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psychoneuroimmunology and hiv

Doug MacDonald PSY 760, 4/7/05. 2. Psychoneuroimmunology and HIV.

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psychoneuroimmunology and hiv

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    1. Psychoneuroimmunology and HIV Doug MacDonald PSY 760 April 7, 2005

    2. Doug MacDonald PSY 760, 4/7/05 2 Psychoneuroimmunology and HIV “Immunology 101” -- overview of the Immune System HIV – overview Psychoneuroimmunology Background Mechanisms Research Methodological Issues

    3. Doug MacDonald PSY 760, 4/7/05 3 Because the human body provides an ideal environment for many microbes, they try to pass your skin barrier and enter. Your immune system is a bodywide network of cells, tissues, and organs that has evolved to defend you against such “foreign” invasions. The proper targets of your immune system are infectious organisms--bacteria such as these streptococci; fungi (this one happens to be Candida, the cause of yeast infections); parasites, including these worm-like microbes that cause malaria; and viruses such as this SARS virus.Because the human body provides an ideal environment for many microbes, they try to pass your skin barrier and enter. Your immune system is a bodywide network of cells, tissues, and organs that has evolved to defend you against such “foreign” invasions. The proper targets of your immune system are infectious organisms--bacteria such as these streptococci; fungi (this one happens to be Candida, the cause of yeast infections); parasites, including these worm-like microbes that cause malaria; and viruses such as this SARS virus.

    4. Doug MacDonald PSY 760, 4/7/05 4 The organs involved with the immune system are called the lymphoid organs, which affect growth, development, and the release of lymphocytes (a type of infection-fighting white blood cell). The blood vessels and lymphatic vessels are important parts of the lymphoid organs, because they carry the lymphocytes to and from different areas in the body. Each lymphoid organ plays a role in the production and activation of lymphocytes. Lymphoid organs include: The Organs of the Immune System Bone Marrow -- All the cells of the immune system are initially derived from the bone marrow. They form through a process called hematopoiesis. During hematopoiesis, bone marrow-derived stem cells differentiate into either mature cells of the immune system or into precursors of cells that migrate out of the bone marrow to continue their maturation elsewhere. The bone marrow produces B cells, natural killer cells, granulocytes and immature thymocytes, in addition to red blood cells and platelets. Thymus -- The function of the thymus is to produce mature T cells. Immature thymocytes, also known as prothymocytes, leave the bone marrow and migrate into the thymus. Through a remarkable maturation process sometimes referred to as thymic education, T cells that are beneficial to the immune system are spared, while those T cells that might evoke a detrimental autoimmune response are eliminated. The mature T cells are then released into the bloodstream. Spleen -- The spleen is an immunologic filter of the blood. It is made up of B cells, T cells, macrophages, dendritic cells, natural killer cells and red blood cells. In addition to capturing foreign materials (antigens) from the blood that passes through the spleen, migratory macrophages and dendritic cells bring antigens to the spleen via the bloodstream. An immune response is initiated when the macrophage or dendritic cells present the antigen to the appropriate B or T cells. This organ can be thought of as an immunological conference center. In the spleen, B cells become activated and produce large amounts of antibody. Also, old red blood cells are destroyed in the spleen. The organs involved with the immune system are called the lymphoid organs, which affect growth, development, and the release of lymphocytes (a type of infection-fighting white blood cell). The blood vessels and lymphatic vessels are important parts of the lymphoid organs, because they carry the lymphocytes to and from different areas in the body. Each lymphoid organ plays a role in the production and activation of lymphocytes. Lymphoid organs include: The Organs of the Immune System Bone Marrow -- All the cells of the immune system are initially derived from the bone marrow. They form through a process called hematopoiesis. During hematopoiesis, bone marrow-derived stem cells differentiate into either mature cells of the immune system or into precursors of cells that migrate out of the bone marrow to continue their maturation elsewhere. The bone marrow produces B cells, natural killer cells, granulocytes and immature thymocytes, in addition to red blood cells and platelets.

