Immunology Lecture Notes PDF

Lec.1 Mayyada F.Darweesh immunology Immunology is the Science that deals with Immunity (protection mechanism ) against foreign macromolecules or invaders organisms which include viruses, bacteria, pro...

Lec.1 Mayyada F.Darweesh immunology Immunology is the Science that deals with Immunity (protection mechanism ) against foreign macromolecules or invaders organisms which include viruses, bacteria, protozoa or even larger parasites. A wide variety of organisms and molecules pose a strong threat to the human body. Immune system- the defensive mechanisms that identify and neutralize these threats-is able to distinguish "non self" organisms and molecules from "self, part of the body". Threats may enter the body from the outside (infectious organisms or toxic agents) or may arise from harmful changes within the body (the malignant transformation of normal cell into a cancer cell ). The immune system consists of three layers of defense : The fiest line of defense is provided by a set of mechanical (skin ) , chemical (acidic environment of stomach) , and biologic (commensal microbes) barriers that protect the body. If these barriers are breached, the second and third line of protective systems are activated : innate immune system and then the adaptive immune system. The innate and adaptive immune systems use cell-surface and soluble receptors to sense potential threats that provide a major distinction between the two systems Immune System Components of immune system 1- Cells of the Immune System Blood is composed of 52–62% liquid plasma and 38–48% cells. The plasma is mostly water (91.5%) and acts as a solvent for transporting other materials (7% protein (consisting of albumins, globulins , fibrinogen ) All blood cells are manufactured by stem cells, which live mainly in the bone marrow. The stem cells produce hemocytoblasts that differentiate into the precursors for all the different types of blood cells. 1  Lec.1 Mayyada F.Darweesh Hemocytoblasts mature into three types of blood cells: erythrocytes (red blood cells or RBCs), leukocytes (white blood cells or WBCs), and thrombocytes (platelets). The leukocytes are further subdivided into Granulocytes (containing large granules in the cytoplasm) and Agranulocytes (without granules). The granulocytes consist of neutrophils (55–70%), eosinophils (1–3%), and basophils (0.5–1.0%). The agranulocytes are lymphocytes (consisting of B cells , NK-cell and T cells) and monocytes. Lymphocytes circulate in the blood and lymph systems, and make their home in the lymphoid organs. Granulocytes: It is composed of 3 distinct cell types, distinguished by the structure both nuclear & cytoplasmic components: 1-Neutrophils: these are the most numerous and widespread of the granulocytes. They are generally the first WBC to localize at the site of a foreign invasion, in the case of microbial infection will actively kill phagocytes a portion of the invading microbes. It represents 40-80 % in normal blood and makes these function: `Phagocyte activity *Margination phenomenon which occurs in 2 phases: The initial binding is mediated by selectins on the neutrophil and the integrins on endothelial surface &later facilitate emigration & migration of neutrophil through the adjacent tissue by ability to bind to fibronectine & other component of the extra cellular matrix. The emigrated neutrophil passes between endothelial cells, with their active collaboration, to migrate out of the vessel into the adjacent tissue. The neutrophil then travel by amoeboid up the concentration gradient of chemo-tactic factors until they arrive to the injury or infection. Adhesion molecules: Activated leukocytes migrate from the blood vessels by a four -step process known as extravasation. 2  Lec.1 Mayyada F.Darweesh 1 - Rolling adhesion P- and E-selectin expressed by endothelium in response to lipopolysaccharide (LPS) interacts with sialyl Lewis x on leukocytes causing them to roll along the endothelial surface. 2. Tight binding. Interaction between leukocyte integrins (e. g. , LFA- 1 , Mac1 ) with endothelial ICAM-1 causes leukocytes to tightly adhere to the endothelium. 3. Diapedesis. A process in which endothelial-bound leukocytes enter tissues underlying the endothelium. 4. Migration. Leukocytes migrate to the site of microbial invasion attracted by chemokines. Basophiles: The granules in basophile cytoplasm contain pharmacologically active substances such as histamine ,serotonin& heparin which release into the blood in response to much the same stimuli that cause degranulation of mast cells. It represent 0-1 % in normal blood & make these function: participate in hypersensitivity as mast cell involved in parasite immunity Eosinophils: These are present in extremely low concentration in the blood. Eosinophils are found in higher concentration at sites of inflammatory reaction, including hypersensitivity, usually late in the response, they appear to be attracted by immune complexes and by substances released by mast cells and basophiles. Its functions:1-Associated with allergic reaction 2-Play a role in defense against parasitic infection. I. Monocytes : The blood monocytes migrate into peripheral tissue where they enlarge & diffrentiate into macrophages or histiocytes. (In liver Kupffer, in kidney mesangid, in lung Alveolar, in spleen Sinusadal, in brain