Immunology and Immunotechnology Course Lecture (PDF)

ADDIS ABABA SCIENCE AND TECHNOLOGY UNIVERSITY SCHOOL OF BIOLOGICAL AND CHEMICAL SCIENCES AND TECHNOLOGY Biotechnology dept. Immunology and immunotechnology ( bIOt 3101) course lecture Musin Kelel (PhD Molecular Medicine) O...

ADDIS ABABA SCIENCE AND TECHNOLOGY UNIVERSITY SCHOOL OF BIOLOGICAL AND CHEMICAL SCIENCES AND TECHNOLOGY Biotechnology dept. Immunology and immunotechnology ( bIOt 3101) course lecture Musin Kelel (PhD Molecular Medicine) October, 2024 1  Chapter 1. Introduction Functions of Our Immune System  Act against the invasive pathogens  Prevent infection  Remove the transformed cells (Cancer)  Remove damaged tissues  Tissue Homeostasis Musin Kelel (PhD Molecular Medicine) 2 October, 2024  1.1 Immunology Historical perspectives Late 18th century: Edward Jenner  observed that cowpox (or vaccinia) seemed to confer protection against the fatal disease of smallpox  1796 – Vaccination –the inoculation of healthy individuals with weakened or attenuated strains of disease-causing agents to provide protection from disease was started Musin Kelel (PhD Molecular Medicine) 3 October, 2024  Smallpox vaccination  A child infected with smallpox, 1973 , control attempt were made by vaccination.  a major distinguishing characteristic of the disease.  Patients with ordinary-type smallpox usually had bumps filled with a thick and opaque fluid, often with a depression or dimple in the center. Musin Kelel (PhD Molecular Medicine) 4 October, 2024 It took almost two centuries for smallpox vaccination to become universal. Smallpox had been eradicated in 1979. Musin Kelel (PhD Molecular Medicine) 5 October, 2024  1.2Overview of the innate immune system Epithelial surfaces of the body provide the first line of defense against infection Musin Kelel (PhD Molecular Medicine) 6 October, 2024  Immune organs Secondary lymphoid organs include lymph nodes, spleen, Peyer's Primary lymphoid organs patches, and mucosal tissues such as the nasal-associated lymphoid tissue, adenoids, and tonsils Musin Kelel (PhD Molecular Medicine) 7 October, 2024  1908 Nobel Prize "in recognition of their work on immunity" Adaptive vs. Innate 1854-1915 1845-1916 Paul Erlich Ilya Metchnikoff «magic bullets» the phenomenon of phagocytosis Musin Kelel (PhD Molecular Medicine) 8 Antibody October, 2024 Phagocytes  Terminology The term immunity is derived from the Latin word immunitas, which referred to the protection from legal prosecution offered to Roman senators during their tenures in office Immunity is defined as resistance to disease, specifically infectious disease The collection of cells, tissues, and molecules that mediate resistance to infections form the immune system The coordinated reaction of these cells and molecules to infectious microbes comprises an immune response Musin Kelel (PhD Molecular Medicine) 9 October, 2024 1.3. Immune system (Active & Passive) Natural Active Occurs during infection It is active because lymphocytes are activated by antigens on pathogen's surface Artificial Active Injecting or taking antigens by mouth Takes time for T and B cells to be activated but gives long lasting immunity Musin Kelel (PhD Molecular Medicine) 10 October, 2024  Active & Passive Passive immunity A type of immunity acquired by the transfer of antibody from one individual to another Acquired by injecting antibodies or sensitized lymphocytes to an organism via a vaccination Natural Passive Mother to child through placenta or milk Artificial Passive Used during potentially fatal diseases. Provides an instant response but only temporary as antibodies are not the body's own so memory cells are not created.  