - Those three scientists discovered genes that regulate immune response (Ir gene). Now is Known as MHC (the major histocompatibility complex) or HLA (Human leukocyte antigen) in humans. It has different names in animals. MHC or HLA contains the immune response genes. Our immune response is governed by genes present in MHC. «Niels Jerne» : - He is famous for his theory (Idiotype-anti-idiotype interaction). Jerne proposed that the humoral immune response must be regulated, and the regulation is achieved by the fact that each Ab is an antigen! So that, Ab will cause the production of another Ab against it, and the second Ab will cause the production of a third Ab against the second Ab, And the third Ab will cause the production of a fourth Ab against the third. In other words, antibody stimulates the production of an anti-antibody, and the anti-antibody also stimulates the production of an anti-anti-antibody. The first Ab has idiotype I, the second Ab has idiotype II, so each idiotype will cause the production of anti-idiotype. - He said that as more Abs are produced, the signal weakens until the Ab production stops, and that s how immune system regulates its production of antibodies. If there was no mechanism to regulate Ab production, the body will continue producing Abs and this will cause damage to the host. - He was awarded Nobel prize for his theory. «Milstein and Kohler» : - They discovered the monoclonal antibody production. «Susumu Tonegawa» : - Tonegawa, a Japanese scientist, worked in MIT (Massachusetts Institute of technology). - He cloned the immunoglobulin gene and he was awarded the Nobel prize in 1987 for the discovery of the genetic principle for generation of Abs diversity. - Now we know how the body produces Abs with different specificities, as a consequence of gene 3

4 rearrangement. The concept of gene rearrangement was proposed by Tonegaw. «Doherty and Zinkernagel» : - They proposed two signal theories for generation of immune response whether it is cellular or humoral mediated. 4

5 Cells, Tissues and Organs of the Immune System - As any system, the Immune system is composed of cells, tissues and organs. - Knowledge of structural and ultrastructural details of the Immune system although they're complex is necessary to understand its function. - The distinct compartments of the immune system are interconnected by blood and lymphatic system, which enable cells to move around between the different tissues and organs that comprise the Immune system. - The immune response is coordinated at system level as a consequence of complex physiologic events that influence the outcome of the immune response. - The immune system is also influenced by other systems, it's interconnected with: The Endocrine system. The Neural system. - The immune response is mediated by cells that interact to produce soluble mediators or to activate cellular effector mechanisms: such as lymphocytes and macrophages which are produced in the bone marrow by the process of Hematopoiesis. HEMATOPOIESIS: is a process that involves the PROLIFERATION, DIFFERENTIATION and MATURATION of blood cells that lead to generation of different types of cells that involve both innate and adaptive immune responses. - Hematopoiesis takes place during the fetal life in the spleen and liver, but after delivery, the bone marrow becomes the site of hematopoiesis. In Fetus Spleen and Liver. In Adults Bone marrow. - The major sites of Hematopoiesis is the red bone marrow that is present in: 1] Flat bones of pelvis 2] Vertebrae 3] skull 4] Ribs and sternum - This doesn't mean that Hematopoiesis doesn't take place in other sites, but these are the major sites of this process that take place in the bone marrow. - Hematopoiesis starts with one cell (stem cell or precursor cell) that have the potential to develop into many different cell types by following two different pathways: Myeloid and Lymphoid pathways. This stem cell is a Totipotent stem cell which is primitive in nature but has the potential to turn into any blood cell. - Differentiation of cells that lead to the production of cells of the immune system follows along two pathways: 1) Myeloid pathway = Myeloid cell line = Myeloid lineage: Leads to the production of granulocytes, erythrocytes, platelets and monocytes. 2) Lymphoid pathway = Lymphoid cell line = Lymphoid lineage: Leads to the production of lymphocytes (T-lymphocytes and B-lymphocytes) and natural killer cells. 5

