IMMUNITY INTRODUCTION.ppt
- 1. IMMUNITY Introduction to the immune system
- 2. Immunity • Immunity is body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells
- 3. History: what imparts Immunity? • Emil von Behring and Kitasato (1890) – Serum from vaccinated animals was protective (diptheria) • Metchinkoff (1880) – Cell based Immunity • Merrill Chase (1940)- Transfer of WBC (immunity to tuberculosis) Both serum and cells contribute to immunity
- 4. Immunology- nobel prizes • Since 1901 there have been 19 Nobel Prizes for immunology-related research.
- 5. The immune system A functional system – NOT an organ system: Complex system – includes • Skin – physical barrier • Lining of mucus membranes – physical barrier • Secretions – tears, mucus etc - antimicrobial • Blood cells and vasculature – WBCs • Bone marrow • Liver – makes complement proteins • Lymphatic system and lymphoid organs • Most tissues – have resident immune cells
- 6. Immunity • Immunity (immunis- Latin-exempt, state of protection from infectious diseases) • Immunity is body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells • consists of following activities: – Defense against invading pathogens (viruses & bacteria) – Removal of 'worn-out' cells (e.g., old RBCs) & tissue debris (e.g., from injury or disease) – Identification & destruction of abnormal or mutant cells (primary defense against cancer) – Rejection of 'foreign' cells (e.g., organ transplant) – Inappropriate responses: • Allergies - response to normally harmless substances • Autoimmune diseases
- 8. Overview of the Immune System Immune System Innate (Nonspecific) 1o line of defense Adaptive (Specific) 2o line of defense Interactions between the two systems
- 9. A typical immune response INNATE IMMUNITY Rapid responses to a broad range of microbes ACQUIRED IMMUNITY Slower responses to specific microbes External defenses Internal defenses Skin Mucous membranes Secretions Phagocytic cells Antimicrobial proteins Inflammatory response Natural killer cells Humoral response (antibodies) Cell-mediated response (cytotoxic lymphocytes) Invading microbes (pathogens) Complement
- 10. Innate immunity vs Adaptive Immunity No memory • No time lag • Not antigen specific • A lag period • Antigen specific • Development of memory Innate Immunity (first line of defense) Adaptive Immunity (second line of defense)
- 11. The innate immune System Innate Immune System External defenses Internal defenses Interactions between the two systems
- 12. Innate immune system External defenses
- 13. Anatomical Barriers - Mechanical Factors • Skin • Flushing action of saliva, tears, urine • Mucociliary escalator
- 14. Anatomical Barriers – Chemical factors Antimicrobial Peptides in sweat Lysozyme in tears /saliva HCl in stomach
- 15. Anatomical Barriers – Biological factors Normal flora – microbes in many parts of the body Normal flora – competes with pathogens for nutrients and space Normal flora – > 1000 species of bacteria
- 16. Innate immune system internal defenses
- 17. Innate immune system: components of Blood Complement proteins Coagulation proteins Cytokines WBCs Extracellular
- 18. White blood cells (WBCs) Macrophages B-lymphocytes T-lymphocytes Natural killer(NK) cells Mast cells
- 19. Neutrophils in innate immune response • First responders • Most abundant WBCs (~50-60%) • Efficient phagocytes • Most important cells of the innate immune system
- 20. Phagocytosis • Phago = to eat • Cyte = cell • WBCs (eg. Neutrophils) – find, eat and digest microbes !
