Basic Immunology - Introduction - PDF

Basic Immunology 1 *Course designation: 412 zoo *Course name: Immunology *No. of credits: 3L- -3C *Prerequisites: - *Co-requisite course: *Course time: sunday: 10-12 *Instructor: Dr. Elham Abd-Elsabour *Office location: *Office hours: To be announced *Course description: To be a...

Basic Immunology 1 *Course designation: 412 zoo *Course name: Immunology *No. of credits: 3L- -3C *Prerequisites: - *Co-requisite course: *Course time: sunday: 10-12 *Instructor: Dr. Elham Abd-Elsabour *Office location: *Office hours: To be announced *Course description: To be attached * QuHeeasltthiyonnutrbitiaonn-kE:lhaTmo be attached 2  Course objectives *At the end of the course the student is expected to have: 1-To gain a detailed studies and essential information of Functional organization of the immune system -Organs and cells of the immune system -Molecules in immune reaction -The immune response - Regulation of the immune processes ect.). 2-To correlate these studies with some practical experiments and their application of the Immunological methods. 3- To gain practical skills and knowledge required to perform laboratory experiments safely with appropriate equipment. 3  Course schedule Week/s Topic/s Week 1+2 Functional organization of the immune system --- Week 3 -Organs and cells of the immune system - Week 4 Molecules in immune reaction Week 5, 6 The immune response Week 7 First Term Exam Week Regulation of the immune processes 8,9,10 Week 10-12 The Immunological methods.. Week 13- Allergy and autoimmunity 14 4  Weighting of assessments 5  Immunology 412 Zoo By Zoology Department Staff New Valley University – Egypt 6  References Immunobiology - the immune system in health and disease, by Charles Janeway, Jr. and Paul Travers. Garland Publishing, Inc. Fifth edition, 2001. - Guyton and Hall Textbook of Medical Physiology: with STUDENT CONSULT Online Access, 12e (Guyton Physiology) by John E. Hall PhD. 7  Overview of the Immune system Guarding against disease Microbes: why they are formidable foes. Gross anatomy of the immune system Cells of the immune system how the immune system protects Immune recognition of pathogens: innate vs adaptive immunity Cytokines and the inflammatory response Allergy and Hypersensitivity 8  You wake up one morning with a stuffy nose, slight fever, and fatigue. Do you have a cold or the flu? Or are they the same? Should you go to your doctor for an antibiotic? Why or why not? The not-so-common cold A “cold” is an infection of the mucus membranes of the respiratory tract by a rhinovirus. Over 100 rhinoviruses have been identified, which is one reason why we don’t become immune to “the cold.” 9  Virus vs. Bacteria Colds and influenza are caused by viruses. Viruses are which is a non-living particle that contains genetic material, and hijacks your cells to reproduce. Viruses cannot be “killed” with antibiotics. Bacteria are living organisms that have a metabolism, have DNA, and can reproduce on their own. Bacteria can be killed with antibiotics because these substances target key processes in bacteria, such as production of the bacterial cell wall. 10  Most bacteria produce a cell wall that is composed partly of a macromolecule called peptidoglycan, itself made up of amino sugars and short peptides. Human cells do not make or need peptidoglycan. Penicillin, one of the first antibiotics to be used widely, prevents the final cross-linking step, or transpeptidation, in assembly of this macromolecule. The result is a very fragile cell wall that bursts, killing the bacterium. No harm comes to the human host because penicillin does not inhibit any biochemical process that goes on within us. 11 Body Defenses 12  Viruses and bacteria are everywhere. Some of them want to invade your body. How does your body defend itself against viruses and bacteria? 13 Defense Against Disease Nonspecific External Barriers skin, mucous membranes If these barriers are penetrated, the body responds with Innate Immune Response Phagocytic (Macrophages, Neutrophils, Monocytes) and natural killer cells (Lymphocytes), Complement System A group of >30 proteins found in the blood , inflammation, fever If the innate immune response is insufficient, the body responds with Adaptive Immune Response cell-mediated immunity, humoral immunity 14  First line of defense Non-specific defenses are designed to prevent infections by viruses and bacteria. These include: Intact skin Mucus and Cilia Phagocytes 15  Role of skin Dead skin cells are constantly sloughed off, making it hard for invading bacteria to colonize. Sweat and oils contain anti-microbial chemicals, including some antibiotics. 16  Role of mucus and cilia Mucus contains lysozymes, enzymes that destroy bacterial cell walls. The normal flow of mucus washes bacteria and viruses off of mucus membranes. Cilia in the respiratory tract move mucus out of the lungs to keep bacteria and viruses out. 17  Role of phagocytes Phagocytes are several types of white blood cells (including macrophages and neutrophils) that seek and destroy invaders. Some also destroy damaged body cells. Phagocytes are attracted by an inflammatory response of damaged cells. 18  Role of inflammation Inflammation is signaled by mast cells, which release histamine. Histamine causes fluids to collect around an injury to dilute toxins. This causes swelling. The temperature of the tissues may rise, which can kill temperature-sensitive microbes. mast cells A mast cell is a type of white blood cell. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a part of the immune system and contains many granules rich in histamine and heparin. The mast cell is very similar in both appearance and function to the basophil. 