E.g. tetanus - injection of antitoxins given Musin Kelel (PhD Molecular Medicine) 11 October, 2024  Active & Passive immunization Passive: In 1890, Shibasaburo Kitasato (1852-1931) and Emil von Behring (1854-1917) immunized guinea pigs against diphtheria with heat- treated blood products from animals that had recovered from the disease. Antibodies to the diphtheria toxin protected the guinea pigs If Blood-derived substance called diphtheria antitoxin is used it is passive immunization If diphtheria toxin it self is used directly , this constitutes the components of active immunization Musin Kelel (PhD Molecular Medicine) 12 October, 2024 Practical example of artificial passive immunization: IMQ-stimulated LCs could induces the proliferation and migration of gdT cells (t cell subset) in mice ear LCs pretreatment with cis-UCA reduced these biological functions of LCs (passive immunization) Musin Kelel (PhD Molecular Medicine) 13 October, 2024  Active & Passive Memory cells are only produced in active immunity Protection for active immunity is permanent whereas in passive immunity it is only temporary Antigens are encountered in active immunity but not necessary in passive Active immunity takes several weeks to become active but passive is immediate Musin Kelel (PhD Molecular Medicine) 14 October, 2024 Immune system (Active & Passive) summary Musin Kelel (PhD Molecular Medicine) 15 October, 2024  Innate vs adaptive immunity Defense against microbes is mediated by sequential and coordinated responses that are called innate and adaptive immunity Innate is essential for defending against microbes in the first few hours or days  is mediate by mechanisms that are in place even before an infection occurs (hence innate) Innate immunity, also called natural immunity or native immunity Always present Musin Kelel (PhD Molecular Medicine) 16 October, 2024  Innate vs adaptive immune system Adaptive Slowly develops Specific Is called specific immunity or acquired immunity requires expansion and differentiation of lymphocytes in response to microbes before it can provide effective defense it adapts to the presence of microbial/pathogene invaders Important for pathogen that resists innate immune response Musin Kelel (PhD Molecular Medicine) 17 October, 2024 Immune system (Innate vs adaptive) Musin Kelel (PhD Molecular Medicine) 18 October, 2024 1.4. Characteristics of the immune system Musin Kelel (PhD Molecular Medicine) 19 October, 2024 Chapter 2:Response of innate immunity Components of innate immunity  Epithelial Barriers  Phagocytes: Neutrophils and Monocytes Macrophages Dendritic Cells Mast Cells Innate Lymphoid Cells Musin Kelel (PhD Molecular Medicine) 20 October, 2024  Innate immune system (mechanism) 1. Stops pathogens at barriers: Physical Chemical Biological 2. Kills at first encounter: Complement Antibacterial enzymes and peptides Phagocytosis, NK cells 3. Recruits help – inflammation Recognition by pattern recognition receptors (PRRs) Secretion of cytokines Influx of more innate immune cells 4. Activates the adaptive immune system Musin Kelel (PhD Molecular Medicine) 21 October, 2024 The innate immune system Musin Kelel (PhD Molecular Medicine) 222 October, 2024  Military analogy Barrier at the border (Great wall of China, Donald Trump’s Mexican border barrier, wall of Berlin) Border patrol – always at the border. Kills on sight. Armies stationed close behind the border – takes a couple of hours to get to the breach, much more numerous and powerful than the border patrol. Everyone who can carry a weapon – much bigger and stronger force than the armies at the border, but it takes a couple of days to assemble. Musin Kelel (PhD Molecular Medicine) 23 October, 2024 2.1.Anatomic, Physiological and Cellular barriers Pathogen Containment by an anatomic barrier Prevention of infection Musin Kelel (PhD Molecular Medicine) 24 October, 2024 1. Physical Prevent pathogen entry into the body’s interior  Skin covers ~2 m2  Mucous membranes that line digestive, respiratory, reproductive tracts cover ~400 m2 2. Chemical Epithelial layers produce protective substances  Acidic pH  Enzymes and binding proteins  Antimicrobial peptides 3. Normal microflora non-pathogenic microbes that suppress the growth of pathogens Musin Kelel (PhD Molecular Medicine) 25 October, 2024  Skin provides physical and chemical protection  The skin approximately covers ~2 m2 Musin Kelel (PhD Molecular Medicine) 26 October, 2024  How skin provides protection ? Intact epithelial surfaces form physical barriers between microbes in the external environment and host tissue The epithelial cells form tight junctions with one another, blocking passage of microbes between the cells The outer layer of keratin, which accumulates as keratinocytes on the surface die, serves to block microbial penetration into deeper