Microglial, in bone Osteoblast) The function of monocytes: * phagocytic * Lysis of tumor cells , * produce IL 1 The function of Macrophage: * Phagocytic , * Secretors complement component , * present Ag to lymphocyte * Lysis tumor cell , * Activate lymphocyte * Secretory IL 1 II. Lymphocytes: Lymphoid Cells: Lymphocytes differentiate into three separate lines: thymic-dependent cells ( T lymphocytes) that operate in cellular immunity, B lymphocytes that differentiate into plasma cells to secrete antibodies, and natural killer (NK) cells. *T- Lymphocytes divided into :- 1-T Helper Cells: These cells are the primary regulators of T cell- and B cell-mediated responses. there are two functional subsets of T helper (Th) cells. Th-1 cells aid in the regulation of cellular immunity, and Th -2 which aid B cells to produce certain classes of antibodies (e.g., IgA and IgE). The functions of these subsets of Th cells depend upon the specific types of cytokines ( interleukin- interferon). 3  Lec.1 Mayyada F.Darweesh 2-Tdh Cells (delayed hypersensitivity) plays an important role in defense against many intracellular infections such as Mycobacterium tuberculosis. 3-T Cytotoxic Cells (Tc): These cells are cytotoxic against tumor cells , virus infected cell , stress cell 4-T Suppressor Cells (Ts or Tr ): These cells suppress the T and B cell responses after antigen clearing **Natural Killer Cells: NK cells are large granular lymphocytes that nonspecifically kill certain types of tumor cells and virus- infected cells. Killing by NK cells is enhanced by cytoplasmic granules (toxin ) called perforin. ***B Lymphocytes: These cells differentiate into plasma cells to secrete antibodies The activation of B cells into antibody producing/secreting cells (plasma cells) is antigen-dependent. Once specific antigen binds to surface Ig molecule, the B cells differentiate into plasma cells that produce and secrete antibodies of the same antigen-binding specificity. Mast Cells: They play a very important role in allergic reaction in most species. They are recognized by numerous large, densely, staining granules in the cytoplasm. In most species these granules contain complexes of histamine, heparin, & zinc, plus a number of hydrolytic enzymes. 4  Lec-2- Mayyada F.Darweesh immunology 2- Lymphoid System( Organs of the Immune System) A) Primary (Central) lymphoid organs : It consists of the Thymus gland which plays a central role in the cellular immune system and bone marrow it is the site where blood cells are formed as well as lymphocytes matured. Figure ( 3 ) : Lymphatics, lymphoid organs, and tissues. 1- Thymus: The thymus is bilobbed organ. Each lobe can be divided by septa of connective tissue into a series of lobular. These septa provide the major supporting framework for the thymic tissue. The thymus can be distinguished; an outer region , more cellular rapidly dividing lymphocytes called the cortex and an inner, less cellular, medulla. Immature lymphoid cells ( prothymocytes) enter the cortex proliferate ( acquire TCR, as well as CD4 and CD8 surface molecules ), mature and pass on to the medulla. From the medulla mature T- lymphocytes enter the circulation.  2- Bone marrow: It is found in cavities of almost all bones of the body. The major function of the bone marrow is in the generation of all the cellular elements of the blood, erythrocytes, granulocytes, reticulocytes, monocytes, lymphocytes and megakaryocytes as well as site for B-lymphocytes proliferate and mature. B) Secondary (peripheral) lymphoid organs : The secondary lymphoid tissues function as filtration devices removing foreign matter, dead cells, and protein aggregates from the circulation. these organs are represented by spleen and peripheral lymph nodes. Spleen The spleen is a haemolymphoid organ ; it is a site where blood cells (RBC) are formed and metabolized. the spleen has a dual function. It is the major site for removal and destruction of dead RBC and it is an important organ of the immune system White Pulp: this tissue is contains small and large lymphocytes, monocytes, macrophages, reticulocytes. Local concentration of lymphocytes called follicles which often contain “germinal center” of intense mitotic activity and maturation of certain small lymphocytes into Ab producing plasma cells, and is responsible for the immunological function of the spleen. Red Pulp: The major function of the red pulp is in the removal and degradation of RBC, ( responsible for the filtration function of the spleen Lymph nodes The Lymph nodes are small bean shaped structure, distributed throughout the entire body and linked together by an equally extensive circulatory system of lymphatic vessels. Each node is surrounded by a dense C.T capsule and composed of lymphocytes. The principle functions of these nodes are the entrapment of foreign material in the lymph circulation and as a site for the maturation of lymphocytes. 