- 21. How do neutrophils eat and digest microbes ? Granules
- 22. What’s in the granules ? Lysozyme – digests bacterial cell wall; other antimicrobial proteins
- 23. Additional role of neutrophils Triggers inflammatory response
- 24. Monocytes • Monocytes (~5% of WBCs) • Migrate into the tissues and become Macrophages Lung Bone Liver Brain intestine
- 25. Macrophages • “Big eaters”-clean up the dead cells. • Phagocytosis of microbes in tissue (neutrophils are present only in blood) • Antigen presentation
- 26. Natural killer cells • Not B-lymphocytes / T- lymphocytes • Important part of the innate immune system • Kill virus /bacteria infected cells (Intracellular pathogens) • Kills cancer cells
- 27. NK cells differentiate choose cells to kill ? Uninfected cell / Normal cell Microbe infected cell / cancer cell Some cell surface proteins are missing
- 28. How does the killer kill ? Kills both host cells and microbes Release of granules with perforins and proteases
- 29. Toll-like receptors (TLRs) • Transmembrane proteins • Present on macrophages / few other cells • Conserved across vertebrates • Important part of innate immune system
- 30. TLRs – What do they do ? They look out for microbes (or their components) They bind to the microbes (or their components) They trigger a cascade of events to kill or protect against pathogens THEY ARE INNATE IMMUNE SENSORS
- 31. TLRs – look out for microbes
- 32. TLRs – bind to microbes / components of microbes
- 33. Which microbial components are recognized by TLRs ?
- 34. What happens when a TLR bind to a microbe ? TLR binding to microbe Inflammation Secretion of Cytokines / Interferon Phagocytosis of infected cell Apoptosis of infected cell
- 35. Summary: innate response – internal defenses – Cellular (WBCs) Come into play when the external defenses are breached • Neutrophils • Monocytes /macrophages • NK cells • TLRs
- 36. Innate immune system: components of Blood Complement proteins Coagulation proteins Cytokines WBCs
- 37. Cytokines • Small proteins – secreted by cells of the immune system • Affect the behaviour of other cells • signalling molecules • Key players in innate and acquired immunity
- 38. Which cells release cytokines ? Cells of the immune system: • Neutrophils – when they encounter a pathogen • Macrophages – when they encounter a pathogen • TLRs – bind to microbe / components of a microbe • NK cells – on encountering a microbe infected cell /tumour cell • Lymphocytes – when they are activated
- 39. Examples of cytokines • Interferons • Interleukins • Tumour necrosis factor (TNF)
- 40. Interferons (IFN) • Signalling proteins produced by by virus infected monocytes and lymphocytes • Secreted proteins – Key anti-viral proteins • “Interfere” with virus replication • Warn the neighbouring cells that a virus is around... • If we did not have IFNs – most of us may die of influenza virus infection
- 41. 41 How does IFN warn the neighbouring cells ?
- 42. 42 The infected cells release IFN antiviral state antiviral state antiviral state antiviral state
- 43. 43 Virus infects the neighbouring cells antiviral state antiviral state antiviral state antiviral state
- 44. 44 Prewarned cells are able to quickly inhibit the virus antiviral state antiviral state antiviral state antiviral state
- 45. How do interferons inhibit viruses ? Host protein Induction Cascade of events Virus ds-RNA Activation Inactive host protein Active host protein Inhibition of host protein synthesis Virus cannot replicate
- 46. Interleukins • Interleukins – 1-37 • Not stored inside cells • Quickly synthesized and secreted in response to infection • Key modulators of behaviour of immune cells • Mostly secreted by T-lymphocytes & macrophages
- 47. What to interleukins do ? Interleukins Proliferation of immune cells Activation of immune cells Increase antibody production Inflammation
- 48. Tumour necrosis factor (TNF) TNF Killing of cancer Fever Inflammation
- 49. Complement (C`) • a large number of distinct plasma proteins that react with one another (C1 to C9) • Complement can bind to microbes and coat the microbes • Essential part of innate immune response • Enhances adaptive immune resposne (taught later)
- 50. Complement proteins: role in innate immune system C`protein s Inflammation Facilitates phagocytosis Direct lysis of pathogens
- 51. How do C` proteins facilitate phagocystosis ? Bacteria coated with C` Neutrophils have C` receptors Initiation of phagocytosis
- 52. How do C` proteins lyse pathogens? Membrane attack complex formed by c` proteins
- 53. Coagulation proteins • Coagulation: mechanism to stop bleeding after injury to blood vessels Complex pathway involves • Platelets • Coagulation factors • Vitamin K
- 54. How does blood clot ?
