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Introduction to the Study of Immunology
- 1. An Introduction to Immunology Dr. Andrea Henle Lecture presented on March 21st, 2013 for the SUTD Biology 10.010 course
- 2. Immunology • The study of the body’s defense against infection. • How does the body eliminate invaders and cure itself? • Why do we develop long-lasting immunity to many infectious diseases that we have encountered once and overcome? – Specificity and Memory
- 3. The Father of Immunology Edward Jenner – Late 18th century • Observed that cowpox offers protection against smallpox • Experiment: took pus from sores of a milkmaid with cowpox and inoculated a small boy. • The boy was then re-inoculated with pus from the sores of a person with smallpox. • The boy did not contract smallpox! • Latin vacca = cow; VACCINE
- 4. 1979: WHO declares smallpox is eradicated from the world
- 5. What causes disease? • At the time vaccinations started in the late 1700’s, nothing was known about what caused disease • In the late 1800’s, Robert Koch proved that microorganisms are responsible for particular diseases • Pathogen: disease causing organism. – Four main types today: viruses, bacteria, fungi, and unicellular and multicellular parasites.
- 6. Vaccination continues… • 1880’s: Louis Pasteur devises several vaccines: – One against cholera in chickens – Another against rabies
- 7. The search for an answer • Scientists asked, “how are vaccines offering protection? What is the mechanism?” • 1890’s: serum of animals immune to tetanus contains antitoxic activity that offers short-lived protection against tetanus toxins in people – Discovery of antibodies! Antibodies bound specifically to the toxins and neutralized their activity. – The toxins are antigens. • Antigen = substance that stimulates antibody generation.
- 9. Immune Responses • Innate Response – First line of defense – Fast response; innate immune cells are always present and ready to act. – Phagocytic cells • Adaptive Response – Developed throughout the lifetime of an individual as an adaptation to infection with a pathogen – Hallmark features: • Specificity – the immune cells recognize a very specific part (an antigen) of a particular pathogen • Clonal Expansion – cells expand and divide after activation by pathogenic antigen • Memory – lifelong protective immunity to same pathogen – White blood cells: lymphocytes
- 10. Key tasks of the immune system • Recognition – detect the presence of an infection • Effector functions – contain the infection and eliminate it completely – Antibodies – Cytotoxic lymphocytes • Regulation – immune response must be kept in check so it doesn’t damage the body – Autoimmune disease – Allergy • Memory – generate an immediate and strong secondary response to protect the individual against recurring disease due to the same pathogen
- 11. The distribution of lymphoid tissues in the body T cells B cells
- 12. Cells of the immune system are derived from precursors in the bone marrow INNATE CELLS ADAPTIVECELLS
- 13. Myeloid lineage: innate immune cells • Monocytes – circulate in blood and migrate into tissues; then they become macrophages • Macrophages – resident in all tissues – mature form of monocytes – Phagocytic: engulf and kill invading microorganisms • Phago = eat; cyte = cell
- 14. • Phagocytes (Macrophages, DCs, neutrophils) – Recognize pathogens through Toll Like Receptors (TLRs) Myeloid lineage: innate immune cells TLR-4 (LPS)
- 15. • Phagocytes (DCs, Macrophages, neutrophils) – Recognize pathogenic ligands through toll-like receptors Myeloid lineage: innate immune cells
- 16. Myeloid lineage: innate immune cells • Macrophages – induce inflammation to initiate a successful immune response • Secrete cytokines to activate other immune cells and recruit them to the site of infection • Cytokine: cyto=cell; kinos=movement. A cytokine is a small protein that is secreted by many cell types. It often causes cell movement and activation.
- 17. Myeloid lineage: innate immune cells • Neutrophils – most numerous and most important cell in innate response. Killers! • A granulocytic cell. Granulo = contains granules; cyte = cell – Receive cytokine signal from macrophages • Causes migration out of bloodstream and into infected tissues. ROLL, STOP, EXIT
- 18. Myeloid lineage: innate immune cells • Neutrophils – most numerous and most important cell in innate response – they KILL – Engulf microorganisms • Destroy them in intracellular vesicles • Degradative enzymes and antimicrobial substances inside the vesicles – Produce additional cytokines – Secrete toxic chemicals into infected tissues
- 19. Myeloid lineage: innate immune cells • Dendritic cells (DCs) – antigen presenting cells (APCs) – phagocytic – Long finger-like projections • “dendrites” – Degrade pathogens – Main role: display antigens from pathogens on their cell surface to activate antigen receptors on T lymphocytes – Provide signals for T cells to become active for first time DCs ARE THE LINK BETWEEN INNATE AND ADAPTIVE IMMUNITY!