3- Reticuloendothelial System This system is represented by mononuclear leucocytes fixed in lungs, liver, spleen & brain. These cells are embedded in reticular C.T & vascular bands also called Mucosa-associated lymphoid tissue (MALT). Functionally, this system may be responsible for local immunity, most notably the gastrointestinal tract, respiratory tract and urogenital tract. Gut associated lymphoid tissue (GALT):This comprises: tonsils, adenoids Peyer's patches lymphoid aggregates in the appendix and large intestine lymphoid tissue accumulating in the stomach small lymphoid aggregates in the oesophagus diffusely distributed lymphoid cells and plasma cells in the lamina propria of the gut l-3 immunology d.mayada f. darweesh Barriers (Mechanical ,chemical and biological)  Skin :- anatomic barrier & contain antimicrobial secretion and it is outer Keratein layer that shields the living cell & beneath it from a hostile environmental.  Eyes :- washing of tears & presence of lysozyme in tears.  Respiratory tract :-  Mucous: it is a protective barrier, blocks adherence of bacteria to epithelial cells.  Ciliated epithelium: prevent foreign molecules from pass and exit it by Coughing & sneezing  Alveolar macrophage: phagocytosis  Digestive tract :-  Lysozyme in saliva *The stomach has mucosa secrete hydrochloric acid (pH < 3.0, very acidic) and protein-digesting enzymes that kill many pathogens. * Normal flora are the microbes, mostly bacteria, that live in / on the body with, no harmful effects. on the skin (Staph aureus, Staph. epidermidis, streptococci, Candida ). Normal flora produce bacteriocins, defensins, and lactoferrin all of which destroy other bacteria that compete their niche in the body. The bacteria can become pathogenic when they invade spaces. As examples: (a) staphylococcus living on the skin can gain entry to the body through small cuts/nicks were causes infection. Genitourinary tract :-  Washing of urine  Acidity of urine  Lysozyme in urine  Acidity of the tract l-3 immunology d.mayada f. darweesh Types of immunity: First\\ Natural (Innate, inherited) immunity : a) Characteristic : 1. Non -specific toward type of pathogen 2. Not affected by prior 3. Species specific :- e.g. human get mumps but dogs don’t. Mammals get anthrax but birds do not. 4. Race differences :- e.g. Black are more resistant to diphtheria than whites. 5. Sex differences 6. Nutritional influence :- Resistance and susceptibility are affected by nutritional status. Low protein diet Low Complement activity Vitamin B1 B2 deficiency Low lymphocytes activity 7. Hormone relation :- hormone imbalance (insulin, diabetes) affect susceptibility to infectious agent. 8. Age effect :- very young and very aged are more susceptible than youth b) Mechanism of natural resistance : a) Humoral innate immunity * Complement * B- lysine * Interferon (one type of cytokines released after 5 minute from virus infection α- interferon released by leucocytes. β- Interferon released by fibroblast. γ- Interferon released by T- cells. *Acute phase protein: proteins present in blood increase during infection. *Lysozyme b) Cellular innate immunity *Phagocytic cells (phagocytes) that include : - Macrophages , Monocytes and Polymorph nuclear cells (Neutrophil) : *Natural killer cells : are large lymphocyte cell that contain cytoplasm granules have ability to kill certain tumor cell , stress cell and virus infected cells.  l-3 immunology d.mayada f. darweesh Fig-2- NK cell recognition by KI R and KAR. NK cells have killer activation receptors (KARs) that recognize stress-associated molecules (e. g. , MIC-A and MIC -B in humans) on the surface of abnormal host cells. Binding of KAR to MICA and MICB provides a kill signal. NK cells also use killer inhibition receptors (KIRs) to assess MHCI molecules on the target cell surface. If insufficient KIR-MHCI binding occurs, the N K cell will proceed to kill the target host cell. But sufficient binding by KIRs will override the KAR kill signal , sparing the life of the host cell. l-3 immunology d.mayada f. darweesh Second // Acquired Immunity The immunity which develops during life time. Characteristics: 1. Antigen (pathogen) specific 2. mediated by : A. Humoral substances. Antibodies , classical pathway of complement ,interferon B. Cellular in origin : associated with activities of cells like macrophages & T- lymphocyte. * Humoral or antibody mediated immunity is very efficient & divided into: 1. Actively acquired immunity mean that a person synthesize his own antibodies & which may be: Natural A.acquired: Result from infection Artificially A. acquired: result from immunization with: - Artificial peptide - Killed M.O - Attenuated (viable but weak organism) produces mild infection - Toxoid - Gene cloning 2. : mean that individual received their Ab from some other individual either human or lower animal & which may be: * Natural 1. Transplacental 2. via colostrums (first milk): This result in the coating of infant digestive tract with antibodies secreted in first milk. * Artificial Acquisition of Ab through: 1. Injection of hyper immune serum 2. Injection of globulin * Cellular mediated immunity  L-4- Antigen, Immunogen ‫اﻟﻤﺴﺘﻀﺪ واﻟﻤﻤﻨﻊ‬ I. DEFINITIONS ‫اﻟﻤﺮﻛﺒﺎت اﻟﺘﻲ ﯾﻤﯿﺰھﺎ اﻟﺠﮭﺎز اﻟﻤﻨﺎﻋﻲ ﺗﻜﻮن اﻣﺎ اﻧﺘﺠﯿﻨﺎت او ﻣﻤﻨﻌﺎت ا‬ The compound that recognized by immune system is referred to either as antigen or immunogen. Antigens (Ag) : is define as an organism , a molecule or part of molecule that recognized by immune system. Ag may be simple or complex ‫اﻟﻤﺴﺘﻀﺪ ھﻮ ﻛﺎﺋﻦ ﺣﻲ‬ ‫ﻛﺎﻟﺒﻜﺘﺮﯾﺎ او ﺟﺰء ﻣﻨﮫ ﻣﺜﻼ ﻛﺒﺴﻮﻟﮫ اﻟﺒﻜﺘﺮﯾﺎ او ﻗﺴﻢ ﻣﻦ اﻟﺠﺰﯾﺌﮫ ﻣﺜﻞ ﺳﻜﺮﯾﺎت اﻟﻜﺒﺴﻮﻟﮫ اﻟﺘﻲ ﯾﻤﯿﺰھﺎ اﻟﺠﮭﺎز‬ ‫اﻟﻤﻨﺎﻋﻲ ﻟﻜﻦ ﻻﯾﻌﻤﻞ ﻟﮭﺎ اﺳﺘﺠﺎﺑﮫ ﻣﻨﺎﻋﯿﮫ‬ Immunogen: A substance that induces a specific immune response after recognized by immune system such as organism or molecules. ‫اﻟﻤﻤﻨﻊ ھﻮ ﻣﺎده ﺗﺤﺚ ﻋﻠﻰ‬ ‫ﺣﺼﻮل اﺳﺘﺠﺎﺑﮫ ﻣﻨﺎﻋﯿﮫ ﺑﻌﺪ ان ﯾﻤﯿﺰھﺎ اﻟﺠﮭﺎز اﻟﻤﻨﺎﻋﻲ ﻗﺪ ﺗﻜﻮن ھﺬه اﻟﻤﺎده ﻛﺎﺋﻦ ﺣﻲ او ﺟﺰء ﻣﻨﮫ‬ Thus all immunogens are antigens but not all antigens need to be immunogens. Haptens : are small molecules which fail to stimulate immune-response in their native form due to their low M.WT and their chemical simplicity,these compounds are not immunogenic unless they are conjugated to high M.WT , complex carriers. Haptens have the property of antigenicity but not immunogenicity. Epitope or Antigenic Determinant : The smallest portion of an antigen that combines with the receptors of immune cells. Figure pitopes and antigens: Complex antigens may ncontain large numbers of different epitopes.  