1. Clicker Question Which of the following process(es) that occur(s) at a synapse could be targeted by a drug designed to treat mental illness? A) Secretion of the neurotransmitter B) Binding of the neurotransmitter to a receptor C) Degradation of the neurotransmitter D) Re-uptake of the neurotransmitter E) All of the above and more

2. Where are we? Last time I discussed… Last time I discussed… –that before the introduction of psychopharmacology, mentally ill patients were treated barbarically. –the brain is a trillion cauldrons of chemical activity in which neurotransmitters in the synapses regulate the transmission of electrical signals. –how psychopharmacological drugs influence the concentration of neurotransmitters in the synapses. –that while we understand a lot about the physico-chemical processes that take place in the brain, we still do not understand the mechanism of normal and abnormal thinking and the way the psychopharmacological drugs work. This time I will discuss… This time I will discuss… –immunity—how the body protects itself from invaders. –the innate immune system. –the acquired immune system that, like the nervous system, can learn, remember and recognize self from non-self. –allergies, anaphylactic shock and autoimmune diseases.

3. The human body is capable of resisting many harmful disease-causing agents in the course of everyday life. Not everyone in a family, dorm, sorority, fraternity or classroom is equally resistant to disease. Not everyone in a family, dorm, sorority, fraternity or classroom is equally resistant to disease. Luckily, immunity (from the Latin word immunis meaning “free of”) against disease can be conferred to sensitive people though vaccinations. Luckily, immunity (from the Latin word immunis meaning “free of”) against disease can be conferred to sensitive people though vaccinations.

4. The Ancients Realized that Survivors of a Disease were often Immune to Getting that Disease Again In 429 BC, Thucydides noticed that smallpox survivors did not get re-infected. In 429 BC, Thucydides noticed that smallpox survivors did not get re-infected. In the 10 th century, also realizing that survivors of small pox were immune to the disease, Chinese doctors put the fluid from small pox pocks into the noses of susceptible people to protect them from small pox. In the 10 th century, also realizing that survivors of small pox were immune to the disease, Chinese doctors put the fluid from small pox pocks into the noses of susceptible people to protect them from small pox.

5. Puritans Learned that Africans also Inoculated People to Make them Immune to Small Pox In 1706, the Puritan minister, Reverend Cotton Mather, learned from a slave named Onesimus, that he had been inoculated with small pox as a child in Africa as a protective measure. In 1706, the Puritan minister, Reverend Cotton Mather, learned from a slave named Onesimus, that he had been inoculated with small pox as a child in Africa as a protective measure. Courageously going against the Church and State, in 1721, during the small pox epidemic in Boston, Cotton Mather and Dr. Zabdiel Boylston inoculated the people. Courageously going against the Church and State, in 1721, during the small pox epidemic in Boston, Cotton Mather and Dr. Zabdiel Boylston inoculated the people.,

6. Lady Mary Wortley Montagu (1721), the wife of the British Ambassador to Turkey, brought back to England a method of preventing the deadly small pox disease. Lady Mary Wortley Montagu (1721), the wife of the British Ambassador to Turkey, brought back to England a method of preventing the deadly small pox disease. Physicians would take a small amount of pus from the pocks of a person with a mild case of small pox and rub it in to a scratch in the arm of a healthy person. Physicians would take a small amount of pus from the pocks of a person with a mild case of small pox and rub it in to a scratch in the arm of a healthy person. Unfortunately, the healthy patient often contracted a full blown case of small pox and died. Unfortunately, the healthy patient often contracted a full blown case of small pox and died.

7. Edward Jenner Jenner (1798) and many milkmaids he treated noticed that people who got cow pox (variolae vaccinia) were immune to the deadly small pox. One day, when Sarah Nelmes came to him with cow pox, he decided to see if inoculating someone with cow pox would prevent them from getting small pox. He took pus from Sarah Nelmes’ pocks and rubbed it into scratches in James Phipps’ arm. The 8 year old son of the gardener developed cow pox. Once he was over the cow pox, Jenner exposed him repeatedly to small pox, but he had become immune to the small pox virus.

9. A Profile in Courage: Edward Jenner Jenner reported his results to the Royal Society; however, Sir Joseph Banks, the president of the Royal Society suggested that he should not risk his reputation by presenting something "so at variance with established knowledge". Jenner reported his results to the Royal Society; however, Sir Joseph Banks, the president of the Royal Society suggested that he should not risk his reputation by presenting something "so at variance with established knowledge". Thankfully Jenner used his meager savings to publish his work privately and within a few years vaccinations for small pox became common practice. Thankfully Jenner used his meager savings to publish his work privately and within a few years vaccinations for small pox became common practice.

11. Cholera: A Bacterial Infection Cholera is transmitted from person to person by the fecal- oral route resulting from drinking water contaminated with feces that contain the bacterium, Vibrio cholerae. Cholera is transmitted from person to person by the fecal- oral route resulting from drinking water contaminated with feces that contain the bacterium, Vibrio cholerae. Vibrio secretes a toxin into the intestine that results in massive diarrhea followed by dehydration. Vibrio secretes a toxin into the intestine that results in massive diarrhea followed by dehydration. If the patient is not rehydrated orally or and/or intravenously within hours of being infected, death can result. If the patient is not rehydrated orally or and/or intravenously within hours of being infected, death can result. Cholera can also be prevented by a vaccine. Cholera can also be prevented by a vaccine.

12. Louis Pasteur Had a Prepared Mind Louis Pasteur (1880) reasoned that if a vaccine could be found for small pox, then a vaccine could be found for all diseases. Pasteur found a vaccine against chicken cholera by chance. Louis Pasteur (1880) reasoned that if a vaccine could be found for small pox, then a vaccine could be found for all diseases. Pasteur found a vaccine against chicken cholera by chance. One of his colleagues had inoculated chickens with chicken cholera bacilli from an old culture and the chickens did not get sick. Even when he exposed these chickens to fresh chicken cholera bacilli that would kill other chickens, the chickens who were exposed to the old strain first still did not get sick. One of his colleagues had inoculated chickens with chicken cholera bacilli from an old culture and the chickens did not get sick. Even when he exposed these chickens to fresh chicken cholera bacilli that would kill other chickens, the chickens who were exposed to the old strain first still did not get sick.