6 Myeloid cell line: 1] Granulocytes: - Myeloid cell line leads to the production of granulocytes ( /μl) which are divided according to their staining characteristics into: 1. Neutrophils: - Neutrophils represent 50-70% of WBCs present in the circulation. - Neutrophils are the most important defense mechanism in acute infections (especially bacterial infections), so acute infections are characterized by recruitment and activation of Neutrophils which are responsible of most of inflammation and tissue damage. - Neutrophils are rich in granules which contain hydrolytic enzymes that digest and destroy tissues, so as a consequence of acute infections, tissue damage mediated by neutrophils results. - Neutrophils are present in abscesses. Abscesses are characterized by collection of pus which represents necrotic dead tissue. Abscesses are the result of the release of hydrolytic enzymes of neutrophils. - When the body requires more neutrophils like in sever disseminated systemic infections, immature forms of neutrophils can be seen in the periphery because of increase demand and production of neutrophils. Immature forms of neutrophils which released into the circulation are known as (band forms) while the mature neutrophils are the (Segmented forms). Segmented neutrophils are normally present in the circulation. Band forms should not be present, if they are present, its either a malignancy or increasing demand for neutrophils. 2. Eosinophils: - Eosinophils represent 1-4% of WBCs. - Eosinophils increase in allergy and parasitic infections. Role in parasitic infections: Eosinophils are very effective against parasites, they can damage and destroy parasites as a consequence of the release of their contents (Cationic proteins and enzymes). Role in allergy: The 2 nd phase of allergy (chronic allergy) is characterized by increase infiltration of eosinophils. Eosinophils have the potential to damage tissues, that s why patients with chronic asthma (chronic allergy) have usually chronic damage to the lungs. 3. Basophils: - Basophils represent less than 1% of WBCs (<1%). - Basophils are involved in allergic reactions, basophils do so by having receptors for IgE which is produced in allergic reactions. Those IgE antibodies bind to the surface of basophils, then Allergen come and bind to IgE on the surface of basophils producing a signal that leads to two processes: The first is the release of granular contents which are mainly Histamine and other very active substances of anaphylaxes. The second is the de novo synthesis of pharmacologically active substances of allergy which are: Slow-reacting substances of anaphylaxis (leukotrienes, platelet activating factor "PAF", cytokines, 6

7 etc ). These substances are responsible for the manifestations of allergy in the form of vasodilation, bronchoconstriction, mucus production and other manifestations. - The tissue counterpart of basophils are (Mast cells), so in some tissues there are mast cells instead of basophils. Both basophils and mast cells are important in allergy. Slide #9: - The figure shows free cells of segmented mature neutrophils which take up neutral dye. Slide #10: - The figure shows eosinophil that is stained with eosin (acidic dye). Eosinophil releases destructive enzymes to destroy invaders. Slide #11: - The figure shows basophil that takes up basic dye (alkaline dye). 2] Monocytes / Macrophages: (2-8% of WBCs) - Other than granulocytes, myeloid cell line also produces monocytes which give rise to macrophages. - Monocytes are transitory cells in the blood, present in the circulation for a short period of time, then they move to tissues where they become macrophages. Resident macrophages have different names: langerhans cells, dendritic cells, kupffer cellsin the liver, microglial cells in the brain, etc 3] Platelets: - Platelets are produced from (Megakaryocytes). - Their normal count is 1,500, ,000/µl blood. - Decreasing count of platelets can result in bleeding because platelets are important in coagulation. Sometimes, platelets could be dysfunctional, and in this case they fail to aggregate and fail to form clots, thus bleeding occurs. So bleeding may result fom platelet quantitative defects or platelet qualitative defects. 4] Red blood cells (RBCs) / Erythrocytes: - RBCs are present in the circulation at a count of million/μl - They can be expressed in two other forms: 1- by Hemoglobin in gm/l (the normal Hb concentration ranges from and it varies between males and females). 2- by PCV (Packed cell volume) or (contarcted cell volume) which is expressed in percentage. The percentage should be around 40% of RBCs in blood. slide #13: - The figure shows monocyte that has kidney shaped nucleus which fills most of the cytoplasm. 7

8 The Lymphatic system - Lymphocytes are present in the lymphatic tissue, and the lymphatic system is strategically distributed all over the body and is connected by lymph and blood vessels. - The two main functions of the lymphatic system: 1) Return tissue fluid to circulation. 2) Fight infection both specific and non specific resistance take place in the lymphatic system - both innate and adaptive immunity take place in the lymphatic system. There are two major lymphatic tissues: 1] Primary lymphoid organs: composed of thymus and Bone marrow. 2] secondary (peripheral) lymphoid organs and tissues: composed of large lymphoid tissue of oropharynx (tonsils and adenoids), Nasopharynx-associated lymphoid tissue, Bronchus-associated lymphoid tissue, Gastrointestinal-associated lymphoid tissue, spleen, lymphoid nodules, Mesenteric lymph nodes, Peyer's patches and Urogenital lymphoid tissue. - Lymphocytes are distributed in secondary lymphoid tissue where they proliferate in response to antigenic stimulation. - Lymphocytes recirculate between secondary organs via blood and lymphatic system, this is called (Trafficking and Homing). - Trafficking and Homing is a characteristic of T-lymphocytes more than B-lymphocytes, because T- lymphocytes are more mobile than B-lymphocytes which are more stationary (less mobile). - With the exception of some sites, lymphocytes are widely dispersed in the body. - The ONLY tissue that lacks mature T-lymphocytesis the (Bone marrow), although T-lymphocytes originate from the bone marrow, it does not have mature T-lymphocytes since they leave the bone marrow to the thymus. - Mature B-lymphocytes are found in bone marrow. Lymphocytes represent 25-35% of WBCs, and they are divided into 2 major types: 1) T-cells: - represent the majority of lymphocytes (70% of lymphocytes). - responsible for cell-mediated immunity. - There are many types of T-cells: T-helper cells, T-cytotoxic cells. T-regulatory cells and other cells. 2) B-cells: - Represent 20-25% of lymphocytes. - Responsible for Humoral immunity. 8