layers of the epidermis Epithelial cells produce antimicrobial chemicals that further impede the entry of microbes Musin Kelel (PhD Molecular Medicine) October, 2024 27 Skin as physical and chemical barrier Epithelial cells as well as some leukocytes produce peptides that have antimicrobial properties Musin Kelel (PhD Molecular Medicine) 28 October, 2024  The defensins and the cathelicidins Defensins  small peptides, 29 to 34 amino acids long,  contain both cationic and hydrophobic regions  three intrachain disulfide bonds Two families of human defensins, α and β, produced by  epithelial cells of mucosal surfaces and  granule-containing leukocytes,  neutrophils,  natural killer cells, and  cytotoxic T lymphocytes Defensins kill microbes by  inserting themselves into and disrupt functions of microbial membranes  the activation of cells involved in the inflammatory response to Musin microbes Kelel (PhD Molecular Medicine) October, 2024 29  Cathelicidin Is produced by neutrophils and barrier epithelial cells in the skin, gastrointestinal tract, and respiratory tract, is synthesized as an 18-kD two domain precursor protein and is proteolytically cleaved into two peptides, each with protective functions protect against infections by direct toxicity to microorganisms and the activation of responses in leukocytes and other cell types that promote eradication of microbes Musin Kelel (PhD Molecular Medicine) 30 October, 2024  Intraepithelial lymphocyte intraepithelial T lymphocytes recognize and respond to commonly encountered microbes are present in the epidermis of the skin and in mucosal epithelia are activated by cytokines and other molecules produced by epithelial cells in response to stress  may also function in host defense by secreting cytokines, activating phagocytes, and killing infected cells Phagocytes Cells that have specialized phagocytic functions, primarily macrophages and neutrophils, are the first line of defense against microbes Dendritic cells (DCs) rapidly and efficiently detect invading microbes because of their location in tissues Musin Kelel (PhD Molecular Medicine) 31 October, 2024 Airways Musin Kelel (PhD Molecular Medicine) 32 October, 2024  Mucosal surfaces The mucosal surfaces provides physical protection in  the gastrointestinal, respiratory, and  genitourinary tracts These interfaces are lined by continuous layers of specialized epithelial cells that serve many physiologic functions, including preventing the entry of microbes Mucus, a viscous secretion containing glycoproteins called mucins physically impairs microbial invasion The function of these barriers is enhanced by ciliary action in the bronchial tree and peristalsis in the gut, which facilitate elimination of microbes. Musin Kelel (PhD Molecular Medicine) 33 October, 2024  Guts Musin Kelel (PhD Molecular Medicine) 34 October, 2024 The intestine is covered by a monolayer of epithelial cells Gut GIT microbiota bilateral regulation mutually beneficial environment. Goto Y.& Kiyono H. Immunological Reviews 2012 Vol. 245: 147–163 Musin Kelel (PhD Molecular Medicine) 35 October, 2024 Protective function of commensal bacteria Musin Kelel (PhD Molecular Medicine) 36 October, 2024 Musin Kelel (PhD Molecular Medicine) 37 October, 2024 The anatomical barriers can be breach by many factors Would and other diseases that leads to barrier dysfunctions favors pathogen penetration Microbes are recognized by various molecules that are always positioned under the anatomical barriers:  Anti-microbial peptides  Soluble pattern recognition receptors (PRRs) or opsonins  Cell surface PRRs Musin Kelel (PhD Molecular Medicine) 38 October, 2024 Musin Kelel (PhD Molecular Medicine) 39 1 October, 2024 4  Pathogens have evolved ways to avoid the defenses at epithelial barriers Attachment factors: Receptors for surface molecules – Influenza’s hemagglutinin Fimbriae (pili) – hair-like protrusions on the surface of bacteria E.Coli attached to urinary tract epithelium Musin Kelel (PhD Molecular Medicine) 40 October, 2024  2.2.Phagocytosis What is a Phagocyte?  