13. Louis Pasteur Had a Prepared Mind Pasteur reasoned that the potency to cause cholera in chickens had attenuated in the old culture. Pasteur reasoned that the potency to cause cholera in chickens had attenuated in the old culture. He guessed that the chickens used the weaker germs to form a defense against the more powerful germs in the fresher culture. He guessed that the chickens used the weaker germs to form a defense against the more powerful germs in the fresher culture. Pasteur pioneered the use of attenuated bacilli for vaccinations, a word he coined in honor of Jenner. Pasteur pioneered the use of attenuated bacilli for vaccinations, a word he coined in honor of Jenner.

14. Anthrax Anthrax is often a fatal disease characterized by hemorrhaging and tissue decay. Anthrax is often a fatal disease characterized by hemorrhaging and tissue decay. It is caused by a toxin produced by Bacillus anthracis, which can enter the body through the lungs, skin or intestines. It is caused by a toxin produced by Bacillus anthracis, which can enter the body through the lungs, skin or intestines.

15. Louis Pasteur and Anthrax Pasteur (1881) aged cultures of anthrax to weaken them and used the weakened germs to make a vaccine. Pasteur (1881) aged cultures of anthrax to weaken them and used the weakened germs to make a vaccine. The idea that germs could make an animal healthier seemed unbelievable and Rossignol, the editor of The Veterinary Press, challenged Pasteur to a public test. The idea that germs could make an animal healthier seemed unbelievable and Rossignol, the editor of The Veterinary Press, challenged Pasteur to a public test. Pasteur inoculated twenty five sheep with his vaccine while twenty-five were not. Pasteur inoculated twenty five sheep with his vaccine while twenty-five were not. Subsequently, all fifty were injected with anthrax. Those injected with the vaccine lived while those that were not inoculated died within two days. Subsequently, all fifty were injected with anthrax. Those injected with the vaccine lived while those that were not inoculated died within two days.

16. Rabies Rabies is a fatal disease characterized by the inflammation of the brain. Rabies is a fatal disease characterized by the inflammation of the brain. Rabies is caused by the rabies virus, which is found in the saliva of an infected animal. Rabies is caused by the rabies virus, which is found in the saliva of an infected animal. Rabies is often transmitted by a bite. Rabies is often transmitted by a bite.

17. Louis Pasteur, Joseph Meister, Human Experimentation and Rabies Pasteur injected healthy dogs with aged rabies germs (viruses) from the spinal cord of rabid rabbits. The vaccinated dogs became immune to rabies. Pasteur injected healthy dogs with aged rabies germs (viruses) from the spinal cord of rabid rabbits. The vaccinated dogs became immune to rabies. A 9 year old boy named Joseph Meister was bit by a rabid dog. Since the boy would have died had he been left untreated, Pasteur (1885) reluctantly took the risk on treating Joseph Meister with the vaccine that had only been tested on dogs. A 9 year old boy named Joseph Meister was bit by a rabid dog. Since the boy would have died had he been left untreated, Pasteur (1885) reluctantly took the risk on treating Joseph Meister with the vaccine that had only been tested on dogs. Happily, the vaccine worked and the boy survived to become the caretaker of the Pasteur Institute. Happily, the vaccine worked and the boy survived to become the caretaker of the Pasteur Institute.

18. Pasteur’s Father and Mother Painted by Louis Pasteur, Himself

19. The Wisdom of the Body in the Fight Against Infectious Diseases The body protects itself from infectious microbes in two ways: –Innate Immunity (skin, phagocytes, interferon) –Acquired Immunity (B and T lymphocytes)

20. The Body’s First Line of Defense: Innate Immunity Skin and the mucosa lining the digestive and urogenital tracts are physical barriers to disease, although a tiny cut will allow pathogens to enter the body. Skin and the mucosa lining the digestive and urogenital tracts are physical barriers to disease, although a tiny cut will allow pathogens to enter the body. Sweat, saliva and tears contain lysozyme, an enzyme that degrades the cell wall of gram positive bacteria. This causes the bacteria to lyse. Lysozyme was discovered by Alexander Fleming in 1922. Sweat, saliva and tears contain lysozyme, an enzyme that degrades the cell wall of gram positive bacteria. This causes the bacteria to lyse. Lysozyme was discovered by Alexander Fleming in 1922. The respiratory tract is guarded by the hairs in the nostrils as well as the mucus that traps microbes and cilia that sweep the mucus out of the respiratory system and down the esophagus. The respiratory tract is guarded by the hairs in the nostrils as well as the mucus that traps microbes and cilia that sweep the mucus out of the respiratory system and down the esophagus. The hydrochloric acid produced by the parietal cells in the stomach kills microbes (with the exception of Helicobacter) that come from the respiratory system or enter the body along with food. The hydrochloric acid produced by the parietal cells in the stomach kills microbes (with the exception of Helicobacter) that come from the respiratory system or enter the body along with food.

21. The Inflammatory Response: Phagocytes and Pus Microbes that breach the first line of defense are accosted by the white blood cells which are found in the blood, the interstitial fluid, and the lymph. Microbes that breach the first line of defense are accosted by the white blood cells which are found in the blood, the interstitial fluid, and the lymph. The white blood cells that engulf microbes by phagocytosis are known as phagocytes. The neutrophils, which are a kind of phagocyte that most rapidly fights infections, make up most of the pus that occurs with an infection. The white blood cells that engulf microbes by phagocytosis are known as phagocytes. The neutrophils, which are a kind of phagocyte that most rapidly fights infections, make up most of the pus that occurs with an infection. nobelprize.org/educational_games

22. Ilya Mechnikov In 1882, Ilya Mechnikov was studying the larvae of starfish. He noticed that when he inserted a splinter into the larva, strange cells gathered at the point of insertion. The cells surrounded the splinter, eating any foreign substances that entered through the ruptured skin. Mechnikov named these new cells phagocytes from the Greek words “eating cells.”

23. Splinters “Sharp splinters were introduced into the bodies of these Bipinnaria and the next day I could see a mass of moving cells surrounding the foreign bodies to form a thick cushion layer. The analogy between this phenomenon and what happens when a man has a splinter that causes inflammation and suppuration is extraordinary.”