    5. Doug MacDonald PSY 760, 4/7/05 5 The organs of your immune system are connected with one another and with other organs of the body by a network of lymphatic vessels. Lymphocytes can travel throughout the body using the blood vessels. The cells can also travel through a system of lymphatic vessels that closely parallels the body’s veins and arteries. Cells and fluids are exchanged between blood and lymphatic vessels, enabling the lymphatic system to monitor the body for invading microbes. The lymphatic vessels carry lymph, a clear fluid that bathes the body’s tissues. Lymph Nodes -- The lymph nodes function as an immunologic filter for the bodily fluid known as lymph. Lymph nodes are found throughout the body. Composed mostly of T cells, B cells, dendritic cells and macrophages, the nodes drain fluid from most of our tissues. Antigens are filtered out of the lymph in the lymph node before returning the lymph to the circulation. In a similar fashion as the spleen, the macrophages and dendritic cells that capture antigens present these foreign materials to T and B cells, consequently initiating an immune response. The Lymphatic System | Back to Top The lymphatic system is composed of lymph vessels, lymph nodes, and organs. The functions of this system include the absorbtion of excess fluid and its return to the blood stream, absorption of fat (in the villi of the small intestine) and the immune system function. Lymph vessels are closely associated with the circulatory system vessels. Larger lymph vessels are similar to veins. Lymph capillaries are scatted throughout the body. Contraction of skeletal muscle causes movement of the lymph fluid through valves. Lymph organs include the bone marrow, lymph nodes, spleen, and thymus. Bone marrow contains tissue that produces lymphocytes. B-lymphocytes (B-cells) mature in the bone marrow. T-lymphocytes (T-cells) mature in the thymus gland. Other blood cells such as monocytes and leukocytes are produced in the bone marrow. Lymph nodes are areas of concentrated lymphocytes and macrophages along the lymphatic veins. The spleen is similar to the lymph node except that it is larger and filled with blood. The spleen serves as a reservoir for blood, and filters or purifies the blood and lymph fluid that flows through it. If the spleen is damaged or removed, the individual is more susceptible to infections. The thymus secretes a hormone, thymosin, that causes pre-T-cells to mature (in the thymus) into T-cells. Once mature, some lymphocytes will be housed in the lymphoid organs, while others will travel continuously around the body through the lymphatic vessels and bloodstream. LINK TO DEPRESSION.The organs of your immune system are connected with one another and with other organs of the body by a network of lymphatic vessels. Lymphocytes can travel throughout the body using the blood vessels. The cells can also travel through a system of lymphatic vessels that closely parallels the body’s veins and arteries. Cells and fluids are exchanged between blood and lymphatic vessels, enabling the lymphatic system to monitor the body for invading microbes. The lymphatic vessels carry lymph, a clear fluid that bathes the body’s tissues. Lymph Nodes -- The lymph nodes function as an immunologic filter for the bodily fluid known as lymph. Lymph nodes are found throughout the body. Composed mostly of T cells, B cells, dendritic cells and macrophages, the nodes drain fluid from most of our tissues. Antigens are filtered out of the lymph in the lymph node before returning the lymph to the circulation. In a similar fashion as the spleen, the macrophages and dendritic cells that capture antigens present these foreign materials to T and B cells, consequently initiating an immune response. The Lymphatic System | Back to Top The lymphatic system is composed of lymph vessels, lymph nodes, and organs. The functions of this system include the absorbtion of excess fluid and its return to the blood stream, absorption of fat (in the villi of the small intestine) and the immune system function. Lymph vessels are closely associated with the circulatory system vessels. Larger lymph vessels are similar to veins. Lymph capillaries are scatted throughout the body. Contraction of skeletal muscle causes movement of the lymph fluid through valves. Lymph organs include the bone marrow, lymph nodes, spleen, and thymus. Bone marrow contains tissue that produces lymphocytes. B-lymphocytes (B-cells) mature in the bone marrow. T-lymphocytes (T-cells) mature in the thymus gland. Other blood cells such as monocytes and leukocytes are produced in the bone marrow. Lymph nodes are areas of concentrated lymphocytes and macrophages along the lymphatic veins. The spleen is similar to the lymph node except that it is larger and filled with blood. The spleen serves as a reservoir for blood, and filters or purifies the blood and lymph fluid that flows through it. If the spleen is damaged or removed, the individual is more susceptible to infections. The thymus secretes a hormone, thymosin, that causes pre-T-cells to mature (in the thymus) into T-cells. Once mature, some lymphocytes will be housed in the lymphoid organs, while others will travel continuously around the body through the lymphatic vessels and bloodstream. LINK TO DEPRESSION.