- 55. Coagulation: Delicate balance Coagulation proteins Anticoagulants Blood clotting Inflammation Apoptosis (prog. Cell death) Prevent blood clotting Inhibit inflammation Inhibit apoptosis Too much of clotting – Problem Too little clotting - Problem Maintenance of a balance
- 56. Coagulation and innate immunity Coagulation proteins Anticoagulants Pathogens and cytokines Increased inflammation and increased apoptosis of infected cells
- 57. Summary: what happens when external defenses fail ? INNATE IMMUNITY Rapid responses to a broad range of microbes ACQUIRED IMMUNITY Slower responses to specific microbes External defenses Internal defenses Skin Mucous membranes Secretions Phagocytic cells Antimicrobial proteins Inflammatory response Natural killer cells Humoral response (antibodies) Cell-mediated response (cytotoxic lymphocytes) Invading microbes (pathogens) Complement
- 58. Summary: innate response – internal defenses Cellular • Neutrophils • Monocytes /macrophages • NK cells • TLRs Extracellular • Cytokines • Complement • Coagulation
- 59. Inflammation
- 60. Inflammation • Complex biological process by which body responds to pathogens and irritants • Associated with swelling of tissue • Key player in innate immune repsone
- 61. All roads lead to inflammation Inflammation Neutrophils Monocytes /macrophages NK cells TLRs Cytokines /IFN C` proteins Coagulation proteins Cellular Extracellular
- 62. Inflammation and vascular changes • Vasodilatation • Increased capillary permeability Normal blood vessel Dilated blood vessel Normal blood vessel Leaky blood vessel
- 63. Signs of inflammation Vascular changes Vasodilatation Capillary permeability Heat / redness Temporary loss of function Fever Swelling Pain
- 65. Inflammation and innate immunity Mast cells – similar to basophils in blood; mast cells are present in tissues and release histamines in response to wound / infection /irritant Histamine Pathogen removal Adaptive immune response + + +
- 66. Summary: role of Inflammation in innate immunity • Initiation of phagocytosis – killing of pathogen • Limiting the spread of infection • Stimulate adaptive immune response • Initiate tissue repair
- 67. Not everything about Inflammation is good
- 68. The good and bad about inflammation Acute /short-term -Good chronic /long-term - Bad
- 69. Chronic inflammation = tissue damage • Chronic inflammation - macrophages in the injured tissue. • Macrophages release toxins (including reactive oxygen species or ROS) that injure tissues • chronic inflammation is almost always accompanied by tissue destruction. Normal tissue Tissue : chronic inflammation
- 70. Chronic inflammation and tissue damage Reduced tissue function Tissue damage Chronic inflammation Activation of immune cells Killing of host cells
- 72. Acquired Immunity • Acquired immunity is defined as the resistance against the infecting foreign substance that an individual acquires or adapts during the course of his life. Types of acquired immunity: Acquired immunity can be classified in two ways: • Active and passive immunity • Artificial and natural immunity
- 73. Active Immunity Active immunity is the resistance developed by an individual toward an antigenic stimulus. Here, the host's immune system is actively involved in response to the antigenic stimulus; leading to the production of immunologically active T cells, B cells and production of specific antibodies. • Active immunity maybe induced naturally or artificially. Natural active immunity occurs following an exposure to a microbial infection (e.g. measles virus infection) Artificial active immunity develops following an exposure to an immunogen by vaccination (e.g. measles vaccine).
- 74. Long-lasting: Active immunity usually Iasts for longer periods, but the duration varies depending on the type of pathogen. It may last life long, e.g. following certain viral infections such as chickenpox, measles, smallpox, mumps and rubella. It may last short, e.g. following influenza virus infection. It may last for as long as the microbe is present. Once the disease is cured, the patient becomes susceptible to the microbe again. This is called premunition or concomitant immunity. Active immunity may not be protective at all, e.g. for Haemophilus ducreyi, the patient may develop genital lesions following reinfection even while the original infection is active. Types of immune response in active immunity vary depending on the microbial exposure that occurs for the first time (called primary immune response) and subsequent time (called secondary immune response).