A cell that engulfs and digests material such as cell debris and microbes, including invading organisms  neutrophils and macrophages, are cells whose primary function is to ingest and destroy microbes and remove damaged tissues  Surface of cell contains pattern recognition receptors to recognize material to be ingested Musin Kelel (PhD Molecular Medicine) 41 October, 2024  A scavenger receptor is an example that recognizes materials with charged molecules on their surface These receptors allow cells to bind to certain molecular configurations on debris and foreign material for ingestion Macrophages located in skin tissue destroy small amounts of bacteria in a wound Macrophages can produce cytokines to recruit additional phagocytes (neutrophils) for help Musin Kelel (PhD Molecular Medicine) 42 October, 2024 Musin Kelel (PhD Molecular Medicine) 43 October, 2024 Phagocytic process by phagocytes Musin Kelel (PhD Molecular Medicine) 44 October, 2024  The Process of Phagocytosis  A series of complex steps allowing phagocytes to engulf and destroy invading microorganisms  Most pathogens have evolved an ability to evade one or more of the steps (resistance) 1 Chemotaxis Phagocytic cells are recruited to site of infection or tissue damage by chemical stimuli (chemoattractants) Musin Kelel (PhD Molecular Medicine) 45 October, 2024 2 Recognition & Attachment Receptors located on outside of phagocyte recognize and bind (directly or indirectly).  Direct binding-receptors recognize and bind to patterns of compounds found on invaders  Indirect binding-particle is opsonized, coating particle with antibody substance for easier ingestion 3 Engulfment Phagocytic cell engulfs invader, forming a membrane- bound vacuole called a phagosome.  Cytoskeleton of phagocyte rearranges to form arm like extensions (pseudopods) that surround material being engulfed. Musin Kelel (PhD Molecular Medicine) 46 October, 2024 4 Fusion of the phagosome with the lysosome (within the phagocyte)  the phagosome moves along the cytoskeleton to where it can fuse with lysosomes.  Lysosomes-membrane bound bodies filled with various digestive enzymes like lysozyme and proteases  Fusion creates a phagolysosome Musin Kelel (PhD Molecular Medicine) 47 October, 2024 5 Destruction & Digestion  Oxygen consumption increases, sugars metabolized (aerobic respiration), highly toxic oxygen products produced (superoxide, hydrogen peroxide, singlet oxygen, hydroxyl radicals)  As available O2 in phagolysosome is consumed metabolic pathway switches to fermentation, producing lactic acid and lowering pH.  Enzymes degrade peptidoglycan of the bacterial cell walls, and other parts of the cell 6 Exocytosis  membrane-bound vesicle containing digested material fuses with the plasma membrane. Material is expelled to the external environment Musin Kelel (PhD Molecular Medicine) 48 October, 2024 Summary of phagocytosis process Musin Kelel (PhD Molecular Medicine) 49 October, 2024  Macrophages Scavengers located in tissue Play essential role in every major tissue in the body Live for weeks to months Maintain killing power by regenerating their lysosomes Musin Kelel (PhD Molecular Medicine) 50 October, 2024  Characteristics Toll-like receptors-allow them to sense dangerous materials Produce pro-inflammatory cytokines, alerting other cells in the immune system Activated macrophages-increases killing power with assistance from certain T cells Musin Kelel (PhD Molecular Medicine) 51 October, 2024 Musin Kelel (PhD Molecular Medicine) 52 October, 2024 If activated macrophages fail to destroy microbes and chronic infection occurs, large numbers can fuse together forming giant cells. Granulomas- concentrated groups of macrophages, T cells, giant cells. Contain organisms and material that can’t be destroyed by walling off and retaining the debris to prevent infection of more cells.  Granulomas are commonly part of the disease process in TB, histoplasmosis, and other diseases. Musin Kelel (PhD Molecular Medicine) 53 October, 2024  Neutrophils Characteristics  Known as the rapid response team,  Critical role in the first stages of inflammation.  First cell type recruited from bloodstream to the site of damage  More killing power than microphages  Short life span (1-2 days) in the tissue  Expend granules, then die  For every neutrophil in the circulatory system, there are 100 more waiting in the bone marrow Musin Kelel (PhD Molecular Medicine) 54 October, 2024