24. Disease: A Fight Between Microbes and Phagocytes This observation led Mechnikov to propose that in humans, phagocytes move to the wound and engulf the bacteria. This observation led Mechnikov to propose that in humans, phagocytes move to the wound and engulf the bacteria. “…disease would be a fight between the morbid agent, the microbe from outside, and the mobile cells of the organism itself. Cure would come from the victory of the cells and immunity would be the sign of their acting sufficiently to prevent the microbial onslaught.” “…disease would be a fight between the morbid agent, the microbe from outside, and the mobile cells of the organism itself. Cure would come from the victory of the cells and immunity would be the sign of their acting sufficiently to prevent the microbial onslaught.”

25. Ilya Mechnikov “Photographs taken of him when he was working at the Pasteur Institute show him with long hair and an unkempt beard. It is said of him that at this time he usually wore overshoes in all weathers and carried an umbrella, his pockets being overfull with scientific papers, and that he always wore the same hat, and often, when he was excited, sat on it.”

26. The Inflammatory Response

27. When the skin is broken, damaged mast cells release histamine (which causes one to burn and itch). The histamine diffuses to the capillaries and cause them to dilate and become leaky. When the skin is broken, damaged mast cells release histamine (which causes one to burn and itch). The histamine diffuses to the capillaries and cause them to dilate and become leaky. The phagocytes and components of blood plasma move out of the leaky capillaries. This results in redness and swelling. The swelling puts pressure on the pain receptors. Consequently, the inflammation leads to pain. The phagocytes and components of blood plasma move out of the leaky capillaries. This results in redness and swelling. The swelling puts pressure on the pain receptors. Consequently, the inflammation leads to pain. In the interstitial fluid, the phagocytes known as neutrophils rapidly engulf microbes and dead or injured body cells. In the interstitial fluid, the phagocytes known as neutrophils rapidly engulf microbes and dead or injured body cells. The pus at the site of injury consists mostly of interstitial fluid and dead neutrophils. The pus at the site of injury consists mostly of interstitial fluid and dead neutrophils.

28. Stinging Nettle Causes Inflammation Because It Contains Histamine The hairs of stinging nettle contain histamine, acetylcholine and serotonin. The hairs of stinging nettle contain histamine, acetylcholine and serotonin. These molecules that occur in the plant and animal kingdoms cause itching, burning, reddening and swelling when you touch the hairs of the plant, informing you that the plant you touched is Urtica dioica. These molecules that occur in the plant and animal kingdoms cause itching, burning, reddening and swelling when you touch the hairs of the plant, informing you that the plant you touched is Urtica dioica.

29. Phagocytes, Antioxidants and Free Radicals The phagocytes kill the invading bacteria by producing a dose of free radicals (including superoxide), which are produced by the phagocyte itself. The phagocytes kill the invading bacteria by producing a dose of free radicals (including superoxide), which are produced by the phagocyte itself. Vitamin C is necessary as an antioxidant to protect the phagocyte from its own high dose of superoxide. Vitamin C is necessary as an antioxidant to protect the phagocyte from its own high dose of superoxide.

30. Corticosteroids and Anti-Inflammation Cortisol released during stress suppresses the inflammation response. In the short term, this minimizes the pain associated with inflammation; but in the long term, it makes it easier to succumb to germs. Cortisol released during stress suppresses the inflammation response. In the short term, this minimizes the pain associated with inflammation; but in the long term, it makes it easier to succumb to germs. Synthetic corticosteroids (hydrocortisone) are used topically to treat the pain and itchiness of dermatitis, eczema, psoriasis, hemorrhoids, and poison ivy or nasally to treat allergy symptoms. Synthetic corticosteroids (hydrocortisone) are used topically to treat the pain and itchiness of dermatitis, eczema, psoriasis, hemorrhoids, and poison ivy or nasally to treat allergy symptoms.

31. Zits Acne occurs during puberty when androgens produced by the adrenal glands in men and women stimulate secretion of oils from the sebaceous (oil) glands beneath the skin. Acne occurs during puberty when androgens produced by the adrenal glands in men and women stimulate secretion of oils from the sebaceous (oil) glands beneath the skin. The oil glands, which are exocrine glands, continuously secrete oil in order to lubricate the skin. The oil glands, which are exocrine glands, continuously secrete oil in order to lubricate the skin. Cells that are close to the opening of an oil gland block the duct and cause a buildup of oil beneath the skin. Bacteria feast on this oil and trigger the inflammation response. Cells that are close to the opening of an oil gland block the duct and cause a buildup of oil beneath the skin. Bacteria feast on this oil and trigger the inflammation response. If the inflammation is near the surface, you get a pimple and if it is deeper, you get a boil. If the inflammation is near the surface, you get a pimple and if it is deeper, you get a boil. When the oil breaks though to the surface, you get a whitehead and the oil becomes oxidized, it turns black and you get a blackhead. When the oil breaks though to the surface, you get a whitehead and the oil becomes oxidized, it turns black and you get a blackhead.

32. Causes and Preventative Measures The three basic causes of acne The three basic causes of acne –Oil from sebaceous glands –Clogged pores –Bacteria Three preventative measures Three preventative measures –Minimize oil (wipe away with mild astringent; or kill oil producing cells with laser). –Unclog pores (soap and water; alpha-hydroxy acids or beta- hydroxy acids) –Kill bacteria (benzoyl peroxide)

33. Alpha-Hydroxy Acids Glycolic acid (from sugar beet and sugar cane) Lactic acid (from milk) (from milk)

34. Beta-Hydroxy Acids Salicylic acid, isolated from the bark of willow (Salix) trees and Spiraea bushes, is involved in the “systemic immune response” of plants. Salicylic acid, isolated from the bark of willow (Salix) trees and Spiraea bushes, is involved in the “systemic immune response” of plants. Notice the greater proportion of CH bonds in this beta- hydroxy acid than in the alpha-hydroxy acids. Notice the greater proportion of CH bonds in this beta- hydroxy acid than in the alpha-hydroxy acids. This makes salicylic acid more soluble in oil (more nonpolar) so it penetrates more deeply into the oil ducts. This makes salicylic acid more soluble in oil (more nonpolar) so it penetrates more deeply into the oil ducts.

35. Innate Immunity Against Viruses: Interferons Interferons are proteins that are produced by virus-infected cells that help other cells become resistant to viruses. Interferons are proteins that are produced by virus-infected cells that help other cells become resistant to viruses. The interferon gene from the infected cell is transcribed and translated to make interferon, which is secreted from the cell and diffuses to the neighboring healthy cells. The interferon gene from the infected cell is transcribed and translated to make interferon, which is secreted from the cell and diffuses to the neighboring healthy cells. The interferon stimulates the healthy cells to make antiviral proteins. The interferon stimulates the healthy cells to make antiviral proteins.