    6. Doug MacDonald PSY 760, 4/7/05 6 Natural and Acquired Immunity Natural immunity: created by the body's natural barriers, such as the skin, and protective substances in the mouth, the urinary tract, and on the eye surface. Acquired immunity: develops through exposure to specific foreign microorganisms, toxins, and/or foreign tissues, which are "remembered" by the body's immune system. When that antigen enters the body again, the immune system "remembers" exactly how to respond to it. Natural immunity is created by the body's natural barriers, such as the skin, and protective substances in the mouth, the urinary tract, and on the eye surface. Another type of natural immunity is in the form of antibodies passed on from mother to child. Acquired immunity develops through exposure to specific foreign microorganisms, toxins, and/or foreign tissues), which are "remembered" by the body's immune system. When that antigen enters the body again, the immune system "remembers" exactly how to respond to it, such as with chickenpox. Once a person is exposed to chickenpox or the chickenpox vaccine, the immune system will produce specific antibodies against chickenpox. When that same person is exposed to chickenpox again, the immune system will trigger the release of the particular chickenpox antibodies to fight the disease. Natural immunity is created by the body's natural barriers, such as the skin, and protective substances in the mouth, the urinary tract, and on the eye surface. Another type of natural immunity is in the form of antibodies passed on from mother to child. Acquired immunity develops through exposure to specific foreign microorganisms, toxins, and/or foreign tissues), which are "remembered" by the body's immune system. When that antigen enters the body again, the immune system "remembers" exactly how to respond to it, such as with chickenpox. Once a person is exposed to chickenpox or the chickenpox vaccine, the immune system will produce specific antibodies against chickenpox. When that same person is exposed to chickenpox again, the immune system will trigger the release of the particular chickenpox antibodies to fight the disease.

    7. Doug MacDonald PSY 760, 4/7/05 7 The immune system: two components Non-Specific: They are generally able to distinguish foreign antigens, but are unable to recognize specific invaders. They will respond to a foreign antigen in the same manner, despite repeated exposures. They do not adapt and improve their effectiveness against previously encountered antigens. Include: Physical Barriers: skin, mucosa, stomach acid Chemical Agents: lysozymes, complement Effector Cells: macrophages, natural killer cells The immune system is divided into two components, non-specific and specific, though the breakdown is for classification purposes only as there is a constant and complex interaction, coordination and communication between all parts of the immune system. Non-Specific: also referred to as innate or non-adaptive. They are generally able to distinguish foreign antigens, but are unable to recognize specific invaders. They will respond to a foreign antigen in the same manner, despite repeated exposures. They do not adapt and improve their effectiveness against previously encountered antigens. Non-specific components include: Physical Barriers: skin, mucosa, stomach acid Chemical Agents: lysozymes, complement Effector Cells: macrophages, natural killer cells Non-specific immune response [back to top] [back to top] Physical, chemical and cellular defenses that prevent microbes from entering the body Present from birth. A quick-response system effective against a wide range of pathogens and foreign substances. This system does not distinguish between different pathogens It always gives the same response. The immune system is divided into two components, non-specific and specific, though the breakdown is for classification purposes only as there is a constant and complex interaction, coordination and communication between all parts of the immune system. Non-Specific: also referred to as innate or non-adaptive. They are generally able to distinguish foreign antigens, but are unable to recognize specific invaders. They will respond to a foreign antigen in the same manner, despite repeated exposures. They do not adapt and improve their effectiveness against previously encountered antigens. Non-specific components include: Physical Barriers: skin, mucosa, stomach acid Chemical Agents: lysozymes, complement Effector Cells: macrophages, natural killer cells Non-specific immune response [back to top] [back to top] Physical, chemical and cellular defenses that prevent microbes from entering the body Present from birth. A quick-response system effective against a wide range of pathogens and foreign substances. This system does not distinguish between different pathogens It always gives the same response.