19  Role of fever Fever is a defense mechanism that can destroy many types of microbes. Fever also helps fight viral infections by increasing interferon production. While high fevers can be dangerous, some doctors recommend letting low fevers run their course without taking aspirin or ibuprofen. 20  Interferons (IFNs): are a group of signaling proteins made and released by host cells in response to the presence of several pathogens, such as viruses, bacteria, parasites, and also tumor cells. In a typical scenario, a virus- infected cell will release interferons causing nearby cells to heighten their anti-viral defenses. IFNs belong to the large class of proteins known as cytokines, Interferons are named for their ability to "interfere" with viral replication by protecting cells from virus infections. IFNs also have various other functions: they activate immune cells, such as natural killer cells and macrophages. 21 Ouch! 22  Why aren’t non-specific defenses enough? Why do we also need specific defenses? Specific defenses Specific defenses are those that give us immunity to certain diseases. In specific defenses, the immune system forms a chemical “memory” of the invading microbe. If the microbe is encountered again, the body reacts so quickly that few or no symptoms are felt 23  Immunity: Body defense against exogenous(microbes) and endogenous(tumor cells) agents. Pathogen: microbe that causes disease Antigen (Ag): material (from a pathogen) that induces an immune response Immunogen: material that induces an immune response (An immunogen refers to a molecule that is capable of eliciting an immune response by an organism’s immune system, whereas an antigen refers to a molecule that is capable of binding to the product of that immune response.) Innate (natural) immunity: rapid, non specific immune response Adaptive (acquired) immunity: slower, specific immune response Leukocytes: WBCs Lymphocytes: specialized blood cells that mediate adaptive immunity (e.g. T and B cells) 24 Reaction of the body against any foreign Ag. 25 Non specific Specific 26 27 by B- cells 28 29 Organs of the immune system The cells of the immune system are developed in the primary lymphoid organs (bone marrow & Thymus), and they interact with antigens in secondary lymphoid organs (lymph nodes, spleen, addendix, Peyer’s patch etc.). Lymph nodes: collect antigens from tissues Spleen: collects antigens from blood stream Lymphocytes arise in the stem cells in the bone marrow and then differentiate in the bone marrow (B cells) or thymus (T cells). 30 Naive lymphocytes: are immune cells that are mature, but have not yet been exposed to an antigen. These cells move freely through the immune system and play an important role in the development and maintenance of immunity. At any given time, the body continuously produces new cells. This can keep the supply steady and reduce the risk of gaps in immunity caused by depletion of immune cells as they respond to infections. 31 B cells, produced in the bone marrow, and T cells, matured in the thymus, can both circulate through the body in a naive state. When these cells encounter an unfamiliar epitope, (a specific protein on the surface of an antigen,) they can formulate a reaction to it. This allows the immune system to continuously learn to recognize new infectious agents and mount responses to them. Once naive lymphocytes have been exposed, they activate, and begin mediating immune responses. 32 T and B lymphocytes migrate via the peripheral blood to the peripheral/secondary lymphoid organs: lymph nodes, spleen, addendix, Peyer’s patch etc. Naive lymphocytes circulate between the blood and these organs until they encounter antigen. They become activated when they recognized an Ag in the secondary lymphoid organs. The afferent lymphatic vessels carry APC cells from infected tissues to the lymph nodes where they activate T cells Activated T cells (after they have undergone proliferation and differentiation) leave via the efferent lymphatic vessels The cells of the immune system circulate through the body via lymph and blood. Pathogens and their antigens are transported from tissues via lymphatic vessels to the lymph nodes where they encounter immune cells. 33  ‫الجهاز الليمفاوي‬ ‫الجهاز الليفاوي شبكة من األوعية الدقيقة التي تشبه األوعية الدموية‪.‬‬ ‫يقوم الجهاز الليمفاوي بإعادة السوائل من أنسجة الجسم إلى مجرى الدم‪.‬وهذه‬ ‫العملية ضرورية ألن ضغط السوائل في الجسم يجعل الماء والبروتينات‬ ‫وغيرها من المواد تتسرب باستمرار خارج األوعية الدموية الدقيقة المسماة‬ ‫بالشعيرات‪ ،‬ويقوم هذا السائل الراشح والمسمى السائل الخاللي بغمر أنسجة‬ ‫الجسم وتغذيتها‪.‬وإذا لم يجد السائل الخاللي الزائد طريقه إلى الدم فإن األنسجة‬ ‫تنتفخ وتتورم‪ ،‬ولذا فإن معظم السائل الزائد يرشح إلى داخل الشعيرات الدموية‬ ‫التي يكون ضغط السائل فيها منخفضاً‪ ،‬ويعود الباقي عن طريق الجهاز‬ ‫اللمفاوي‪ ،‬ويسمى اللمف‪.‬ويعد بعض العلماء الجهاز اللمفاوي جزءا ً من‬ ‫الجهاز الدوري‪ ،‬ألن اللمف يأتي من الدم ويعود إليه‪.‬‬ ‫‪34‬‬ ‫اللمف يشبه إلى حد كبير من حيث التركيب الكيميائى البالزما‪ ،‬وهو‬ ‫‪‬‬ ‫الجزء السائل في الدم‪.‬ولكنه ال يحتوي إال على حوالي نصف كمية‬ ‫البروتين الموجودة في البالزما‪ ،‬ألن جزئيات البروتين الكبيرة ال‬ ‫تستطيع أن تنفذ من جدران األوعية الدموية بنفس السهولة التي تنفذ‬ ‫بها بعض المواد األخرى‪.‬واللمف سائل شفاف ولونه مثل لون القش‪.‬‬ ‫العقد اللفماوية‪ :‬توجد في أماكن كثيرة على طول األوعية اللمفاوية‪.‬‬ ‫‪‬‬ ‫وهي تشبه نتوءات أو أوراماً يبلغ قطرها ‪ 35‬مليمترا‪ ،‬كما أنها تشبه‬ ‫العقد على خيوط األوعية اللمفاوية‪.‬وتتجمع هذه العقد في أماكن‬ ‫معينة خصوصاً في العنق واألبطين وفوق األربية وبقرب األعضاء‬ ‫المختلفة واألوعية الدموية الكبيرة‪.‬‬ ‫وتحتوي العقد اللمفاوية على خاليا ضخمة تسمى البالعم‪ ،‬تمتص‬ ‫‪‬‬ ‫المواد الضارة واألنسجة الميتة‪.