- 20. Myeloid lineage: innate immune cells DCs ARE THE LINK BETWEEN INNATE AND ADAPTIVE IMMUNITY!
- 21. DCs are recruited to the site of infection by innate immune cells and travel to the lymph nodes to activate the adaptive immune system
- 22. Immune Responses • Innate Response – First line of defense – Fast response; innate immune cells are always present and ready to act. – Phagocytic cells • Adaptive Response – Developed throughout the lifetime of an individual as an adaptation to infection with a pathogen – Hallmark features: • Specificity – the immune cells recognize a very specific part (an antigen) of a particular pathogen • Clonal Expansion – cells expand and divide after activation by pathogenic antigen • Memory – lifelong protective immunity to same pathogen – White blood cells: lymphocytes
- 24. Lymphoid lineage: adaptive immune cells • Humoral Immunity: naïve B cells are activated due to the help of helper T cells. Antibodies are produced by activated B cells. Antibodies cause the destruction of extracellular microorganisms. – HUMORAL RESPONSE = B CELLS MAKE ANTIBODIES • Cell-Mediated Immunity: activation of naïve T cells in response to antigen and their subsequent proliferation and differentiation into effector T cells. – CELL-MEDIATED RESPONSE = T CELLS KILL BAD CELLS
- 25. Lymphoid lineage: adaptive immune cells • T cells or T lymphocytes – Helper T cells (Th cells) – Killer T cells (Cytotoxic T lymphocytes, CTL) • Display T Cell Receptors (TCR) on their surface
- 26. Diverse array of TCRs to recognize all possible antigens
- 27. Lymphoid lineage: adaptive immune cells • TCR recognizes antigen presented by antigen presenting cells (Macrophages, DCs, B cells) • Whole antigens are not recognized – Must be cleaved into smaller epitopes • Epitope: peptide fragment of an antigen
- 28. Lymphoid lineage: adaptive immune cells • “Naked” epitopes are not presented to T cell • Epitopes must be bound in an MHC molecule, then presented to TCR
- 29. Lymphoid lineage: adaptive immune cells • MHC molecule = Major HistoCompatibility molecule – histo = tissue – These molecules are present on the surface of cells in all tissues – Very important for transplantation • “Matched” donor means the donor organ expresses the same MHC molecules as your cells
- 30. Lymphoid lineage: adaptive immune cells • DCs activate T cells by presenting antigen epitopes in MHC to the TCR. • T cells circulate between lymph nodes, waiting for DCs presenting the correct antigen and MHC to bind their TCR and activate the T cell.
- 31. Lymphoid lineage: adaptive immune cells • DCs activate T cells • T cells proliferate and become effector cells – CLONAL EXPANSION
- 32. Lymphoid lineage: adaptive immune cells • Helper T cell – Secretes cytokines to activate other immune cells
- 33. Lymphoid lineage: adaptive immune cells • Helper T cell – Secretes cytokines to activate other immune cells – Helps activate B cells (which then make antibodies)
- 34. Lymphoid lineage: adaptive immune cells • Cytotoxic T lymphocyte (CTL) or Killer T cells – Kills target cells presenting cytosolic antigens • Virally infected cells • Tumor cells
- 35. Lymphoid lineage: adaptive immune cells • Cytotoxic T lymphocyte (CTL) or Killer T cells – Kills target cells presenting cytosolic antigens • Virally infected cells • Tumor cells
- 36. Lymphoid lineage: adaptive immune cells • B lymphocytes (Humoral Immunity) – Antigen binds to a B cell receptor on the B cell surface – B cell internalizes antigen and presents it to T helper cell • Th cell will activate B cell then – The B cell proliferates and differentiates into plasma cells – CLONAL EXPANSION
- 37. Lymphoid lineage: adaptive immune cells • B lymphocytes (Humoral Immunity) – Plasma cells make antibodies • Plasma cells are the effector form of B lymphocytes – Antibodies look just like the B cell receptor, except they are secreted instead of bound to the B cell surface. – The antigen that initially bound the B cell receptor is the same antigen targeted by the antibodies produced by the B cell’s progeny. – All classes of antibodies are referred to as immunoglobulins
- 39. Antigens are molecules recognized by the immune response. Epitopes are sites within antigens to which antibodies bind.