37. Recombinant DNA Technology Makes Interferon Cheap and Accessible for the Treatment of Hepatitis and other Viral Infections

38. The Immune System: The Mind Body Connection IL-6 is produced by the white blood cells that participate in the innate immune response. Participants looked at a 10 minute slide show of people holding guns or people with disease symptoms. After seeing pictures of the sick people, the interleukin-6 (IL-6) level in the participant’s blood rose significantly. The increased levels of IL-6 can give a boost to the entire immune system. Psychology Today Psych Sci

39. Our Blood—Our Identity Experience with blood transfusions indicate that our body can distinguish between our own blood and the blood of others. Experience with blood transfusions indicate that our body can distinguish between our own blood and the blood of others. Karl Landsteiner found that the red blood cells in the blood seemed to fall into four groups (A, B, AB and O). Karl Landsteiner found that the red blood cells in the blood seemed to fall into four groups (A, B, AB and O). Jean Dausset, Baruj Benacerraf and George Snell found that the white blood cells (as well as all the other cells in our body) also have proteins, now known as the major histocompatibility complex, in their plasma membranes that represent our self. Jean Dausset, Baruj Benacerraf and George Snell found that the white blood cells (as well as all the other cells in our body) also have proteins, now known as the major histocompatibility complex, in their plasma membranes that represent our self.

40. Karl Landsteiner (1930): Our Blood and Our Biological Individuality Anthropological Studies Anthropological Studies –Northern Europeans are mostly Type A. –Asians are mostly Type B. –American Indians are mostly Type O. Forensic Studies Forensic Studies –Tests of blood found at a crime scene has been used to acquit innocent people. Paternity Tests Paternity Tests –Blood tests has been used to exclude a putative father. to exclude a putative father.

41. Karl Landsteiner

42. Jean Dausset, Baruj Benacerraf and George Snell

43. John Galbraith Simmons: The Self “The self is not just a narrative fiction of language and mind, nor is a physical structure its only boundaries. The self may also be said to exist on a molecular level, comprised of a group of antigenic proteins found in all cells of the body. The specific complexion of these antigens is configured by a set of genes known as the “major histocompatibility complex” (MHC).”

44. Peter Medawar and Macfarlane Burnet: Acquired Immunity (1960) If the innate defenses can not eliminate an infection, the immune system kicks in. If the innate defenses can not eliminate an infection, the immune system kicks in. The immune system provides acquired immunity, consisting of humoral immunity and cell-mediated immunity. The immune system provides acquired immunity, consisting of humoral immunity and cell-mediated immunity. Whereas the innate system may be effective before one is exposed to a microbe, the immune response develops after exposure to microbes. Whereas the innate system may be effective before one is exposed to a microbe, the immune response develops after exposure to microbes. The immune system is triggered by an antigen, a molecule that is foreign to the host’s body. The immune system is triggered by an antigen, a molecule that is foreign to the host’s body.

45. Peter Medawar (1946): The Uniqueness of the Individual “Philosophy and common sense, though often parted, have long agreed about the uniqueness of individual man. Different men have different faces, sizes, shapes and origins; different aptitudes, skills and predilections; and different ambitions, hopes and fears. Science now makes it a trio of concordant voices, for the uniqueness of individual mice and men is a proposition which science can demonstrate with equal force, perhaps with deeper cogency, and certainly with a hundred times as much precision.”

46. Books by Peter Medawar

47. Books by MacFarlane Burnet

48. Clonal Selection Theory How does the immune system recognize so many different foreign particles, mobilize against them and remember them? MacFarlane Burnet suggested that it “would make real sense if cells produced a characteristic pattern of globulin [antibody molecule] for genetic reasons and were stimulated to proliferate by contact with the corresponding antigenic determinant.”

49. Antigens Generate the Proliferation of Antibodies Proteins that make up the coats of viruses, the surfaces of protozoa and other parasites act as antigens. Proteins that make up the coats of viruses, the surfaces of protozoa and other parasites act as antigens. Carbohydrates from the walls of bacteria and fungi also act as antigens. Carbohydrates from the walls of bacteria and fungi also act as antigens. Various venom and toxins that get into the blood stream also act as antigens. Various venom and toxins that get into the blood stream also act as antigens. Vaccines act as antigens. Vaccines act as antigens. Unfortunately, proteins from the surface of donated blood cells, tissues and organs also act as antigens. Unfortunately, proteins from the surface of donated blood cells, tissues and organs also act as antigens.

50. Antigen: Antibody-Generating Substance An antigen triggers the immune system to produce large quantities of the antibody that will bind to it. An antigen triggers the immune system to produce large quantities of the antibody that will bind to it. An antibody is a protein found in the circulatory system that specifically binds to an antigen with high affinity. An antibody is a protein found in the circulatory system that specifically binds to an antigen with high affinity. The immune system, like the brain, learns about the antigens to which a host is exposed and has a memory which allows it to react rapidly against an antigen it has experienced before. The immune system, like the brain, learns about the antigens to which a host is exposed and has a memory which allows it to react rapidly against an antigen it has experienced before.

51. Antibodies An antibody has two identical antigen binding sites that allow it to form large complexes with antigens or microbes with exposed antigens. An antibody has two identical antigen binding sites that allow it to form large complexes with antigens or microbes with exposed antigens. This process of forming large complexes is called agglutination. This process of forming large complexes is called agglutination. Macrophages are a kind of phagocyte that engulfs the insoluble agglutinated complexes of antigens and/or microbes in a process called phagocytosis. Macrophages are a kind of phagocyte that engulfs the insoluble agglutinated complexes of antigens and/or microbes in a process called phagocytosis.

52. Paul Ehrlich (1908) The antigen and the antibody “…enter into a chemical bond which, in view of the strict specificity is most easily explained by the existence of two groups of distinctive configuration - of groups which according to the comparison made by Emil Fischer fit each other ‘like lock and key’.”