Requirement for immunogenecity ‫ﻣﺘﻄﻠﺒﺎت اﻟﺘﻤﻨﯿﻊ‬ Substances must possess the following characteristics to be immunogenic: ‫اﻟﻤﻮاد ﯾﺠﺐ‬ ‫ان ﺗﻤﺘﻠﻚ ﺑﻌﺾ اﻟﻤﻤﯿﺰات ﻟﺘﺼﺒﺢ ﻗﺎدره ﻋﻠﻰ اﻟﺘﻤﻨﯿﻊ‬ a- Foreignness: The ability of immune system to discriminates between self and non- self such that only foreign molecules are immunogenic.The guinea pig recognizes the rabbit serum albumin as foreign & mounts an immune response against it. ‫اﻟﻐﺮاﺑﮫ ﻗﺪره‬ ‫اﻟﺠﮭﺎز اﻟﻤﻨﺎﻋﻲ ﻗﺎدر ﻋﻠﻰ اﻟﺘﻤﯿﯿﺰ ﺑﯿﻦ اﻟﺠﺰﯾﺌﺎت اﻟﺬاﺗﯿﮫ وﻏﯿﺮ اﻟﺬاﺗﯿﮫ ) ااﻟﻐﺮاﺑﮫ( ﻟﺬا ﻛﻠﻤﺎ اﻟﻤﺎده ﻏﺮﯾﺒﮫ‬ b- Method of administration: ‫طﺮﯾﻘﮫ اﻋﻄﺎء اﻟﻤﺎده اﻛﻮ ﻟﻘﺎﺣﺎت ﺗﻌﻄﻰ ﺑﺎﻟﻔﻢ وﻟﻘﺎح ﯾﻌﻄﻰ ﺑﺎﻟﺤﻘﻦ ﺗﺤﺖ‬ ‫اﻟﺠﻠﺪ ﺣﺴﺐ ﻧﻮع اﻟﻠﻘﺎح‬ * Dose and Route of antigen administration can alter the nature of the response C-Genetic constitution of the host animal: ‫اﻟﻤﻜﻮن اﻟﻮراﺛﻲ ﻟﻠﻜﺎﺋﻦ ﯾﺆﺛﺮ ﻋﻠﻰ ﺟﮭﺎزه اﻟﻤﻨﺎﻋﻲ‬ d-Chemical composition: ‫اﻟﻤﻜﻮﻧﺎت اﻟﻜﯿﻤﯿﺎﺋﯿﮫ) اﻟﻤﺎده اﻟﻤﻜﻮﻧﮫ ﻣﻦ اﻛﺜﺮ ﻣﻦ ﺟﺰﯾﺌﮫ ﺗﻜﻮن اﻛﺜﺮ ﺗﺤﻔﯿﺰ‬ ‫ﯾﻌﻨﻲ اذا اﻟﻤﺎده ﻣﺘﻜﻮﻧﮫ ﻣﻦ ﺑﺮوﺗﯿﻦ وﺳﻜﺮﯾﺎت اﻛﺜﺮ ﺗﻤﻨﯿﻊ ﻣﻦ ﻣﺎده ﻣﺘﻜﻮﻧﮫ ﻣﻦ ﺳﻜﺮﯾﺎت ﻓﻘﻂ‬ e- Molecular weight: ‫اﻟﻮزن اﻟﺠﺰﯾﺌﻲ ﻛﻠﻤﺎ اﻟﻤﺎده ﻛﺒﯿﺮه اﻟﺤﺠﻢ ﺗﺤﻔﺰ اﻟﺠﮭﺎز اﻟﻤﻨﺎﻋﻲ اﻛﺜﺮ‬ f-Chemical complexity: ‫اﻟﺘﻌﻘﯿﺪ اﻟﻜﯿﻤﯿﺎﺋﻲ ﻛﻠﻤﺎ اﻟﻤﺎده ﻣﻌﻘﺪه اﻛﺜﺮ ﺗﻨﺸﻂ اﻟﺠﮭﺎز اﻟﻤﻨﺎﻋﻲ اﻛﺜﺮ‬ g-Degradability: ‫اﻟﻘﺪره ﻋﻠﻰ اﻟﺘﺠﺰﺋﮫ‬ TYPES OF ANTIGENS ‫اﻻﻧﺘﺠﯿﻦ ) اﻟﻤﺴﺘﻀﺪ ( ﯾﻘﺴﻢ اﻟﻰ ﻧﻮﻋﯿﻦ‬ T-independent antigens (TI) : are antigens which can directly stimulate the B cells to produce antibody without the requirement for T cell help. In general, polysaccharides are T-independent antigens. The responses to these antigens differ from the responses to other antigens. ‫اﻟﻤﺴﺘﻀﺪ ﻏﯿﺮ اﻟﻤﻌﺘﻤﺪ ﻋﻠﻰ اﻟﺨﻼﯾﺎ اﻟﺘﺎﺋﯿﮫ وھﻮ اﻟﻤﺴﺘﻀﺪ‬ ‫اﻟﺬي ﯾﺤﻔﺰ اﻟﺨﻼﯾﺎ اﻟﺒﺎﺋﯿﮫ ﻣﺒﺎﺷﺮﺗﺎ دون اﻟﺤﺎﺟﮫ اﻟﻰ اﻟﺨﻼﯾﺎ اﻟﺘﺎﺋﯿﮫ ﻣﺜﻞ ﻣﺘﻌﺪد اﻟﺴﻜﺮﯾﺎت ا‬ T-dependent Antigens – (TD) are antigens that do not directly stimulate the production of antibody without the help of T cells. Proteins are Tdependent antigens. Structurally these antigens are characterized by a few copies of many different antigenic determinants ‫اﻟﻤﺴﺘﻀﺪ اﻟﻤﻌﺘﻤﺪ ﻋﻠﻰ اﻟﺨﻼﯾﺎ اﻟﺘﺎﺋﯿﮫ وھﻮ اﻟﻤﺴﺘﻀﺪ اﻟﺬي ﻻﯾﺴﺘﻄﯿﻊ‬ ‫ﺗﺤﻔﯿﺰ اﻟﺨﻼﯾﺎ اﻟﺒﺎﺋﯿﮫ ﻻﻧﺘﺎج اﻻﺿﺪاد ﺑﺪون ﻣﺴﺎﻋﺪه اﻟﺨﻼﯾﺎ اﻟﺘﺎﺋﯿﮫ ﻣﺜﻞ اﻟﺒﺮوﺗﯿﻨﺎت‬  l-5 immunology d.mayyada f.darweesh The immune response A)Characteristic of I.S. :‫ﻣﻤﯿﺰات اﻟﺠﮭﺎز اﻟﻤﻨﺎﻋﻲ‬ The immune system has at least 3 major functional properties that distinguish it from all of the bodies system : 1. Its extreme specificity: ‫ﺧﺼﻮﺻﯿﮫ ﻓﺎﺋﻘﮫ‬ 2. The immune system discriminates between self & non self.‫ﻟﮫ ﻗﺪره ﻋﻠﻰ اﻟﺘﻤﯿﯿﺰ ﺑﯿﻦ اﻟﺬات وﻏﯿﺮ اﻟﺬات‬ 3.The immune system has memory so that subsequent encounters with a foreign pathogen more rapid & more strong responses than occurred at the initial encounter.‫ﻟﮫ‬ ‫ذاﻛﺮه‬ Non specific immune response:‫اﺳﺘﺠﺎﺑﮫ ﻣﻨﺎﻋﯿﮫ ﻏﯿﺮ ﻣﺘﺨﺼﺼﮫ‬ Phagocytosis : a process by which microorganisms are engulfed, digested and killed. ‫ھﻲ ﻋﻤﻠﯿﮫ ﺑﻮاﺳﻄﺘﮭﺎ اﻟﻤﯿﻜﺮوب ﯾﺒﺘﻠﻊ وﯾﮭﻀﻢ ﻋﻦ طﺮﯾﻖ ﻧﻮﻋﯿﻦ ﻣﻦ اﻟﺨﻼﯾﺎ ھﻤﺎ‬  Cells : Microphages( polymorphonuclear Nutrophil (PMN) Macrophages: Tissue phagocytes (Monocytes in blood and macrophages in tissue as Histiocytes).  Phagocytic process :Include 4 steps: ‫ ﺧﻄﻮات ھﻲ‬٤ ‫ﺗﺘﻀﻤﻦ اﻟﺒﻠﻌﻤﮫ‬ 1. Chemotaxis ‫اﻻﻧﺠﺬاب اﻟﻜﯿﻤﯿﺎﺋﻲ‬ 2. Opsonization ‫اﻟﺘﻐﻠﯿﻒ‬ 3. Ingestion (engulfment) ‫اﻻﺑﺘﻼع‬ 4. Killing‫اﻟﻘﺘﻞ‬ (1) Chemotaxis :- Migration of phagocytic cells towards micro -organism and the motility may be Random or Directional. Phagocytic cells respond to chemotactic peptides of bacterial and host origin and migrate across the capillary wall (diapedesis) to the site of infection/inflammation. ‫اﻻﻧﺠﺬاب ھﻲ ﺣﺮﻛﮫ او ھﺠﺮه اﻟﺨﻠﯿﮫ اﻟﺒﻠﻌﻤﯿﮫ ﺑﺎﺗﺠﺎه اﻟﻤﯿﻜﺮوب وﺗﻜﻮن ﺣﺮﻛﺘﮭﺎ ﻋﺸﻮاﺋﯿﮫ او ﻣﺒﺎﺷﺮه‬ Chemotaxins : Substances that promote directional motility of phagocytes. (2) Opsonization :- Coating of microbe with molecules(Ab) that promote attachment of phagocytes to this microbe. ‫اﻟﺘﻐﻠﯿﻒ ھﻮ ارﺗﺒﺎط او اﺣﺎطﮫ اﻟﺠﺰﯾﺌﺎت اﻟﻤﻨﺎﻋﯿﮫ ﻣﺜﻞ اﻟﻀﺪ واﻟﺘﻲ ﺗﺴﮭﻞ اﻟﺨﻼﯾﺎ اﻟﺒﻠﻌﻤﯿﮫ ﻟﻼرﺗﺒﺎط ﺑﮫ‬ Opsonins may be : Specific ( Antibodies) or Non – specific ( C3b) of the alternative pathway.  l-5 immunology d.mayyada f.darweesh (3) Ingestion :- Encirclement of microbe by cytoplasmic projectes of phagocytic cell and the formation of a vacuole called phagosome. ‫ﻋﻤﻠﯿﮫ ﺗﻐﻠﻒ اﻟﻤﯿﻜﺮوب ﺑﺎﻟﺰواﺋﺪ اﻟﺴﺎﯾﺘﻮﺑﻼزﻣﯿﮫ ﻟﺨﻠﯿﮫ اﻟﺒﻠﻌﻤﯿﮫ وﺗﻜﻮﯾﻦ اﻟﺤﻮﯾﺼﻠﮫ اﻟﺒﻠﻌﻤﯿﮫ‬  Steps of ingestion: 1) Formation of phagosome by encirclement of foreign body by cytoplasm. 2) Formation of phagolysosome by fusion of lysosomal granules with phagosome. 