- 75. PRIMARY IMMUNE RESPONSE SECONDARY IMMUNE RESPONSE Slow, sluggish (appear late) and short lived Prompt, powerful and prolonged (long lasting) Lag period is longer(4-7 days) Lag period is absent or short (1-3 days} No negative phase Negative phase may occur Antibody produced in low titer and is of lgM type. Antibody produced in high titer and is of lgG type Antibodies are more specific but less avid Antibodies are less specific but more avid Antibody producing cells- Naive B cells Antibody producing cells- Memory B cells Both T dependent and T independent antigens are processed Only T dependent antigens are processed
- 76. Passive immunity • Passive immunity is defined as the resistance that is transferred passively to a host in a "readymade" form without active participation of the host's immune system. • Passive immunity can also be induced naturally or artificially. • Natural passive immunity involves the igG antibody tansfer from mother to fetus across the placenta. • Artificial passive immunity develops following readymade transfer of commercially prepared immunoglobulin (e.g, Rabies immunoglobulin).
- 77. Passive immunity Passive immunity plays a very important role in: • lmmunodeficient individuals (as host's immune apparatus is not effective) and; • Post exposure prophylaxis; when an immediate effect is warranted. •Passive immunity develops faster there is no lag phase or negative phase. •There is no immunological memory as the memory cells are not involved. •Booster doses are not effective: As memory component is absent, the effect produced following subsequent immunoglobulin administration is same as the effect produced after the primary dose. Some time, the booster doses of an immunoglobulin may be less effective because of its immunological clearance, which is mediated by the antibodies produced against the first dose of immunoglobulin.
- 78. Other types of immunity Herd immunity is defined as the overall immunity of a community (or herd) towards a pathogen. Herd immunity plays a vital role in preventing epidemic diseases. If the herd immunity is good, that means large population of the community are immune towards a pathogen. Hence, epidemics are less likely to occur and eradication of the disease may be possible. Herd immunity develops following effective vaccination against some diseases like: •Dipthieria and pertussis vaccine •Measles, mumps and rubella (MMR) vaccine •Polio (oral polio vaccine) •Smallpox vaccine
- 79. Adoptive Immunity Adoptive immunity is a special type of cell-mediated immune response (CMI) which develops following injection of immunologically competent T-lymphocytes known as transfer factor. It is useful for treatment when the CMI is low, e.g. in lepromatous leprosy. Local or mucosal immunity is the immune response that is active at the mucosal surfaces such as intestinal or respiratory or genitourinary mucosa. Example: Following administration of live oral polio vaccine (OPV) or following infection with poliovirus; secretory lgA antibodies are synthesized and coated on intestinal mucosa which prevent subsequent poliovirus infections. Such immunity does not develop following injectable killed polio vaccine (IPV).
- 80. THANK YOU
Editor's Notes
- #4: Emil von Behring -German Kitasato –Japanese Metchinkoff –Russian Merrill Chase - American
- #5: Examples: Discovery of human blood groups (1930) and Transplantation immunology(1991), Emil von Behring – nobel Metchinkoff - nobel
- #6: The lymphatic system is part of the circulatory system and a vital part of the immune system, comprising a network of lymphatic vessels that carry a clear fluid called lymph (from Latin lympha meaning water[1]) directionally towards the heart. The lymphatic system was first described in the seventeenth century independently by Olaus Rudbeck and Thomas Bartholin. Unlike the cardiovascular system, the lymphatic system is not a closed system. The human circulatory system processes an average of 20 litres of blood per day through capillary filtration, which removes plasma while leaving the blood cells. Roughly 17 litres of the filtered plasma are reabsorbed directly into the blood vessels, while the remaining three litres remain in the interstitial fluid. One of the main functions of the lymph system is to provide an accessory return route to the blood for the surplus three litres.[2] The other main function is that of defense in the immune system. Lymph is very similar to blood plasma: it contains lymphocytes and other white blood cells. It also contains waste products and debris of cells together with bacteria and protein. Associated organs composed of lymphoid tissue are the sites of lymphocyte production. Lymphocytes are concentrated in the lymph nodes. The spleen and the thymus are also lymphoid organs of the immune system. The tonsils are lymphoid organs that are also associated with the digestive system. Lymphoid tissues contain lymphocytes, and also contain other types of cells for support.[3] The system also includes all the structures dedicated to the circulation and production of lymphocytes (the primary cellular component of lymph), which also includes the bone marrow, and the lymphoid tissue associated with the digestive system.[4]
- #9: Two arms of the immune system
- #11: Analogy – IIT campus is the human body. The compound wall is the first line of defense or equivalent of innate immunity. It does not allow entry into the campus. Barbed wire fence may hurt intruders, if any. NO LAG, Not speific for any intruder (pathogen). It has no memory (It does not remember the intruder). Let’s say an intruder manages to get into the campus. Then the second line of defense (let’s say security personnel) - get into action. They identify the intruder and pin him down and get him out. (Lag to mobilize resources, they just target a specific intruder (pathogen) and they remember the intruder and become better equipped if they encounter the same intruder again (Memory).