53. Antibody-Antigen: Lock and Key The part of the antigen that the antibody recognizes is called the antigenic determinant or epitope. The part of the antigen that the antibody recognizes is called the antigenic determinant or epitope. The antibody has amino acids with the correct chemical properties to bind the epitope. The antibody has amino acids with the correct chemical properties to bind the epitope. If the epitope be positively charged, the binding site will be negatively charged. If the epitope be positively charged, the binding site will be negatively charged. If the epitope be negatively charged, the binding site will be positively charged. If the epitope be negatively charged, the binding site will be positively charged. If the epitope be polar, the binding site will also be polar. If the epitope be polar, the binding site will also be polar. If the epitope be nonpolar, binding site will be nonpolar. If the epitope be nonpolar, binding site will be nonpolar.

54. The Complement System “Complements the Antibody-Macrophage System” The complement proteins recognize the antibodies when they bind to an antigen on a microbe. The complement proteins recognize the antibodies when they bind to an antigen on a microbe. The complement proteins poke holes in the plasma membrane of the microbe and the microbes die. The complement proteins poke holes in the plasma membrane of the microbe and the microbes die.

55. B (bone marrow) Cells and T (thymus) Cells The cells that produce antibodies are called lymphocytes. They are derived from lymphocyte stem cells. The cells that produce antibodies are called lymphocytes. They are derived from lymphocyte stem cells. The lymphocyte stem cells are derived from pluipotent stem cells in the bone marrow. The lymphocyte stem cells are derived from pluipotent stem cells in the bone marrow. Lymphocytes that mature in the bone marrow are known as B cells. Lymphocytes that move to the thymus and mature there are known as T cells. Lymphocytes that mature in the bone marrow are known as B cells. Lymphocytes that move to the thymus and mature there are known as T cells. The mature B and T cells enter the lymphatic system and go to the spleen, lymph nodes, tonsils, adenoids and appendix. The mature B and T cells enter the lymphatic system and go to the spleen, lymph nodes, tonsils, adenoids and appendix.

56. The Lymphatic System The lymphatic system is an open conducting system that returns fluid from the interstitial fluid back to the circulatory system. The lymphatic system is an open conducting system that returns fluid from the interstitial fluid back to the circulatory system. When the lymph fights a large microbe attack, the lymphocytes and macrophages accumulate in the lymph glands and one gets “swollen glands.” When the lymph fights a large microbe attack, the lymphocytes and macrophages accumulate in the lymph glands and one gets “swollen glands.”

57. Humoral Immunity: B cells B cells, with antibodies on their surfaces, travel through the circulatory and lymphatic systems. B cells, with antibodies on their surfaces, travel through the circulatory and lymphatic systems. The B cells also secrete antibodies that circulate in the blood stream, interstitial fluid and lymph. The B cells also secrete antibodies that circulate in the blood stream, interstitial fluid and lymph.

58. Susumu Tonegawa (1987): Generation of Immune Diversity by Splicing Distant Segments of DNA How can lymphocytes create antibodies to millions of antigens when there are approximately 20-30 thousand different genes in a person? Susumu Tonegawa discovered that, in each lymphocyte clone, the antibody genes are formed by splicing segments of DNA in a unique way. By recombining segments of DNA, millions of genes and antibodies can be created.

60. Revolutionary Idea Before Susumu Tonegawa obtained experimental evidence that the DNA that encodes a single polypeptide in an antibody occurs in two widely separated regions of the genome in non-lymphocyte cells, this revolutionary theory, originally proffered by W. J. Dreyer and J. Bennett in 1965, was not taken seriously because it contradicted two of the most widely accepted dogmas of biology: – –one gene encodes one polypeptide – –the genome is constant during ontogeny and cell differentiation

62. B Cells When a B cell develops, its antibody gene is transcribed, the mRNA is translated and the resultant antibody proteins move through the secretory system until 100,000 of them become incorporated into the plasma membrane. When a B cell develops, its antibody gene is transcribed, the mRNA is translated and the resultant antibody proteins move through the secretory system until 100,000 of them become incorporated into the plasma membrane. These antibodies, which can be considered receptors for antigens, stick out of the plasma membrane. These antibodies, which can be considered receptors for antigens, stick out of the plasma membrane. Some of the antibodies produced are in the exocytotic vesicles and are not incorporated into the plasma membrane, but are secreted from the B cells into the blood (one of the four humors). Some of the antibodies produced are in the exocytotic vesicles and are not incorporated into the plasma membrane, but are secreted from the B cells into the blood (one of the four humors).

63. B Cells There are millions of different kinds of B cells. There are millions of different kinds of B cells. Each B cell has a different gene and produces a different antibody. Each B cell has a different gene and produces a different antibody. B cells that have the antibody to an antigen that enters the body become activated. B cells that have the antibody to an antigen that enters the body become activated.

64. B Cells The activated B cells divide to produce plasma cells and memory cells. The activated B cells divide to produce plasma cells and memory cells. The memory cells have the antibody on the B cell surface. The memory cells have the antibody on the B cell surface. The plasma cells live for 4-5 days producing and secreting a given antibody at a rate of 2000 molecules per second. The plasma cells live for 4-5 days producing and secreting a given antibody at a rate of 2000 molecules per second.

65. B Cells The memory cells, which live as long as the person does, are poised to divide into plasma cells that will rapidly produce antibodies and memory cells following a later exposure to the same antigen.

66. Only B Cells that Encounter their Antigen Propagate Every minute our body produces several million lymphocytes—each one expressing its unique antibody. If a B cell encounters its antigen, it will divide to form plasma cells and memory cells, which will last a lifetime. If a B cell does not encounter its antigen, it will die. “After the great randomized gene lottery natural selection will pick the winners, thereby generating specific immunity, the cheapest and most efficient protection there is against infections.”

67. Memory Cells and Acquired Immunity Acquired immunity results from the buildup of memory cells in your body. Acquired immunity results from the buildup of memory cells in your body. The number of types of B memory cells your body has depends on prior exposure to various antigens. The number of types of B memory cells your body has depends on prior exposure to various antigens.

68. Childhood Immunity A mother’s antibodies, but not her lymphocytes, are passed through the placenta from mother to child. Her antibodies and macrophages are passed through her breast milk. A mother’s antibodies, but not her lymphocytes, are passed through the placenta from mother to child. Her antibodies and macrophages are passed through her breast milk. These antibodies provide a child with immunity to many germs, including polio. These antibodies provide a child with immunity to many germs, including polio. While the child is immune, he/she can come in contact with these germs and build up his/her own acquired immunity, so that an infection will be fought in the child for the rest of his/her life by the powerful secondary immune response and he/she would not even realize they were infected. While the child is immune, he/she can come in contact with these germs and build up his/her own acquired immunity, so that an infection will be fought in the child for the rest of his/her life by the powerful secondary immune response and he/she would not even realize they were infected.