4-Killing :- Death of engulfed M.O. Oxygen – dependent Mechanisms of killing Oxygen – independent that contain myeloperoxidase results in the production of( I and Br) and halogenation of bacterial proteins. This ultimately leads to bacterial killing Figure (1) Phagocytosis, macropi nocytosis,protrusions of the plasma membrane capture extracellular fluids whose contents pathogen then phagosome, and phagolysosome formation. That subsequently ingested the pathogen in phagolysosomes then excite When an antigen enter the body *Encounters a specialized class of cells called Antigen Presenting Cells(APC) which capture a minute amount of the antigen & display it in a form that can be recognized by helper T lymphocyte (Th), this step called Ag processing & presentation, * T cells only recognize immunogens that are bound to major histocompatibility complex (MHC) proteins on the surface of other cells, this stage called activation of the helper T cell which in turn promote the activation of other classes of lymphocyte such as B cells or cytotoxic T cells l-5 immunology d.mayyada f.darweesh Department of Biology Dr. Huda Jameel Six Lecture/ Class three Immunity Antibodies: Structure and Function A. Basic structure Immunoglobulin’s (Igs) are glycoprotein molecules also called antibodies(Abs), that are produced in response to foreign substances entering the living body- antigens or immunogens(viruses, bacteria, or toxins etc.), binding to them and forming antigen- antibody complexes. An antibody molecule is composed of four polypeptide chains, including two identical Heavy (H) chains and two identical light (L) chains, with each chain containing a variable region and a constant region (Fig. 1). The four chains are assembled to form a Y-shaped molecule. Each light chain is attached to one heavy chain, and the two heavy chains are attached, all by disulfide bonds. Each L chain consists of one variable domain, VL, and one constant domain, CL. , and a heavy chain consisting of a variable domain, VH, and three constant domains CH1, CH2 and CH3. The antigen-binding site of an antibody is composed of the V regions of both the heavy chain and the light chain, and the core antibody structure contains two identical Antigen binding sites. The hinge region is the area of the H chains between the first and second C region domains and is held together by disulfide bonds. This flexible hinge (found in IgG, IgA and IgD, but not IgM or IgE) region allows the distance between the two antigen- binding sites to vary. FIGURE (1): Structure of antibodies  The antigen-binding fragment (Fab) is a region on an antibody that binds to antigens. It is composed of one constant and one variable domain of each of the heavy and the light chain. The variable domain contains the paratope (the antigen-binding site), comprising a set of complementarity-determining regions, at the amino-terminal end of the monomer. Each arm of the Y thus binds an epitope on the antigen. The remaining heavy-chain C domains make up the Fc (fragment, crystalline) region; this fragment tends to crystallize in solution. Figure (2) Between the Fab and Fc regions of most antibody molecules is a flexible portion called the hinge region. The hinge allows the two antigen-binding Fab regions of each antibody molecule to move independently of each other. The C-terminal end of the heavy chain may be anchored in the plasma membrane, as seen in B cell receptors, or it may terminate in a tailpiece that lacks the membrane anchor so that the antibody is produced as a secreted protein. Light chains are not attached to cell membranes. Figure (2): Fab and Fc position in the antibody. Classes of immunoglobulin The five primary classes of immunoglobulin’s are IgG, IgM, IgA, IgD and IgE. These are distinguished by the type of heavy chain found in the molecule. IgG molecules have heavy chains known as gamma-chains; IgMs have mu-chains; IgAs have alpha-chains; IgEs have epsilon-chains; and IgDs have delta-chains. While there are five different types of heavy chains, there are only two main types of light chains: kappa (κ) and lambda (λ). differ in their C regions. Each B cell expresses either κ or λ, but not both. 1. IgM-miu heavy chain 2. IgD- delta heavy chain 3. IgG- gamma heavy chain 4. IgE- epsilon heavy chain. 5. IgA- alpha heavy chain 1-IgM It normally exists as a pentamer in serum but can also occur as a monomer. It has an extra domain on the mui chain (CH4) and another protein covalently bound via S-S. Called J-chain. This chain helps it to polymerize to the pentamer form. In general, lgM is the first immunoglobulin to be formed following antigenic stimulation. lgM is effective in activating the classical pathway of complement. Figure (3) Properties 1. It is the first Ig to be made by fetus in most species and new B cells when stimulated by Ags. 2. It is the 3rd most abundant Ig in serum. 3. It is a good complement fixing Ig leading to lyses of microorganisms 4. It is also a good agglutinating Ig, hence clumping microorganisms for eventual elimination from the body. 5. It is also able to bind some cells via Fc receptors. 6. B cells have surface IgMs, which exists as monomers and lacks J chain but have an extra 20 amino acid at the C-terminal that anchors it to the cell membrane. Figure (3): IgM structure. 2- IgD It exists as monomers, and is almost exclusively displayed on B-cell surfaces. Which exists in small amounts in the blood, little is known of its function. Figure (4): Properties 1. It is found in low levels in serum and its role in serum is uncertain 2. It is found primarily on B cells surface and serves as a receptor for Ag. 3. It does not fix complement. Figure(4):IgD structure. 