‬‬ ‫‪35‬‬ 36  Cells of the immune system Blood cells lineages Most blood cells act o™ decnsead eem ie(knF LT iuQ ce to fight infection. W t )d Ze d F a rIT Q uickT are TIFF im needed (LZWe™ ) toand seeathis decom pressor picture. Dentritic cell (DC) Adaptive Innate immunity immunity 37  Dentritic cell (DC) Antigen (Ag) dT ie Ze L(kn ce F iuQ F rIT a Q T a uick IF re F neTeim (L Zed dW e™ da ) to n esdem co e ath pre isss pictu or re. Antigen presenting cells (APC) Lymphocytes of the adaptive immune system T helper cells: regulate other immune cells T cytotoxic (killer) cells: kill infected cells B cells: produce antibodies (immunoglobulin) DC : directly kill microbes by phagocytosis and other mechanisms. They also help to activate T cells (connection between innate and adaptive immunity) NK cells are lymphocytes that have characteristics of innate and adaptive immunity. 38  Cells of the Immune system (WBCs) 1- Granulocytes Neutrophils Eosinophils Basophils 2- Agranulocytes Lymphocytes B cells T cells (many types) NK cells Monocytes/Macrophages Dendritic cells 39  Divisions of leukocytes Granulocytes AGranulocytes Neutrophils (Mononuclear cells) Band cells (immature neutrophils) Lymphocytes (many Eosinophils types) Basophils Monocytes Dendritic cells 40 Neutrophils Granulocyte Phagocytes Short life span (hours) Very important at “clearing” bacterial infections Cytoplasmic granules 41 Eosinophils granulocyte A cell-killing cells Orange granules contain toxic compounds Important in parasitic infections 42 Basophils granulocyte A cell-killing cells Blue granules contain toxic and inflammatory compounds Important in allergic reactions 43 Lymphocytes Many types; important in both humoral and cell-mediated immunity B-cells produce antibodies T- cells Cytotoxic T cells Helper T cells Memory cells NK cells 44  Monocytes/Macrophage Monocyte is a young macrophage present in blood. There are tissue- specific macrophages produce cytokines (esp., IL1 & IL6) 45  Dendritic cells Found mainly in lymphoid tissue Function as antigen presenting cells (APC) These APC engulf and process antigens and present them on their surface to T-cells. Most potent stimulator of T-cell response ( very importnt in T-cell activation. Rememmber that: (DC are the only cells that originate from myeloid and lymphoid progenitor) 46 Mechanism of the Immune response 47 48 49  Alternaive pathway of complement Physiological barriers at the portal of entry (The Skin & Mucous Membranes)- antomic barriers 50 Mechanisms of Innate Immunity A. Epithelial Surfaces 1. Skin & mucous membrane - protect against invasion by microbes. Healthy skin - high salt conc. in sweat - sebaceous secretions Respiratory tract - nose architecture - cough reflex - mucosal secretions - phagocytes in alveoli - Intestinal mucosa - mucus 51 A. Epithelial Surfaces 2. Saliva - inhibits many micro-organisms. 3. Gastric acidity - destroys many microbes. 4. Conjunctiva - flushing action of lachrymal secretions. antibacterial substance - present in tissue fluid & all secretions except CSF, urine & sweat - also present in phagocytes 52 A. Epithelial Surfaces 5. Flushing action of urine 6. Acidic pH of adult vagina 7. Spermine (polyamine) & zinc in semen is antibacterial. B. Antibacterial substances in blood & tissues 1. Complement system - Alternative pathway of complement leads to opsonization of microbes (make a foreign cell more susceptible to phagocytosis) 2. Basic polypeptides – like leukins derived from leucocytes & platelets – interleukins: A bactericidal substance or substances produced by leukocytes 53 The complement system the complement system is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promotes inflammation, and attacks membrane. It is part of the innate immune system, It is now known that it consists of over 30 proteins , including serum proteins, serosal proteins, and cell membrane receptors. and contributes 3 g/L to overall serum protein quantities. Only IgG and IgM can activate complement 54 3. Lactic acid in muscle & inflammatory zone 4. Lactoperoxidase (family of enzymes in milk and mucosa), plays an important role in the innate immune system by killing bacteria in milk and mucosal secretion 5. Interferons – antiviral 55 Interferons (IFNs): are a group of signaling proteins made and released by host cells in response to the presence of several pathogens, such as viruses, bacteria, parasites, and also tumor cells. In a typical scenario, a virus- infected cell will release interferons causing nearby cells to heighten their anti-viral defenses. IFNs belong to the large class of proteins known as cytokines, Interferons are named for their ability to "interfere" with viral replication by protecting cells from virus infections. IFNs also have various other functions: they activate immune cells, such as natural killer cells and macrophages. 56 C. Microbial antagonism - resident flora on skin & mucosa prevent colonization by pathogens. - An example of microbial antagonism in the human body is the resistance of established mouth bacteria to new strains that can be introduced via mouth-to-mouth contact. After a kiss, for example, new bacteria are introduced into the hostile environment of a foreign mouth. Once there, the invasive bacteria's growth is inhibited by antimicrobial compounds secreted by the native flora, as well as by the tight competition for resources. 57 D. Cellular factors 1. Phagocytic cells are 2 types - polymorphonuclear (PMN) leukocytes - mononuclear phagocytes: in blood & tissues monocytes macrophages Chemotaxis - phagocytes are attracted to the site of infection by chemotactic factors. 58 Chemotaxis: a response involving movement that is positive (toward) or negative (away from) a chemical stimulus. the phagocytic activity of neutrophils and monocytes in response to chemical factors released by invading microorganisms. 