69. Dropped Pacifiers, Dirty Hands and Faces Exposure to some amount of dirt and germs during childhood primes the immune system so that the secondary immune response is armed and ready. Exposure to some amount of dirt and germs during childhood primes the immune system so that the secondary immune response is armed and ready. Antibacterial soaps kill germs, but they also slow down the priming of the immune system. Antibacterial soaps kill germs, but they also slow down the priming of the immune system.

70. How Polio Became a “Disease of the Clean” Polio is a contagious disease. Polio is a contagious disease. The polio virus enters the body through the mouth and leaves the body in the feces. By not flushing the toilet or washing one’s hands, the polio virus can be transferred between infected and uninfected people by the fecal-oral route. The polio virus enters the body through the mouth and leaves the body in the feces. By not flushing the toilet or washing one’s hands, the polio virus can be transferred between infected and uninfected people by the fecal-oral route. There was a polio epidemic in the United States in the 1950s. There was a polio epidemic in the United States in the 1950s. Consequently, health officials and scientists recommended good sanitary practices to prevent the spread of polio. Consequently, health officials and scientists recommended good sanitary practices to prevent the spread of polio.

75. How Polio Became a “Disease of the Clean” However, the recommended sanitary measures, including washing one’s hands, cleaning ones house and ensuring a polio virus-free water supply, prevents a child from developing acquired immunity to the polio virus while still being protected by his/her mother’s antibodies. However, the recommended sanitary measures, including washing one’s hands, cleaning ones house and ensuring a polio virus-free water supply, prevents a child from developing acquired immunity to the polio virus while still being protected by his/her mother’s antibodies. Consequently, a child or an adult, who has lost the protection of the maternal antibodies, but had not developed his/her own acquired immunity, could easily come down with polio. Consequently, a child or an adult, who has lost the protection of the maternal antibodies, but had not developed his/her own acquired immunity, could easily come down with polio. Consequently, polio predominantly infected those who followed the new sanitary guidelines. Consequently, polio predominantly infected those who followed the new sanitary guidelines.

76. Polio Vaccines Virtually Eradicated Polio Jonas Salk found that humans became immune to the polio virus when they were injected with a “formaldehyde-killed” virus. Jonas Salk found that humans became immune to the polio virus when they were injected with a “formaldehyde-killed” virus. Albert Sabin found that people became immune to the polio virus after eating a lump of sugar containing a live attenuated virus. The dead virus vaccine could be prepared quickly, but it took a while to find the conditions that would yield a live virus that could enter the body through the digestive system by itself and was safe. Albert Sabin found that people became immune to the polio virus after eating a lump of sugar containing a live attenuated virus. The dead virus vaccine could be prepared quickly, but it took a while to find the conditions that would yield a live virus that could enter the body through the digestive system by itself and was safe. The live-attenuated virus has an advantage in that it easily passes from the immunized person to his/her family and friends by the fecal-oral route resulting in the immunization of many people. The live-attenuated virus has an advantage in that it easily passes from the immunized person to his/her family and friends by the fecal-oral route resulting in the immunization of many people. Comic Book about Polio Vaccines

77. Eckard Wimmer (2002), who was Driven by Curiosity, Created a Synthetic Poliovirus that is Identical to the Natural Virus “Research on viruses is driven not only by an urgent need to understand, prevent, and cure viral disease. It is also fueled by a strong curiosity about the minute particles that we can view both as chemicals and as “living” entities.” “Research on viruses is driven not only by an urgent need to understand, prevent, and cure viral disease. It is also fueled by a strong curiosity about the minute particles that we can view both as chemicals and as “living” entities.” Should Scientists Create Synthetic Disease-Causing Viruses?

78. Allergies Allergies are an overreaction to common environmental antigens. Allergies are an overreaction to common environmental antigens. Antigens that cause (or generate) allergies are known as allergens. Antigens that cause (or generate) allergies are known as allergens. When a person is first exposed to an allergen, the allergen binds to the B cell with a complementary receptor. The activated B cells divide to form plasma cells which secrete antibodies to the allergen. When a person is first exposed to an allergen, the allergen binds to the B cell with a complementary receptor. The activated B cells divide to form plasma cells which secrete antibodies to the allergen.

79. Allergic Response These antibodies bind to receptors on Mast cells. These antibodies bind to receptors on Mast cells. When the antibodies on the mast cell recognize and bind the allergen, the mast cells secrete histamine, which triggers the inflammation response. When the antibodies on the mast cell recognize and bind the allergen, the mast cells secrete histamine, which triggers the inflammation response.

80. Antihistamine Histamine released from damaged mast cells causes blood capillaries to become leaky so the phagocytes can get to the region where the cells are damaged. Histamine released from damaged mast cells causes blood capillaries to become leaky so the phagocytes can get to the region where the cells are damaged. In the case of allergies, histamine released from mast cells does the same thing, but the fluid is just a nuisance causing nasal irritation and watery eyes. In the case of allergies, histamine released from mast cells does the same thing, but the fluid is just a nuisance causing nasal irritation and watery eyes. Antihistamines block the histamine receptor on the capillaries and consequently reduce the release of fluid. Antihistamines block the histamine receptor on the capillaries and consequently reduce the release of fluid.

81. The Histamine Receptors in the Stomach Differ from those in Blood Vessels Histamine increases the production of gastric acid. Histamine increases the production of gastric acid. James Whyte Black discovered that antihistamines, which successfully block the allergic reactions, do not inhibit the production of' gastric acid because the histamine receptors in the stomach (H-2 receptors) are different. James Whyte Black discovered that antihistamines, which successfully block the allergic reactions, do not inhibit the production of' gastric acid because the histamine receptors in the stomach (H-2 receptors) are different. Histamine-2 receptor blockers, including Tagamet, Zantac and Pepcid are effective treatments for ulcers. Histamine-2 receptor blockers, including Tagamet, Zantac and Pepcid are effective treatments for ulcers.