3-IgG all IgG are monomers, Each IgG has two antigen binding sites. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood and extracellular fluid allowing it to control infection of body tissues. By binding many kinds of pathogens such as viruses, bacteria, and fungi, IgG protects the body from infection. Figure (5): Properties. 1. It is the most versatile Ig and can carry out all functions of Ig molecules. 2.IgG also binds and neutralize toxins; 3. It is also found/ the major Ig in extravascular spaces. 4. It is the only Ig that crosses the placenta. 5. It fixes complement although not all subclasses do this well. 6. It binds to cells and is a good poisoning(substance that enhances phagocytosis). 4-IgE It occurs as a monomer and has an extra domain in the constant region. Which is associated mainly with allergic reactions (when the immune system overreacts to environmental antigens such as pollen or pet dander)? It is found in the lungs, skin, and mucous membranes. Figure (5): Properties 1. It is the least common serum Ig, but it binds very tightly to Fc receptors on basophils and mast cells even before interacting with Ags. 2. It is involved in allergic reactions because it binds to basophils and mast cells. 3. It plays a role in parasitic helminthic diseases. Serum levels rise in these diseases. Eosinophils have Fc receptors for IgEs and when eosinophils bind to IgEs coated helminthes death of the parasite results. 5-IgA Serum IgA is monomeric, but IgA found in secretions is a dimer having a J chain. Secretory IgA also contains a protein called secretory piece or T- piece; this is made in epithelial cells and added to the IgA as it passes into secretions helping the IgA to move across mucosa without degradation in secretions so that is found in high concentrations in the mucous membranes, particularly those lining the respiratory passages and gastrointestinal tract, as well as in saliva and tears. Figure (5): Properties 1. It is the second most abundant Ig in serum 2. It is the major class of Ig in secretions- tears, saliva, , mucus, and is important in mucosal immunity. 3. It binds to some cells- PMN cells and lymphocytes 4. It does not normally fix complement.  Figure (5): Antibody classes Table(1):Effector functions of antibodies  Department of Biology/ third stag/L-7 Dr. Huda Jameel Complement system The complement system is a complex set of soluble molecules that generate various reactions that attract immune cells to the site of infection and lead to destruction of microbes. Complement is a collective term for a system of enzymes and proteins that function in both the innate and adaptive branches of the immune system as soluble means of protection against pathogens that evade cellular contact. In the innate immune system, complement can be activated in two ways: via the alternative pathway, in which antigen is recognized by particular characteristics of its surface, or via the mannan-binding lectin (M B L) pathway. Complement can also be activated in the adaptive immune system via the classical pathway that begins with antigen-antibody complexes. Functions of complement include lysis of bacteria, cells, and viruses; promotion of phagocytosis (opsonization); triggering of inflammation and secretion of immunoregulatory molecules; and clearance of immune complexes from circulation. Figure (1). Figure (1): Terminal or Membrane attack complex three complement pathways lead to formation of the membrane attack complex.  Department of Biology/ third stag/L-7 Dr. Huda Jameel Complement Activation Pathways. 1-The alternative pathway Is initiated by cell-surface constituents that are recognized as foreign to the host, such as LPS (Fig. 5.6). Various enzymes (e.g.. , kallikrein , plasmin , and elastase) cleave C3, the most abundant ( ~ 1 300 mg/m l) serum complement component, into several smaller fragments. One of these, the continuously present, short-lived, and Unstable C3b fragment, is the major opsonin of the complement system and readily attaches to receptors on cell surfaces. 1. C3b binds Factor B. 2. Factor B in the complex is cleaved by Factor D to produce C3bBb, an unstable C3 convertase. 3. Two proteins, C3b in activator (I) and B1H-globulin (H), function as important negative regulators, making an inactive form of C3b (C3b) to prevent the unchecked over amplification of the alternative pathway. 4. Alternatively, C3bBb binds proper din (Factor P) to produce stabilized C3 convertase, C3bBbP. 5. Additional C3b fragments join the complex to make C3bBbP3b, also known as C5 convertase. C5 convertase cleaves C5 into C5a and C5b. 6. C5b inserts into the cell membrane and is the necessary step leading to formation of the membrane attack complex (MAC) and cell lysis. Figure(2). Figure (2): Alternative pathway of complement activation. Beginning with the binding of C3b to a microbial surface, this pathway results in an amplified production of C3b and formation of a C5convertase.  