9 - Under the microscope, Lymphocytes can be divided into: Large granular lymphocytes and Small lymphocytes (T-cells and B-cells). - Large granular lymphocytes which represent the remaining small portion of lymphocytes are the Natural killer cells. B- and T-lymphocytes can not be distinguished morphologically, they are morphologically identical. So, there is no way to distinguish between these cells on morphologic basis. However, they can be distinguished by surface marker since each one of them carry different surface marker. Comparison between T-cells and B-cells: T-cells Origin: Bone marrow Maturation: Thymus Long-lived Highly mobile No complement receptors No surface Ig No antibody synthesis Effector: cellular & humoral They are necessary to activate B-cells B-cells Bone marrow Bone marrow, Bursa in birds Short-lived (most of them) / long-lived Fairly mobile / stationary Complement receptors (C3d receptors) Surface immunoglobulins (IgM and IgD) Antibody synthesis Humoral only - B-cells were given this name not because they mature in the bone marrow, but because they were discovered to mature in Bursa of Fabricius in birds. *Please refer to slide #21 to study the scheme of Hematopoiesis. You have to memorize the names of stem cells, early progenitor cells and late progenitor cells. Mechanisms of regulation of Hematopoiesis What governs Hematopoiesis? why certain cells develop into granulocytes and the other into lymphocytes? - This is the function of Cytokines and Stromal cells (where cell contact is involved). So, under the influence of certain cytokines like IL-3, T-lymphocytes develop ( I'm not sure! ), whereas under the influence of Granulocyte-Colony stimulating factor, granulocytes develop, and so on.. - Of course, pre-b-lymphocytes must be exposed to cytokines in the bone marrow, whereas pre-tlymphocytes must be exposed to cytokines in the Thymus. Pre-T-lymphocytes that are not in the Thymus can not develop into T-lymphocytes although cytokines are present. [ The site is an important factor ]. Mechanisms of regulation of hematopoiesis include: 1) Control of cytokine production by stromal cells (altering the microenvironment where the cells are present) 2) Movement of developing cells from one microenvironment to another, such as T-lymphocytes which move from bone marrow to the Thymus, and this movement is necessary for maturation of 9

10 T-lymphocytes. 3) Production of cytokines by non-stromal cells. 4) up- or down-regulation of cytokine receptor expression by developing cells. 5) Removal of developing (and developed) cell by apoptosis. Critical cytokines in Hematopoiesis 1] IL-3: - Produced by T-cells (Th1 and Th2). - Binds to IL-3 Receptors on progenitors. - Maintains stem cells and early progenitors. - Induces proliferation. - Does not induce differentiation. 2] Stem-cell Factor: - stem cell factor = AKA = Steel factor = Mast cell Growth factor = c-kit ligand. - produced by stromal cells. - Binds to c-kit on progenitors. - Maintains stem cells and early progenitors. - Induces proliferation. - Does not induces differentiation. 3] Factors important for late progenitors: - Erythropoietin (EPO): needed for red blood cell development. - GM-CSF (Granulocyte Monocyte Colony Stimulating Factor): is necessary to produce Promyeloblasts which develop either into (Myeloblasts Granulocytes) by G-CSF, or into (Monoblasts Monocytes Macrophages) by M-CSF. - G-CSF: is necessary to produce Ganulocytes. - M-CSF: is necessary to produce Monocytes. Slide #27: - Both the ligand (Cytokine) and the receptor are necessary for Hematopoiesis to take place, if one is lacking, No response will result. The End Done by: Asmaa AlBitar. 0