59 is the movement of an organism in response to a chemical stimulus. This is important for bacteria to find food (e.g., glucose) by swimming toward the highest concentration of food molecules, or to flee from poisons (e.g., phenol). In multicellular organisms, chemotaxis is critical to early development (e.g., movement of sperm towards the egg during fertilization) and subsequent phases of development (e.g., migration of neurons or lymphocytes) as well as in normal function. In addition, it has been recognized that mechanisms that allow chemotaxis in animals can be subverte ‫ تُهدم‬during cancer metastasis. 60  Phagocytosis This process involves - recognition & binding - ingestion - digestion Requires opsonizs - molecules on the surface of certain bacteria which bind to the receptor on phagocytes – Opsonization (make a foreign cell more susceptible to phagocytosis). 61  Killing by granulocytes through phagocytosis Macrophages and neutrophils recognize pathogen by means of cell-surface receptors Example: mannose receptor, CD14 receptor, scavenger receptors, glucan receptor etc. Binding of macrophage (MØ) or neutrophils with pathogen leads to phagocytosis Bound pathogen is surrounded by phagocyte membrane Internalized (phagosome) Killing of pathogen (Phagolysosome) * Phagolysosome = lysosome + phagosome 62 Process of Phagocytosis 63  release of lysosomal contents phagolysosome Invagination fusion with lysosome phagosome formation 64 Lipid mediators are chemical messengers that are released in response to tissue injury. When a harmful invader, such as bacteria, enters the body, some lipid mediators are released to help stimulate cells involved in the immune response. CD cluster of differentiation, which indicates a defined subset of cellular surface receptors(epitopes) that identify cell type and stage of differentiation, and which are recognized by antibodies. There are more than 250 identified clusters, each a different molecule, coating the surface of B lymphocytes and T lymphocytes. CD14, is a human gene, acts as a co-receptor for the detection of bacterial lipopolysaccharide (LPS CD14 can bind LPS only in the presence of lipopolysaccharide-binding protein (LBP). 65  ‫عنقود تمايز أو كتلة تمايز ‪cluster of differentiation ) :‬‬ ‫هي طريقة اختبارية تجرى على خطوات بغرض التفرقة بين جزيئات كثيرة تظهر على أسطح‬ ‫الخاليا في الجسم ؛ وتستهدف تلك االختبارات معرفة ودراسة خاليا الجهاز المناعي‬ ‫‪،‬وغالبا تقوم بوظيفة مستقبل في خاليا جهاز المناعة أو تكون في شكل ربيطة (وهو جزيء ينشط‬ ‫مستقبل خلية مناعية ) ولها أهميتها بالنسبة للخلية‪.‬‬ ‫عادة تنشأ إشارات متبادلة بين الخاليا تغير من سلوكها ‪.‬الكثير من عناقيد التمايز يشترك في‬ ‫اإلشارات التي تتم بين الخاليا كما يكون لها دور كإنزيمات ؛ وبعض عناقيد التمايز من البروتين‬ ‫وليس لها دور في تبادل اإلشارات بين خاليا الجسم ولكن يكون لها تأثيرات آخرى مثل التصاق‬ ‫الخاليا‪.‬وقد اكتشف حتى اآلن ‪ 364‬من البروتينات المختلفة في اإلنسان (حتى عام‬ ‫‪)2014‬والتي توصف بأنها عناقيد تمايز ‪CD‬؛ وهي تكون على أسطح الخاليا‪(.‬اعتبارا من‬ ‫نوفمبر ‪]3[]2[.)2014‬‬ ‫وقد تعرفنا على مثالي كتلة التمايز ‪ 4‬و كتلة التمايز ‪ 8‬في وصفنا لـ خلية تي قاتلة ‪ ،‬وأنهما‬ ‫عظيمي الشأن في التعرف على مستضد يهدد سالمة جسم اإلنسان‪.‬ويقومان بتحفيز خلية تي‬ ‫القاتلة للقضاء على المستضد الدخيل‪.‬‬ ‫‪66‬‬  Cytokines Cytokines are soluble proteins that are produced in response to an antigen and function as chemical messengers for regulating the innate and adaptive immunity, they are a broad category of small proteins that are important in cell signaling. Their release has an effect on the behavior of cells around them. It can be said that cytokines are involved in autocrine signalling, paracrine signallingand endocrine signalling as immunomodulating agents. Their definite distinction from hormones is still part of ongoing research. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors but generally not hormones or growth factors (despite some overlap in the terminology). Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells (connective tissue cells of any organ); a given cytokine may be produced by more than one type of cell 67  Innate immune system Macrophages and Dendritic cells produce: Tumor necrosis factor-alpha (TNF-) Interleukin-1 (IL-1) Interleukin-12 (IL-12) Adaptive immune system T-lymphocytes produce: Interleukin-2 (IL-2) Interleukin-4 (IL-4) 68  D. Cellular factors 2. Natural killer cells: Class of lymphocytes important in non- specific defense against viral infections & tumor cells. Activated by interferons & selectively kills viral infected cells & tumor cells. Phagocytic cells are two types: 1- polymorphonuclear cells (PMN) leukocytes (neutrophil- basophile- esoinophil). 2- mononuclear phagocyte: in blood (monocyte) in tissue (macrophages). Phagocytosis process: is an important link between innate and adaptive immunity. 69  Cell killing – NK cells NK cells do not require prior immunization or activation They attach to ‘target’ cells Produce cytotoxic proteins (perforin & Granzymes ) onto the surface of tumor or viral infected cells. Effector proteins penetrate cell membrane and induce programmed cell death (Apoptosis) Necrosis: sudden cell death 70 71 72 73 Apoptosis: Cellular Suicide Remnants Nuclear fragmentation undergo Proteolysis phagocytosis Blebbing- ‫تكوين فقاعات‬ Death 74 Cell death by necrosis is more likely to produce inflammation. 75  D. Cellular factors 2. Eosinophils: Number increases during parasitic infections & allergic conditions. Not efficient phagocytes but their granules contain molecules that are toxic to parasites. E. Temperature - Many micro- organisms are temperature dependent e.g. tubercle bacilli, pathogenic to mammals, do not infect cold-blooded animals. - destroys infecting pathogen : e.g. fever induction used to destroy Treponema pallidum before penicillin became available for treatment. 