Department of Biology/ third stag/L-7 Dr. Huda Jameel The terminal or lytic pathway can be entered from the alternative, man nan-binding lectin, or classical pathway of complement activation. Attachment of C5b to the bacterial membranes initiates formation of the membrane attack complex (MAC) and lysis of the cell (Fig. 3). The attachment of C5b leads to the addition of components C6, C7, and C8. C8 provides a strong anchor into the membrane and facilitates the subsequent addition of multiple C9 molecules to form a pore i n the membrane. Loss of membrane integrity results in the u n regulated flow of electrolytes and causes the lytic death of the cell. Figure (3): Terminal or membrane attack complex (MAC) of complement. The MAC forms a pore i n the surfaces of microbes to which it is attached, causing lytic death of those microbes. 2. Mannan-binding lectin pathway: Lectins are proteins that bind to specific carbohydrates. This pathway is activated by binding of mannan-binding lectin (MBL) to mannose-containing residues of glycoproteins on certain microbes (e.g.. , Listeria spp. , Salmonella spp. , Candida albicans). MBL is an acute phase protein, one of a series of serum proteins whose levels can rise rapidly in response to infection, inflammation, or other forms of stress. MBL, once bound to appropriate mannose-containing residues, can interact with MBL-activated serine protease (MASP). Activation of MASP leads to subsequent activation of components C2, C4, and C3 Figure (4).  Department of Biology/ third stag/L-7 Dr. Huda Jameel Figure (4): Mannan-binding lectin (MBL) pathway of complement activation. The lectin binding pathway is initiated by the binding of certain glycoproteins commonly found on microbial surfaces, and results in the formation of a C3 convertase (that acts to produce C3b) and a C5 convertase (that can lead to MAC formation). The small fragments (C3a, C4a, C5a) generated by the cleavage of C3 and C5 in the alternative pathway and of C3, C4, and C5 in the MBL pathway act as anaphylotoxins. Anaphylotoxins attract and activate different types of leukocytes. 3- CLASSICAL PATHWAY OF COMPLEMENT ACTI VATION Interaction of antibody with antigen initiates the classical pathway of complement activation. This biochemical cascade of enzymes and protein fragments facilitates destruction of microbes by the membrane attack complex (MAC) , by increased opsonization through C3b binding of microbial surfaces and by the production of anaphylotoxins C3a, C5a, and C4a. The cascade begins with the activation of component C 1. (Fig.5)  Department of Biology/ third stag/L-7 Dr. Huda Jameel Figure (5): Classical pathway of complement activation. The classical pathway is initiated by the binding of antibody (usually lgG or lgM) to an antigen and then to the C1 complement component. The pathway produces a C3 convertase (responsible for the cleavage of C3 into its component parts: C3a, C3b, etc.) and a C5 convertase (that can lead to MAC formation). Department of Biology Dr.Huda Jameel Clinical Immunology Stage third /eight lectures Immunological diseases Immunodeficiency Immunodeficiency is a condition caused by one or more immune system defects and is Characterized clinically by increased susceptibility to infections with consequent severe, acute, recurrent or chronic disease. Immunodeficiency may be either primary or secondary. IMMUNODEFICIENCY SYNDROMES Immunodeficiency are divided into two major categories: primary immunodeficiencies, which may be hereditary or acquired, in which the deficiency is the cause of disease; and secondary immunodeficiencies, in which the immune deficiency is a result of other diseases or conditions. 1- Primary immunodeficiency Is also named CONGENITAL ("PRIMARY") IMMUNODEFICIENCIES - Victims are born with these diseases, which are the result either of inherited or developmental defects. The primary immunodeficiency is classified into four main groups depending on which component of the immune system is deficient: B cells, T cells, phagocytic cells or the Complement cascade. See also: Complement; Lymphocytes. Primary immunodeficiency appear initially in infants and children; about 80% of those affected are under 20 years old and, owing to X-linked inheritance of many syndromes, 70% occur in males. Of the primary immunodeficiency, B-cell-associated antibody defects predominate; selective IgA deficiency (usually asymptomatic) may occur in 1 in 400 people. Excluding asymptomatic IgA deficiency-cell defects still account for 50% of the primary immunodeficiency, but another 15% involve antibody deficiency due to T-cell abnormalities. T-cell defects account for about 30%.phagocytic deficiencies account for 15% and complement deficiencies account for 5%. T-cell defects include several disorders with associated B-cell (antibody) defects, With the exception of IgA deficiency, the frequency of primary immunodeficiency syndromes is very low—about 1 in 10,000. In general, the earlier the genetic defect or block occurs in development, the more arms of the immune system are affected and the more severe the disease. DiGeorge syndrome e.g. for Primary immunodeficiency was due to the movement of neural crest cells inside the pharyngeal pouch of the fetus during the fourth week of pregnancy. These cells are responsible for the development and growth of the bones of the skull, face and palate, Thymus gland, Thyroid gland, Parathyroid gland, and is responsible for nerve compounds in the neck and head. In 90% of people with de Jorge syndrome, a chromosome (mutation) is diagnosed (q2211.2). This syndrome affects one in every 3000- 4000 live births. 