82. Anaphylactic Shock When a person is hypersensitive to a given allergen (e.g. peanut protein, bee venom and penicillin), an exposure to the antigen will cause all their mast cells to release histamine simultaneously. When a person is hypersensitive to a given allergen (e.g. peanut protein, bee venom and penicillin), an exposure to the antigen will cause all their mast cells to release histamine simultaneously. This will cause all the capillaries to become leaky and the blood pressure will suddenly and drastically drop. This will cause all the capillaries to become leaky and the blood pressure will suddenly and drastically drop. Anaphylactic shock can be thwarted by injecting adrenaline into the patient. Anaphylactic shock can be thwarted by injecting adrenaline into the patient.

83. Cell-Mediated Immunity: T Cells T cells proliferate into cytotoxic T cells, Helper T cells and memory T cells. T cells proliferate into cytotoxic T cells, Helper T cells and memory T cells. Cytotoxic T cells recognize and destroy the body’s own cells that have become infected or cancerous. Cytotoxic T cells recognize and destroy the body’s own cells that have become infected or cancerous.

84. Cytotoxic T Cells Cytotoxic T cells bind to body’s cells that have a non-self antigen bound to the surface. Cytotoxic T cells bind to body’s cells that have a non-self antigen bound to the surface. The cytotoxic T cells then synthesize and secrete a number of deadly proteins, one of which is known as perforin, a protein that kills the infected host cell by making holes in its membrane. The cytotoxic T cells then synthesize and secrete a number of deadly proteins, one of which is known as perforin, a protein that kills the infected host cell by making holes in its membrane.

85. Helper T Cells The macrophages that digest microbes interact with the rest of the immune system. They have receptor proteins that bind the antigen from the microbe. The macrophages that digest microbes interact with the rest of the immune system. They have receptor proteins that bind the antigen from the microbe. The antigen-receptor complex then migrates to the surface of the macrophage. The antigen-receptor complex then migrates to the surface of the macrophage.

86. Helper T Cells Helper T cells have receptors that bind to the macrophage receptor-antigen complex.Helper T cells have receptors that bind to the macrophage receptor-antigen complex. Each Helper T cell has only one type of receptor that recognizes only one macrophage receptor-antigen complex.Each Helper T cell has only one type of receptor that recognizes only one macrophage receptor-antigen complex.

87. Interleukins (or Cytokines) The macrophage secretes a protein known as interleukin-1 that promotes the binding of the Helper T cell to the macrophage. The macrophage secretes a protein known as interleukin-1 that promotes the binding of the Helper T cell to the macrophage. The Helper T cell, once bound to the macrophage receptor-antigen complex, secretes a protein known as interleukin-2, which activates B cells and T cells to divide in order to form B and T memory cells and more plasma B cells and cytotoxic T cells that can be used right away. The Helper T cell, once bound to the macrophage receptor-antigen complex, secretes a protein known as interleukin-2, which activates B cells and T cells to divide in order to form B and T memory cells and more plasma B cells and cytotoxic T cells that can be used right away. The protein is called interleukin because it is involved in communication between (inter) white blood cells (leukocytes). The protein is called interleukin because it is involved in communication between (inter) white blood cells (leukocytes).

88. Interleukin-1 and Fever Interleukin-1 travels to the hypothalamus and causes it to change the set-point for your body temperature higher than 98.6 ̊ F. Interleukin-1 travels to the hypothalamus and causes it to change the set-point for your body temperature higher than 98.6 ̊ F. Even though you have a fever, you feel cold when your temperature is less than the temperature of the set-point. Even though you have a fever, you feel cold when your temperature is less than the temperature of the set-point. When you have a fever, your blood is diverted from the skin to the core of the body to heat up the core. You also shiver to heat up your body core. All this makes you want to bundle up in bed. When you have a fever, your blood is diverted from the skin to the core of the body to heat up the core. You also shiver to heat up your body core. All this makes you want to bundle up in bed.

89. Interleukin-1 Makes you Feel Crummy Interleukin-1 also causes the hypothalamus to secrete releasing factors that activate the flight or flight response, which kills your appetite. Interleukin-1 also causes the hypothalamus to secrete releasing factors that activate the flight or flight response, which kills your appetite. Interleukin-1 also lowers the threshold of the nerves that carry stimuli from pain sensing neurons to the brain. Consequently, your joints begin to ache. Interleukin-1 also lowers the threshold of the nerves that carry stimuli from pain sensing neurons to the brain. Consequently, your joints begin to ache.

90. Interleukin-1, Prostaglandins and Aspirin Interleukin-1 causes fever, loss of appetite and pain through a signal transduction chain that involves the synthesis of prostaglandins. Interleukin-1 causes fever, loss of appetite and pain through a signal transduction chain that involves the synthesis of prostaglandins. Luckily, aspirin blocks prostaglandin synthesis and prevents the crummy feelings caused by interleukin-1 that are associated with being sick. Luckily, aspirin blocks prostaglandin synthesis and prevents the crummy feelings caused by interleukin-1 that are associated with being sick.

91. Acetaminophen The action of acetaminophen is not well understood. It blocks prostaglandin synthesis and it may also prevent pain by binding to the endogenous cannabinoid receptor in the brain.

92. Recombinant DNA Technology Makes Immuno-Boosters (Interleukins) Cheap and Accessible for People with Immune Deficiency Diseases (Although it also makes them feel crummy)

93. HIV Causes a Deficiency in the Immune System HIV (human immunodeficiency virus), which is the cause of AIDS (Acquired Immune Deficiency Syndrome), specifically binds to and destroys Helper T cells. HIV (human immunodeficiency virus), which is the cause of AIDS (Acquired Immune Deficiency Syndrome), specifically binds to and destroys Helper T cells. The depletion of Helper T cells drastically impairs the body’s ability to fight infections through cell-mediated immune responses. The depletion of Helper T cells drastically impairs the body’s ability to fight infections through cell-mediated immune responses.

94. Severe Combined Immunodeficiency Disease (SCID) One form of SCID results from the production of a mutant form of adenosine deaminase (ADA) by B cells and T cells. One form of SCID results from the production of a mutant form of adenosine deaminase (ADA) by B cells and T cells. Some clinical trials are underway to treat this immunodeficiency disease with gene therapy. Some clinical trials are underway to treat this immunodeficiency disease with gene therapy. Other clinical trials have been suspended because the random gene insertions has caused leukemia. Other clinical trials have been suspended because the random gene insertions has caused leukemia.