76  F. Inflammation “Inflame” – to set fire.  Inflammation is “A dynamic response of vascularized tissue to injury.”  It is a protective response.  It serves to bring defense & healing mechanisms to the site of injury. A type of non specific defense mechanism. Tissue injury or irritation caused by the entry of pathogens or other irritants lead to inflammation. Events: that occur are – vasoconstriction followed by vasodilatation - Increased vascular permeability, stasis, hyperemia, accumulation of leukocytes, exudation of fluid, and deposition of fibrin. Changes are brought about by chemical mediators like histamine. Signs : redness, heat, swelling, pain and lose of function. 77  Cardinal Signs of Inflammation  Redness : Hyperaemia (increase of blood flow to different tissues).  Warm : Hyperaemia  Pain : Nerve, Chemical mediators.  Swelling : Exudation (escape of fluid, cells, and cellular debris from blood vessels and their deposition in tissues)  Loss of Function 78 79 Process of Inflammation 80  Innate vs. adaptive immunity Innate immunity First line of defense (present in all individuals at all times) Immediate (0 – 4 hours) Non-specific Does not generate lasting protective immunity Adaptive immune response (late: > 96 hours) Is initiated if innate immune response is not adequate (> 4 days) Antigen-specific immunity Generates lasting protective immunity (e.g. Antibodies, memory T-cells) 81 82 83 84 85  Bone marrow The bone marrow is the site of generation of all circulating blood cells in the adult, including immature lymphocytes. The site of generation of all immune cells. The site of differentiation and maturation of all immune cells except T cells. 86 87 88 89 90  Cells in thymus 1-thymus stromal cells(TSC): Thymus epithelial cells(TEC) Fibrocytes, macrophages, dendritic cells (DC) 2- thymocytes: the cells migrate from the bone marrow (lymphocytes) to the thymus and then become thymocytes. 91 Secodary lymphoid organs (SLO) The site where lymphocytes locate. Site for antigen recognition. Produce specific antibody and sensitized T lymphocytes. 92 93  1- Lymph node (LN) LY are the organs in which the adaptive immune responses to lymph- borne antigens are initiated Rememmber: LY collecting antigens from tissues 94  2- spleen It is the major site of immune responses to blood- borne antigens. Remember: spleen collect antigens from blood streams. 95 96 97 98 SALT (skin associated lymphoid tissue) The skin contains a specialized coetaneous immune system consisting of lymphocytes and APCs (such as Langerhans cell) Langerhanʼs cell : is a type of dendritic cells but it homing in the skin and called Langerhans cell. Remmber: skin is the first line of defense 99  MALT(Mucosal associated lymphoid tissue) The mucosal surface of the gastrointestinal and respiratory tracts, like the skin, are colonized by lymphocytes and PACs that initiate immune response to ingested and inhaled antigens. Functions of MALT and SALT: The first line of defense against any foreign antigens. The site of immune response Participate in delayed hypersensitivity. 100  cellular components of the coetaneous immune system Epidermis: 1- epidermal Langerhanʼs cell (type of dendritic cells) 2- intraepidermal lymphocytes (tpye of T lymphocytes) Dermis: 1- T lymphocytes 2- perivascular lymphocytes 3- macrophages Remember that monocytes are the precursors of macrophages 101 102 103 Adaptive, Acquired, Specific immunity Acquired Immunity Passive Active Cell mediated immunity Humoral Immunity By T cell activation By B cell activation & production of Abs 104  Adaptive immune system Initiated by ingestion of pathogen. Antigen-presenting cell (APC) Dendritic cells, macrophages, B cells and neutrophil. (APC) Migrate through lymph to the regional lymph nodes (secondary lymphoid organ). (APC ) Interact with naive T lymphocytes (present antigen to activate T cells) Proliferation and Differentiation (activated T cells proliferated and differentiated into short lived- effectors T cells and long lived- memory T cells) 105  Response to invasion When the body is invaded or attacked by bacteria, viruses, or other pathogens, it has three means of defending itself: 1. The phagocytic immune response 2. The humoral or antibody immune response 3. The cellular immune response Phagocyte immune response. - The first line of defense. - Involves the WBCs (granulocytes and macrophages), which have the ability to ingest foreign particles. - Phagocytes also remove the body’s own dying or dead cells. 106  Humoral and cellular immune response A second response, the humoral immune response (sometimes called the antibody response), begins with the B lymphocytes, which can transform themselves into plasma cells that manufacture antibodies. The third mechanism of defense, the cellular immune response, also involves the T lymphocytes, which can turn into special cytotoxic (or Killer) T cells that can attack the pathogens themselves. 107 108 Comparison of Active & Passive Immunity Active immunity Passive immunity Produced actively by host’s Received passively, no active immune system host participation Induced by infection or by Readymade antibody transferred immunogen Durable effective protection Transient, less effective Immunity effective only after Immediate immunity long period Immunological memory present No memory Booster effective Not effective Not applicable in the Applicable in the immunodeficient immunodeficient 109  Active immunity Natural active immunity (produces memory cells); Production of one's own antibodies or T cells as a results from an infection or natural exposure to antigen. Artificial active immunity (produces memory cells); Production of one's own antibodies or T cells as a results of vaccination. Vaccine are preparations of live or killed micro- organisms. 