1 2-Secondary immunodeficiency Is also named ACQUIRED ("SECONDARY") IMMUNODEFICIENCIES: Secondary immunodeficiency is an impairment of the immune system resulting from an infection, medications or malignancy in a previously normal person. The impairment is often reversible if the underlying condition or illness resolves. Such as infection, therapeutic treatment, cancer and malnutrition. These deficiencies may occur at any time of life. A. SECONDARY TO DISEASE 1) Many infectious diseases result in more or less general immunosuppression. In the case of Human Immunodeficiency Virus (HIV), the agent which causes Acquired Immunodeficiency Disease (AIDS), its pathogenicity is a direct consequence of its severe depression of immune responsiveness. 2) Malignancies can often result in immunosuppression, either by generally interfering with normal physiological functions, or through the production of factors which specifically suppress immune functions (this may be a significant aspect of the natural biology of malignancy). 3) Renal failure can cause the loss of large amounts of serum immunoglobulins into the urine, resulting in humoral immunodeficiency. 4) Enteropathies can lead to loss of immunoglobulin through the gut, with similar Results. B-IATROGENIC. ("Caused by the healer"; referring to a condition which is the result of therapeutic treatment.) This category includes the most common immunodeficiency conditions which most physicians will encounter. 1) Corticosteroids. Prednisone is widely used for both its anti-inflammatory effect and immunosuppressive capability; lymphocytes in general are very sensitive to steroids. 2) Cytotoxic drugs. Many anti-tumor drugs (such as azathioprine and cyclophosphamide) are strongly immunosuppressive as well, and may also be used intentionally for this purpose. Susceptibility to infections may therefore be a major side effect of anti-tumor therapy, in a patient who may already be immunosuppressed by the presence of the tumor itself. 3) Anti-Lymphocyte Antibodies. Sera from horses immunized with human thymocytes contain effective anti-T-cell antibodies, and have been used extensively since the 1950's to inhibit rejection of transplanted organs; such preparations are known as Anti- lymphocyte Serum (ALS) or Anti-Lymphocyte Globulin (ALG). Their use is much more limited now than in the past and the development of new classes of immunosuppressive drugs such as cyclosporin. 4) Ionizing Radiation. X-rays or gamma-rays, often used in tumor therapy, also destroy whatever lymphoid tissue happens to be in their path. 2 NUTRITION AND IMMUNE RESPONSES The relationship between nutrition and resistance to infection has been suggested by historical accounts of famine and pestilence, clinical observations, and epidemiological data. Generally, nutrient deficiencies are associated with impaired immune responses. The five aspects of immunity most consistently affected by malnutrition are cell-mediated immunity, phagocyte function, the complement system, secretory antibody, and cytokine production. Worldwide, under nutrition is the commonest cause of immunodeficiency. Economically underprivileged countries have a high prevalence of nutritional deficiencies, as do poor segments of society in many industrialized countries. In addition, many individuals show a nutrition problem secondary to another primary systemic disorder: patients with cancer, chronic renal disease, burns, multiple trauma and chronic infection show a high prevalence of malnutrition. Paradoxically, obesity and excess intake of nutrients are also associated with reduced immune responses. Malnutrition and infection Infection and malnutrition usually aggravate each other. However, nutrition does not affect all infections equally: the clinical course and final outcome of pneumonia, diarrhea, measles and tuberculosis are affected adversely by nutritional deficiency; for some infections (e.g. tetanus and viral encephalitis), the effect of nutritional deficiency is minimal; for others (e.g. influenza virus and human immunodeficiency virus), nutrition exerts a moderate influence. There are many factors that predispose to development of infection in the malnourished individual, including poor sanitation, contaminated food and water, lack of nutritional and health knowledge, illiteracy and overcrowding. CLINICAL APPLICATION HIV infection and AIDS AIDS (acquired immune deficiency syndrome) is caused by HIV (human immunodeficiency virus). HIV is a retrovirus that damages the cells of the body's immune system. People with HIV may develop opportunistic infections and various forms of cancer. The CD4 molecule expressed on subsets of human T cells, dendritic cells, and macrophages is the major means by which H I V binds and enters cells. However, it also uses two chemokine receptor molecules as coreceptor for the two types of cells that are preferentially infected: CCR5 on macrophages and dendritic cells and CXCR4 on Lymphocytes (Fig. 1). In the absence of these coreceptor, HIV is unable to successfully enter the cells. A small percentage of individuals of Caucasian descent fail l to express CCR5 and are protected from infection by HIV. Infection of CD4 + CCR5+ dendritic cells appears to be the primary route of initial infections; infection of CD4 + CXCR4 + T cells occurs later in the disease process. 3 Figure (1): Coreceptor for cell infection by HIV. In addition to the CD4 molecule, HIV requires either CCR5 or CXCR4 to successfully enter and infect a cell. 4