- 40. Antibody diversity – how antibodies are specific for so many antigenic epitopes
- 41. The humoral response is mediated by antibodies secreted by plasma cells Neutralization: Antibody prevents Bacterial adherence Opsonization: Antibody promotes phagocytosis Complement activation: antibody activates complement which enhances opsonization and lyses some bacteria B cell activation by antigen and helper T cells Antibody secretion by plasma cells
- 42. B cell receptor binds virus through viral coat protein Virus particle is internalized and degraded Peptides (epitopes) from internal proteins of the virus are presented to the T helper cell, which then activates the B cell Activated B cell produces antibody against viral coat protein B cells also respond to viruses
- 43. Lymphoid lineage: one exception to the rule • Natural Killer cell (NK cell) – Lymphoid lineage, but is considered an innate immune cell – Responds to presence of infection but is not antigen specific – Recognizes and kills abnormal cells • Virally infected cells • Cancer cells – Killing mechanism: release lytic granules or signal through receptors to turn on “death” pathway in target cell
- 44. Quick Review • Innate vs Adaptive • Humoral vs Cell-Mediated • Primary vs Secondary Response (Memory)
- 45. Your turn to act out the immune response! DC Th cell B cell Antibodies Tissues Lymph Nodes Tissues
- 46. Normal course of an antibody response
- 49. Normal course of an antibody response Memory cells are present which quickly proliferate and fight off the second exposure to antigen A
- 50. Memory Response • After a primary response & clearance of infection, most effector B and T cells die off. • Some memory B and T cells remain for future re- infection with pathogen • Memory cells are more numerous than original “naïve” B and T cells • Memory cells are easier to activate • Thus adaptive system is much faster the second time around – May not even know you are sick the second time!
- 51. Tolerance vs Autoimmunity • Tolerance: the immune system ignores self proteins and molecules • An immune response is not generated against self • Self reactive immune cells are deleted before maturing • Tolerance is good!
- 52. Tolerance vs Autoimmunity • Autoimmunity: immune system attacks your body • Self molecules/proteins are the antigens
- 53. Cancer- need the immune system to recognize self cells which are proliferating uncontrollably
- 54. Cytotoxic T Cell HER-2/neu+ Breast Cancer Cell ER lumen Cytosol T cell receptor p373-383:HLA-A2 HER-2/neu Proteasome or immunoproteasome HER-2/neu p373-382 ONCOGENE HER-2/neu Cancer Epitope:MHC
- 55. AIDS/HIV acquired immune deficiency syndrome human immunodeficiency virus
- 56. Viral life cycle of HIV
- 57. AIDS/HIV
- 58. AIDS/HIV – possible drug targets
- 59. Pregnancy – Hemolytic disease of the newborn
- 61. Sources
- 62. Additional Resources (videos) • Nicely animated overview of the immune system: http://youtu.be/LSYED-7riNY • Watch a classic video (from the 1950s) showing a neutrophil engulfing a bacterium! http://youtu.be/OWUmXx5V_wE • An overview of the immune response from Garland Science: http://www.youtube.com/watch?v=G7rQuFZxVQQ&feature=s hare&list=PL7D18C93964A61F67 • Antibody mediated immunity: http://youtu.be/hQmaPwP0KRI • Cell mediated immunity: http://youtu.be/1tBOmG0QMbA
Hinweis der Redaktion
- T cell interacting (red) an an antigen presenting cell (blue) (left).Macrophageengulfing bacteria (bottom right).Dendritic cell (blue) interacting with T cell (gold) (top right).
- We live surrounded by microorganisms, many of which cause disease. Yet despite this continually exposure we become ill only rarely. How does the body defend itself? This is the main topic of immunology!