110 Passive immunity Natural passive immunity – temporary ( through placenta or milk) fetus acquired antibodies from mother. Artificial passive immunity – temporary As a result of snakebites, rabiesًً‫ داءًالكلب‬or tetanus resistance passively transferred by the administration of readymade antibodies (injection of serum). 111  Lymphocytes (effector cells of the adaptive immune system) Humoral immune response 1. Before exposure to a specific antigen, the clones of B lymphocytes remain dormant in the lymphoid tissue. 2. On entry of a foreign antigen, macrophages in the lymphoid tissue phagocytize the antigen and then present it to adjacent B lymphocytes. 3. In addition, the antigen is presented to T cells at the same time, and activated helper T cells are formed. 4. Those B lymphocytes specific for the antigen immediately enlarge and take on the appearance of lymphoblasts. T and B cells have 2 distinct recognition systems for detecting pathogens T cells - recognize intracellular pathogens (T cell receptors, TCR) B cells – recognize extracellular pathogens (immunoglobins, BCR) 112 113  Humoral Immunity It is the production of proteins called “immunoglobulin's” or “antibodies”.. Memory (long-lived cells). 114 115  WHAT ARE ANTIBODIES? Antigen specific proteins produced by plasma cells Belong to immunoglobulin (Ig) superfamily Located in blood and extravascular tissues, secretions and excretions Bind pathogenic microorganism and their toxins in extracellular compartments 116 117 Humoral Immunity B Cell Receptors for Antigens Antigen- Antigen- binding binding site site Disulfide bridge Light Variable chain regions Constant C C regions Transmembrane region Plasma membrane Heavy chains B cell Cytoplasm of B cell (a) A B cell receptor consists of two identical heavy chains and two identical light chains linked by several disulfide bridges. 118  Structural configuration of Antibody Chains: Light (L) Heavy (H) Domains: Variable (V) Single V domain in H Constant (C) Single C domain in L chains Three to four (C) domains in H chains 119  CLASSES (ISOTYPES) OF IMMUNOGLOBULINS Classes based on constant region of heavy chains Immunoglobulin A (IgA) alpha heavy chains Immunoglobulin D (IgD) Delta heavy chains Immunoglobulin E (IgE) Epsilon heavy chains Immunoglobulin G (IgG) Gamma heavy chains Immunoglobulin M (IgM) Mu heavy chains 120 Different classes of Antibodies 121  Immunoglobulin Classes IgG  Structure: Monomer  Percentage serum antibodies: 80%  Location: Blood, lymph, intestine  Half-life in serum: 23 days  Placental Transfer: Yes (the only Ig)  Known Functions:  Enhances phagocytosis, neutralizes toxins and viruses, protects fetus and newborn. 122  Immunoglobulin Classes IgM  Structure: Pentamer  Percentage serum antibodies: 5-10%  Location: Blood, lymph, (intravascular serum).  Half-life in serum: 5 days  Placental Transfer: No  Known Functions: First antibodies produced during an infection. Effective against microbes and agglutinating antigens. Activate the complement system 123  Immunoglobulin Classes IgA  Structure: Dimer  Percentage serum antibodies: 10-15%  Location: Secretions (tears, saliva, milk, pulmonary, gastroinsetinal, prostatic and vaginal), blood and lymph.  Half-life in serum: 6 days  Placental Transfer: No  Known Functions: Localized protection of mucosal surfaces. Provides immunity to infant digestive tract. Protection against respiratory, gastrointestinal, urinogenital infection.  Prevents absorption from antigens from foods.  Passes to neonate in breast milk for protection. 124  Immunoglobulin Classes IgD  Structure: Monomer  Percentage serum antibodies: 0.2%  Location: B-cell surface, blood, and lymph  Half-life in serum: 3 days  Placental Transfer: No  Known Functions: In serum function is unknown. On B cell surface, initiate immune response, in serum appears in small amount, possibly influnce B-lymphocytes differentiation but role are unclear. 125  Immunoglobulin Classes IgE  Structure: Monomer  Percentage serum antibodies: 0.002%  Location: Bound to mast cells and basophils throughout body. Blood.  Half-life in serum: 2 days  Placental Transfer: No  Known Functions: Allergic reactions. Possibly lysis of worms (combats parasitic infecions). 126  Cell mediated immunity: Antigen recognition by T-cells Cytotoxic T cells TH1 cells recognize TH2 cells recognize recognize antigen antigen presented by antigen presented by presented by MHC I MHC II and activates MHC II and activates and kills the cell macrophages B cells Kills Activates Activates MHC I MHC MHC II Cytotoxic Virus- TH2 B cell T cell II infected cell TH1 Macrophage Dead intracellular bacteria Anti-toxin antibodies Apoptotic cell 127  Antigen presenting cells (APC) B cell Dendritic cell Lymph node Macrophages Lymph node Lymph node Antigen-presenting cells are distributed differentially in the lymph node An antigen-presenting cell (APC) or accessory cell is a cell that displays foreign Ag complexe with major histocompatibility complexes (MHC) on their surfaces. T cells may recognize these complexes using their T cell receptor (TCR). These APC engulf and process antigens and present them on their surface to T-cells. 128 129 130 131 132 133 134 135 136 137 138 139 Allergy & Hypersensitivity 140  Allergy  Type of hypersensitivity reactions of the immune system. Allergy may involve more than one type of reaction.  An allergy is an immune reaction to something that does not affect most other people. Allergen are substances that often cause allergic reactions are:  Pollen  Dust mites  Mold spores  Pet dander (animal hairs)  Food  Insect stings, venoms  drugs 141  Allergy Risk factor  Host factors; heredity, gender, race, and age.  