- #12: Two arms of the immune system
- #15: Sweat – AMP – dermcidin
- #22: Two additional roles: Antigen presentation – (role in adaptive immunity) Triggers an inflammatory repsonse
- #23: Two additional roles: Antigen presentation – (role in adaptive immunity) Triggers an inflammatory repsonse
- #24: Two additional roles: Antigen presentation – (role in adaptive immunity) Triggers an inflammatory repsonse
- #26: Increased number of adipose tissue macrophages correlates with increased adipose tissue production of proinflammatory molecules.
- #27: are defined as large granular lymphocytes (LGL)
- #50: C` recognizes PAMPs on microbes and binds to them......
- #54: Terminology: Blood clotting is also called coagulation. Hemostasis is a word for the process where a blood clot forms. Blood clots form to stop excess blood leaking from your body after you break or cut the surface of your skin. If a blood vessel (a capillary, vein or artery) is damaged (internally or by external injury like a cut) bleeding occurs until a clot forms. Once the site of injury has healed, the blood clot will naturally dissolve. If no blood clot forms it is called a hemorrhage. A hemorrhage is uncontrolled bleeding and can be highly dangerous. Hemophiliacs are people with a blood disorder where there blood does not clot. A small injury can lead to uncontrolled bleeding. In the 1960s, before treatment became available, the life expectancy of someone with hemophilia was just 11 years. Today fortunately, with regular infusions of clotting medications, most can expect to live a relatively normal life expectancy.
- #56: Antithrombin, protein C and protein S are anticoagulants. Other functions of coagulation proteins – by cross-talk......
- #64: Heat – increases metabolic rate – leads to fever Compression of nerve endings due to swelling leads to pain Temp loss of function – eg. Joint not usable due to inflammation
- #68: Same is true for many components of the immune system – several of them may have undersired effects.....
- #71: Reactive oxygen species (ROS) are chemicallyreactive molecules containing oxygen. Examples include peroxides. superoxide, hydroxyl radical, Since these calcium regulatory proteins are also preferentially oxidized or nitrated under in vitro conditions, these results suggest an enhanced sensitivity of these critical calcium regulatory proteins, which modulate signal transduction processes and intracellular energy metabolism, to conditions of oxidative stress. Thus, the selective oxidation of critical signal transduction proteins probably represents a regulatory mechanism that functions to minimize the generation of ROS through respiratory control mechanisms. The reduction of the rate of ROS generation, in turn, will promote cellular survival under conditions of oxidative stress, when reactive oxygen and nitrogen species overwhelm cellular antioxidant defense systems, by minimizing the non-selective oxidation of a range of biomolecules. Since protein aggregation occurs if protein repair and degradative systems are unable to act upon oxidized proteins and restore cellular function, the reduction of the oxidative load on the cell by the down-regulation of the electron transport chain functions to minimize protein aggregation. OXIDATIVE damage to cellular proteins