95. Autoimmune Diseases An out-of-control immune system causes trouble when the lymphocytes make antibodies directed against the body itself. An out-of-control immune system causes trouble when the lymphocytes make antibodies directed against the body itself. Lupus ( → ) occurs when the B cells make antibodies against the normal molecules in the body. The antibodies can be directed against a variety of organs. Lupus ( → ) occurs when the B cells make antibodies against the normal molecules in the body. The antibodies can be directed against a variety of organs. Type 1 diabetes occurs when the insulin-producing cells of the pancreas are the targets of Cytotoxic T cells. Type 1 diabetes occurs when the insulin-producing cells of the pancreas are the targets of Cytotoxic T cells. Multiple sclerosis occurs when the oligodendrocytes in the central nervous system are the targets of Cytotoxic T cells. Multiple sclerosis occurs when the oligodendrocytes in the central nervous system are the targets of Cytotoxic T cells. lupus.org

96. Lymphoma and Leukemia Lymphomas are cancers that occur in the lymphatic system and are caused by malignant lymphocytes (T cells and B cells). Lymphomas are cancers that occur in the lymphatic system and are caused by malignant lymphocytes (T cells and B cells). Leukemias are typically cancers that occur in the bone marrow or circulatory system and are caused by other kinds of malignant white blood cells. Leukemias are typically cancers that occur in the bone marrow or circulatory system and are caused by other kinds of malignant white blood cells.

97. Development of Lymphoid and Myeloid Cells [Granulocytes]

98. Biotechnology: Monoclonal Antibodies A mouse can be injected with an antigen and after it produces antibodies to the antigen, its B cells are isolated from its spleen. A mouse can be injected with an antigen and after it produces antibodies to the antigen, its B cells are isolated from its spleen. The B cells are then fused with cultured cancer cells and the fusion cells divide often and grow indefinitely, producing an antibody to the antigen injected into the mouse. The B cells are then fused with cultured cancer cells and the fusion cells divide often and grow indefinitely, producing an antibody to the antigen injected into the mouse. Single fusion cells are isolated and grown on culture plates. They produce a single kind of antibody. Single fusion cells are isolated and grown on culture plates. They produce a single kind of antibody.

99. Biotechnology: Monoclonal Antibodies A monoclonal antibody produced this way can become part of a diagnostic kit to detect molecules, like human chorionic gonadotropin, which is an indicator of pregnancy; or the antibody to HIV, which is an indicator of HIV infection.

100. Cell Mediated Immunity and Organ Transplants Unless one gets an organ from an identical twin, a transplanted organ will have cells whose surface is coated with antigens that are not recognized as “self” by the recipient’s immune system. Unless one gets an organ from an identical twin, a transplanted organ will have cells whose surface is coated with antigens that are not recognized as “self” by the recipient’s immune system. Consequently, the recipient’s Cytotoxic T cells will begin to kill the cells of the donated organ. Consequently, the recipient’s Cytotoxic T cells will begin to kill the cells of the donated organ. Luckily, cell-mediated immunity can be suppressed by the immunosuppressant drugs Cyclosporin and Tacrolimus. These immunosuppressant drugs are important in making organ transplants possible. Luckily, cell-mediated immunity can be suppressed by the immunosuppressant drugs Cyclosporin and Tacrolimus. These immunosuppressant drugs are important in making organ transplants possible.

101. Immunosuppressants are Isolated from Fungi and Actinobacteria Cyclosporin is produced by the fungus, Tolypocladium inflatum. Tacrolimus is produced by the Actinobacterium, Streptomyces tsukubaensis.

102. Individuality: How Our Blood Defines Us Agglutination or clumping will occur if the blood contains antibodies and antigens that bind to each other. Agglutination or clumping will occur if the blood contains antibodies and antigens that bind to each other. Blood Group A (A antigen on RBCs, B antibody in blood serum— can donate to A and AB). Blood Group A (A antigen on RBCs, B antibody in blood serum— can donate to A and AB). Blood Group B (B antigen on RBCs, A antibody in blood serum— can donate to B and AB). Blood Group B (B antigen on RBCs, A antibody in blood serum— can donate to B and AB). Blood Group AB (A and B antigens on RBCs, no antibodies in blood serum—universal recipient). Blood Group AB (A and B antigens on RBCs, no antibodies in blood serum—universal recipient). Blood Group O (No antigens on RBCs, A and B antibodies in blood serum—universal donor). Blood Group O (No antigens on RBCs, A and B antibodies in blood serum—universal donor). http://nobelprize.org/educational_games/

103. Aside: Abraham Lincoln Contracted Small Pox Just Before He Delivered the Gettysburg Address This portrait of President Abraham Lincoln was taken on November 8, 1863 by Alexander Gardner eight days before he delivered the Gettysburg Address. This portrait of President Abraham Lincoln was taken on November 8, 1863 by Alexander Gardner eight days before he delivered the Gettysburg Address.

104. Abraham Lincoln at Gettysburg rmc.library.cornell.edu

105. Abraham Lincoln Probably Had a Mild Case of Small Pox While He Delivered his Address at Gettysburg on November 19, 1863 Dr. Washington van Bibber told Abraham Lincoln when he returned from Gettysburg that he had "a touch of the varioloid." Dr. Washington van Bibber told Abraham Lincoln when he returned from Gettysburg that he had "a touch of the varioloid." Lincoln responded: "Then am I to understand that I have the small pox?” Van Bibber nodded his head, “yes”. Lincoln responded: "Then am I to understand that I have the small pox?” Van Bibber nodded his head, “yes”. Lincoln responded, "How interesting. I find every now and then that even unpleasant situations in life have certain compensation. As you came in just now, you passed through a room full of people. Do you have any idea what they are there for…they are there, every mother's son of them, for one purpose only: namely, to get something from me. For once in my life as president, I find myself in a position to give everybody something!" Lincoln responded, "How interesting. I find every now and then that even unpleasant situations in life have certain compensation. As you came in just now, you passed through a room full of people. Do you have any idea what they are there for…they are there, every mother's son of them, for one purpose only: namely, to get something from me. For once in my life as president, I find myself in a position to give everybody something!"

106. While Lincoln Survived Small Pox, William H. Johnson, Lincoln’s Valet, Was Not as Lucky William H. Johnson, Lincoln’s valet, traveled with him to Gettysburg. Johnson died of small pox two months later, and was buried at what is now Arlington National Cemetery.