Environmental factor; infectious diseases during early childhood, environmental pollution, allergen levels and dietary changes. 142  Hypersensitivity  Hypersensitivity (hypersensitivity reaction) refers to undesirable immune reactions produced by the normal immune system.  Hypersensitivity reactions require a pre-sensitized (immune) state of the host.  Hypersensitivity reactions: four types; based on the mechanisms involved and time taken for the reaction, a particular clinical condition (disease) may involve more than one type of reaction. 143 Classification of Immunologic Reactions (Gell and Coombs) 144 Hypersensitivity Reactions 145  Allergy Ig E mediated (Type I hypersensitivity) Allergy Non Ig E mediated 146  IgE Mediated Type I allergy Overreaction to an allergen that is contact through skin, inhaled through lung, swallowed or injected.  Triggeredً‫ تثار‬by harmless substances such as; pollen, dust, animal dander, food, drug or bee stings or stings from other insects (an allergen).  An allergen; an antigen that causes allergy. Either inhaled, ingested,.. Can be complete protein antigens (Pollen and animal dander) or low molecular weight proteins. 147  Atopy  Atopy is the genetic predispositionً‫ إستعداد‬to make IgE antibodies in response to allergen exposure.  Atopy (atopic syndrome) is a syndrome characterized by a tendency to be “hyperallergic”. A person with atopy typically presents with one or more of the following : eczema(atopic dermatitis), allergic rhinitis (hay fever), or allergic asthma.  Etiology is unknown but there is strong evidence for a complex of genes with a variable degree of expression encoding protein factors.  Allergic rhinitis, allergic athma, atopic dermatitis are the most common manifestation of atopy. These manifestation may coexist in the same patients at different times.  the term "atopy" used for a genetically mediated predisposition to an excessive IgE reaction.  Atopic: denoting a form of allergy in which a hypersensitivity reaction such as dermatitis or asthma may occur in a part of the body not in contact with the allergen. 148 Mechanism of IgE Mediated Type I allergy While first-time exposure may only produce a mild reaction, repeated exposures may lead to more serious reactions. Once a person is sensitized (has had a previous sensitivity reaction), even a very limited exposure to a very small amount of allergen can trigger a severe reaction. Most occur within seconds or minutes after exposure to the allergen, but some can occur after several hours, particularly if the allergen causes a reaction after it is partially digested. In very rare cases, reactions develop after 24 hours. 149  Immunopathogenesis Both mast cells and basophils are involved in immunopathogenesis of IgE mediated diseases. Mast cells and basophils have a high affinity IgE cell membrane receptors for IgE.  Immediate hypersensitivity reactions are mediated by IgE, but T and B cells play important roles in the development of these antibodies 150 Allergen (antigen) 2 APC presents antigenic determinant to TH2 cell TH2 cell 3 IL-4 from TH2 cell 1 Antigen-presenting stimulates B cell cell (APC) IL-4 phagocytizes and processes antigen B cell 4 B cell becomes plasma cell, which secretes IgE Plasma cell IgE 5 IgE binds to mast cells, basophils, and eosinophils IgE Mast cell Basophil Eosinophil 151  Mast cells  Mast cell are abundant in the mucosa of the respiratory, gastrointestinal tracts and in the skin, where atopic reaction localize.  Mast cell release mediator cause the pathophysiology of the immediate and late phases of atopic diseases. 152 Mast Cell Activation 153  Mast cells Mast cell Hours Minutes Classic Allergic Reaction Flushing Late –phase Reaction Hypotension Eosinophil infiltration Increased mucus production Neutrophil infiltration Pruritus Fibrin deposition Smooth muscle contraction Mononuclear infiltration Vascular leakage Tissue destruction 154  Mast cells Performed Mediators/ Primary Mediators Histamine: is one well-known mediator. This mediator acts on histamine 1(H1) and histamine 2 (H2) receptors to cause: contraction of smooth muscles of the airway and GI tract, increased vascular permeability and vasodilation, nasal mucus production, airway mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion. Serotonin: increased vascular permeability and contraction of smooth Muscles. Tryptase: is a major protease released by mast cells; its exact role is uncertain. Tryptase is found in all human mast cells. few other cells and thus is a good marker of mast cell activation. 155  Non IgE Mediated Allergy Hypersensitivity pneumonitis involves inhalation of an antigen. This leads to an exaggerated ‫مبالغ‬ ‫ فيها‬immune response (hypersensitivity). Type III hypersensitivity and type IV hypersensitivity occur in hypersensitivity pneumonitis. 156  Prevention  Avoid triggers such as foods and medications,…… that have caused an allergic reaction, even a mild one. This includes detailed questioning about ingredients when eating away from home. Ingredient labels should also be carefully examined.  A medical ID tag should be worn by people who know that they have serious allergic reaction.  If any history of a serious allergic reactions, carry emergency medications (such as diphenihydramine and injectable epinephrine.  