- In the 1790’s a disease called smallpox was a major health problem. Hundreds of thousands of people died, and many more were horribly disfigured. Jenner observed that milkmaids frequently contracted a disease called cowpox which caused lesions on their hands. These looked similar to the sores caused by the smallpox virus. Jenner also noted that milkmaids who got cowpox almost never got smallpox, which as it turns out is caused by a close relative of the cowpox virus. For his experiment he took pus from the infected sores of a milkmaid who had cowpox. He used this pus to inoculate (ie. inject) a little boy named James Phipps. Later he re-inoculated Phipps with the pus from the sores of a person infected with smallpox. Phipps did not contract the disease. Edward Jenner began vaccinating the English against smallpox virus. Importantly, the smallpox vaccination only protected against smallpox or closely related viruses like cowpox. Phipps was still able to contract mumps, measles, or other diseases. This is one of the hallmarks of the adaptive immune system, which we will talk about soon, it adapts to defend against SPECIFIC invaders.
- Pasteur's later work on diseases included work on chicken cholera. During this work, a culture of the responsible bacteria had spoiled and failed to induce the disease in some chickens he was infecting with the disease. Upon reusing these healthy chickens, Pasteur discovered he could not infect them, even with fresh bacteria; the weakened bacteria had caused the chickens to become immune to the disease, though they had caused only mild symptoms.[2][11] His assistant, Charles Chamberland (of French origin), had been instructed to inoculate the chickens after Pasteur went on holiday. Chamberland failed to do this, but instead went on holiday himself. On his return, the month-old cultures made the chickens unwell, but instead of the infection's being fatal, as it usually was, the chickens recovered completely. Chamberland assumed an error had been made, and wanted to discard the apparently faulty culture when Pasteur stopped him. Pasteur guessed the recovered animals now might be immune to the disease, as were the animals at Eure-et-Loir that had recovered from anthrax.[12]Pasteur produced the first vaccine for rabies by growing the virus in rabbits, and then weakening it by drying the affected nerve tissue. The rabies vaccine was initially created by Emile Roux, a French doctor and a colleague of Pasteur who had been working with a killed vaccine produced by desiccating the spinal cords of infected rabbits. The vaccine had been tested only on 11 dogs before its first human trial.[2][9] This vaccine was first used on 9-year old Joseph Meister, on July 6, 1885, after the boy was badly mauled by a rabid dog.[9] This was done at some personal risk for Pasteur, since he was not a licensed physician and could have faced prosecution for treating the boy. After consulting with colleagues, Pasteur decided to go ahead with the treatment. Meister did not contract the disease. It is sometimes said that Pasteur saved the boy's life, but this cannot be maintained with certainty, since the risk of contracting rabies after such an exposure is estimated at around 15%.[14] Nonetheless, Pasteur was hailed as a hero and the legal matter was not pursued. The treatment's success laid the foundations for the manufacture of many other vaccines.
- Above is a look at the past morbidity (how many people became sick) of what were once very common infectious diseases, and the current morbidity in the U.S. There’s no smallpox and no polio, almost no measles, dramatically less chickenpox (also known as varicella) and H. influenza (that’s not flu, but a bacteria that can cause deadly meningitis).
- Immune response is the response the body makes against infection by potential pathogens. There are two main types of immune responses – Innate and adaptive.The innate response is the first response. It is fast acting. In the innate response, microorganisms are engulfed and digested by phagocytic cells called macrophages. The word phagocytic literally means eating cell.The innate and adaptive responses work together! Many infections are handled just fine by the innate immune system and cause no disease. However, if the disease can’t be resolved then the innate immune cells will activate the adaptive immune response. If the disease is overcome, long lasting immunological memory often follows to prevent any disease if reinfection occurs in the future.The white blood cells known as lymphocytes possess the most powerful ability to recognize and target pathogenic microorganisms, but they need the participation of the innate immune system to initiate and mount their offensive.
- All lymphocytes arise from stem cells in the bone marrow. However they differentiate in different central lymphoid organs shown in yellow. B cells in the bone marrow and T cells in the thymus. They cells migrate from the bone marrow to these tissues and are carried in the bloodstream to the peripheral lymphoid organs shown in blue (lymph nodes, spleen, gut associated mucosa, tonsils, peyer’s patches, etc. Lymphocytes get activated at these peripheral lymphoid organs and then recirculate between the blood and these organs until they encounter their specific antigen. .
- Immune responses depend upon the activities of white blood cells or leukocytes. These cells originate in the bone marrow. Many of them also develop and mature there. Once mature, they migrate to the tissues. Some reside in the tissues while others circulate in the bloodstream in special vessels called the lymphatics. The lymphatic system drains extracellular fluid from tissues and transports it through the body as lymph, eventually emptying back into the blood system. All cellular elements of the blood derive from the hematopoietic stem cells of the bone marrow. The eventually give rise to the two main categories of white blood cells – the lymphoid and myeloid lineages.
- Both monocytes and macrophages are phagocytic, but most infections occur in the tissues so it is primarily macrophages that perform the protective function.
- Toll like receptors represent an evolutionary ancient host defense system. The receptor protein Toll was first identified in the fruitfly Drosophila melanogaster as being important for controlling dorso-ventral patterning in the embryo. But in 1996 it was also discovered that in the adult insect signaling through Toll induces the expression of several host-defense mechanisms including antimicrobial peptides which help fight against bacteria and fungal pathogens. Antimicrobial peptides seem to be the earliest form of defense against infection to evolve, so receptors that recognize pathogens and send signals to produce antimicrobial peptides may be the earliest receptors dedicated to defense against infection in multicellular organisms.
- There are 10 TLR genes in humans and each is devoted to recognizing a distinct set of molecular patterns that are not found in healthy vertebrate cells. These patterns are characteristic of components in pathogeneic microorganisms. The mammalian TLRs recognize molecular patterns characteristic of gram-negative and gram positive bacteria, fungi, and viruses. Lipopolysaccaride (LPS) found on the outer membrane of gram-negative bacteria is particularly important in the recognition of bacteria by the innate immune system through TLRs.
- Neutrophils are the foot soldiers of the immune system. Their job is to kill things and break stuff. They live a very short time. They are not antigen presenting cells. They are professional killers which are “on call” from the blood.
- Neutrophils are the foot soldiers of the immune system. Their job is to kill things and break stuff. They live a very short time. They are not antigen presenting cells. They are professional killers which are “on call” from the blood. They are phagocytic and produce powerful chemicals like reactive oxygen species to kill what they take in. They secrete cytokines to alert other immune cells. They also secrete toxic chemicals to turn tissues into toxic soup. These chemicals are lethal to microbes.
- Both monocytes and macrophages are phagocytic, but most infections occur in the tissues so it is primarily macrophages that perform the protective function.
- DCs receive signals from other innate tissues to go to the site of infection in the tissue. They pick up antigen there, travel through the lymph and present it to the T cells of the adaptive immune response in the lymph nodes!
- Immune response is the response the body makes against infection by potential pathogens. There are two main types of immune responses – Innate and adaptive.The innate response is the first response. It is fast acting. In the innate response, microorganisms are engulfed and digested by phagocytic cells called macrophages. The word phagocytic literally means eating cell.The innate and adaptive responses work together! Many infections are handled just fine by the innate immune system and cause no disease. However, if the disease can’t be resolved then the innate immune cells will activate the adaptive immune response. If the disease is overcome, long lasting immunological memory often follows to prevent any disease if reinfection occurs in the future.The white blood cells known as lymphocytes possess the most powerful ability to recognize and target pathogenic microoganisms, but they need the participation of the innate immune system to initiate and mount their offensive.
- There are two words to introduce here before we talk about the specific lymphocytes that comprise the adaptive immune system. When we talk about adaptive immune responses we often refer to humoral and cell-mediated immune responses.
- B cells the specificity comes from the immunoglobulin structure on the cell surface. If either of its identical binding sites gets cross-linked upon recognizing an antigen, a signal is transmitted to the other chains, which ultimately delivers an intracellular signal that will affect the behavior of the B cell. But the fine specificity of the B cells comes form the surface immunoglobulin. For B cells we refer to that as signal 1 – a surface immunoglobulin recognizing an antigen.
- NK cells mature in the bone marrow, just like B cells do, but NK cells are short lived, with a half-life of only about a week. NK cells are “on call” and are found in the blood or in the spleen and liver. They are not sentinels found in the tissues like macrophages are. They leave the blood and enter tissues at sites of infections and proliferate in the tissues to rapidly build up their numbers. NK cells give off cytokines to help with immune defenses and they can destroy tumor cells, virus infected cells, bacteria, parasites and fungi. The “don’t kill” signal is conveyed by receptors that recognize class I MHC on the surface of a potential target cells. Class I MHC molecules are found in different amounts on the surface of most healthy cells. If the surface molecule is there, the cell is doing ok. If it isn’t there then the cell may be infected with a virus or is becoming cancerous and that triggers the NK cells to destroy the target cells.
- Use these videos to further your studying and help you review the main concepts from this lecture.