Do not use your injectable epinephrine on anyone else. They may have a condition (such as a heart problem) that could be affected by this drug. 157  Where does antigen processing take place? Add Listeria T Listeria specific T cells M M M M T CELLS BIND Listeria Incubate with CHLOROQUINE M M M M NO T CELLS BIND Chloroquine inhibits lysosomal function (a lysosomotrophic drug) Antigen processing involves the lysosomal system 158 Ag presentation to T cells 159  The T cell antigen receptor (TCR) Antigen Resembles an Ig Fab fragment combining site Fab Fc Domain structure: Ig gene superfamily Carbohydrates Monovalent No alternative constant regions Hinge Never secreted Heterodimeric, chains are disuphide- + bonded + + Very short intracytoplasmic tail Positively charged amino acids in the TM region Cytoplasmic tail Transmembrane region Antigen combining site made of juxtaposed V and Vb regions 160  T cell co-receptor (TCR) molecules TCR TCR Ag CD8 CD4 b  MHC Class I MHC Class II CD4 and CD8 can increase the sensitivity of T cells to peptide antigen MHC complexes by ~100 fold 161  Th1 and Th2 response To Th1 Th2 IFN- IL-4 IL-10 IL-2 IL-5 NK IL-6 TNF- MØ IL-13 IL-8 B cell Tc PMN 162  Production of antibodies Pathogen (virus or Pathogen is bacteria) internalized and degraded B cell B cell binds pathogen Plasma cells MHC II TH1 B cell B cells differentiate into Peptides from the pathogen are B cell proliferation antibody-secreting plasma presented (MHC II) to the T cell cells resulting in the activation of the B cell Produce antibodies against pathogen 163  Th1 and Th2 response To Th1 Th2 IFN- IL-4 IL-10 IL-2 IL-5 NK IL-6 TNF- MØ IL-13 IL-8 B cell Tc PMN 164  Antigen recognition by T-cells Cytotoxic T cells TH1 cells recognize TH2 cells recognize recognize antigen antigen presented by antigen presented by presented by MHC I MHC II and activates MHC II and activates and kills the cell macrophages B cells Kills Activates Activates MHC I MHC MHC II Cytotoxic Virus- TH2 B cell T cell II infected cell TH1 Macrophage Dead intracellular bacteria Anti-toxin antibodies Apoptotic cell 165 TCR and BCR (B cell Receptor) 166  Mechanism of Humoral immunity Antibodies can participate in host defenses in 3 main ways: Neutralization Ab bind and neutralize bacterial toxins, bacteria and virus particles – preventing interaction with host cells Ingestion by macrophages Opsonization Allows recognition by phagocytes or NK cells (antibody-dependent cell mediated cytotoxicity Ingestion or killing Complement activation Activation of complement system Ingestion by phagocytes 167  Antibody (Immunoglubulin, Ig) enhances phagocytosis Membrane Ig receptor mediated uptake Y Phagocytosis Complement receptor mediated phagocytosis Pinocytosis Y Fc receptor mediated phagocytosis Uptake mechanisms direct antigen into intracellular vesicles for exogenous antigen processing 168  B cells act as APC 1. Capture by antigen specific Ig maximises B uptake of a single antigen 2. Binding and internalisation via Ig induces expression of CD40 B 3. Antigen enters exogenous antigen processing pathway 4. Peptide fragments of antigen are loaded onto MHC molecules intracellularly. MHC/peptide complexes are expressed at the cell surface 169  T cell help to B cells Signal 2 - T cell help B Th Th Y 1. T cell antigen receptor Signal 1 2. Co-receptor (CD4) antigen & antigen receptor 3.CD40 Ligand MHC class II 170 Clonal Selection Only one type of antibody—and one type of B cell— responds to the antigenic determinant That cell type then produces a large number of clones 171 Benefits of Immunological Memory Primary Latent period Gradual rise in Ab production taking days to weeks Secondary Second exposure to same Ag. Memory cells are a beautiful thing. Recognition of Ag is immediate. Results in immediate production of protective antibody, mainly IgG but may see some IgM 172 173  Mast cells Performed Mediators/ Secondary Mediators Platelet activating factor Leukotriens Prostaglandinin Bardykainin Cytokines IL1 ,TNF IL2,IL3,IL4,IL5,L6 174 Food Hypersensitivity 175  Autoimmunity  Autoimmunity, is the presence of self-reactive immune response (e.g., auto-antibodies, self-reactive T-cells), with or without damage or pathology resulting from it. - Immune system has evolved to discriminate between self and non-self or discriminate between safe and dangerous signals Ability developed during fetal life, during the ontogeny of the immune system. Termed tolerance, a form of censorship of the immune system. Majority of T cells that are processed through the thymus do not survive. Self reactive T cells are destroyed. 176  When an Ab is produced for the first time, the variable region may be seen as foreign by the host. The host may then produce antibodies against it. Defects in natural killer cells, in the secretion of ILs, in phagocytosis and complements may also contribute. Hormones especially estrogen have been found to enhance B-cell activation and suppress regulator activities of T cell Environmental conditions such as infectious agents like viruses, bacteria and drugs contribute to autoimmunity 177  5 % to 7% adult affected. Two third women. More than 40 human diseases autoimmune in origin. AUTOIMMUNITY & LEFT-HANDEDNESS LEFT handed individuals more affected. 11% of left handed & 4% of right handed. Reasons for this are obscure. left-handedness & immune malfunction may both result from abnormal endocrine function in fetal life. 178 179  Effects of autoimmunity 1) Tissue destruction Diabetes: CTLs destroy insulin-producing b-cells in pancreas 2) Antibodies block normal function 3) Antibodies stimulate inappropriate function Graves’ disease: Ab binds TSH receptor Mimics thyroid-stimulating hormone Activates unregulated thyroid hormone production 4) Antigen-antibody complexes affect function Rheumatoid arthritis: IgM-IgG complexes deposited in joints inflammation 180 181 182  Treatment for autoimmunity Immunosuppression (e.g., prednisone, cyclosporin A) Removal of thymus (some MG patients) Plasmapheresis (remove Ab-Ag complexes) T-cell vaccination (activate suppressing T cells??) Block MHC with similar peptide anti-CD4 monoclonal Ab anti-IL2R monoclonal Ab 183