    8. Doug MacDonald PSY 760, 4/7/05 8 The immune system: two components Specific: also referred to as acquired immunity or adaptive. able to distinguish foreign cells from self cells and can distinguish one foreign antigen from another. Acquired immunity cells have mechanisms for selecting a precisely defined target and for remembering the specific antigen so that subsequent exposures will result in a more effective and efficient response. Components of the specific system are broken down into 2 categories: humoral (B-cells, antibodies) cell mediated. (T-cells) The immune system is divided into two components, non-specific and specific, though the breakdown is for classification purposes only as there is a constant and complex interaction, coordination and communication between all parts of the immune system. Specific: also referred to as acquired immunity or adaptive. Is able to distinguish foreign cells from self cells and can distinguish one foreign antigen from another. Acquired immunity cells have mechanisms for selecting a precisely defined target and for remembering the specific antigen so that subsequent exposures will result in a more effective and efficient response. Components of the specific system are broken down into 2 categories, humoral and cell mediated. Specific immune response    [back to top]    [back to top] Specific immune response occurs when a particular antigen passes the body’s passive defenses. It involves cells and proteins within the blood and lymph that attach, disarm, destroy and remove foreign bodies.   The specific system gives a highly effective, long lasting immunity against anything the body recognise as foreign. It responds to specific microorganisms and enhances the activity of the non-specific system. Antibody-mediated (humoral immunity) Antibody-mediated (humoral) immunity is regulated by B cells and the antibodies they produce. Cell-mediated immunity is controlled by T cells. Antibody-mediated reactions defend against invading viruses and bacteria. Cell-mediated immunity concerns cells in the body that have been infected by viruses and bacteria, protect against parasites, fungi, and protozoans, and also kill cancerous body cells.The immune system is divided into two components, non-specific and specific, though the breakdown is for classification purposes only as there is a constant and complex interaction, coordination and communication between all parts of the immune system. Specific: also referred to as acquired immunity or adaptive. Is able to distinguish foreign cells from self cells and can distinguish one foreign antigen from another. Acquired immunity cells have mechanisms for selecting a precisely defined target and for remembering the specific antigen so that subsequent exposures will result in a more effective and efficient response. Components of the specific system are broken down into 2 categories, humoral and cell mediated. Specific immune response    [back to top]    [back to top] Specific immune response occurs when a particular antigen passes the body’s passive defenses. It involves cells and proteins within the blood and lymph that attach, disarm, destroy and remove foreign bodies.   The specific system gives a highly effective, long lasting immunity against anything the body recognise as foreign. It responds to specific microorganisms and enhances the activity of the non-specific system. Antibody-mediated (humoral immunity) Antibody-mediated (humoral) immunity is regulated by B cells and the antibodies they produce. Cell-mediated immunity is controlled by T cells. Antibody-mediated reactions defend against invading viruses and bacteria. Cell-mediated immunity concerns cells in the body that have been infected by viruses and bacteria, protect against parasites, fungi, and protozoans, and also kill cancerous body cells.

    9. Doug MacDonald PSY 760, 4/7/05 9 Cells of the Immune System What are lymphocytes? Lymphocytes - a type of infection-fighting white blood cell - are vital to an effective immune system. Lymphocytes "patrol" the body for infectious microorganisms. How are lymphocytes formed? All cells, including immune cells such as lymphocytes, are produced in the bone marrow (the soft, fatty tissue found in bone cavities). Certain cells will become part of the group of lymphocytes, while others will become part of another type of immune cells known as phagocytes. Once the lymphocytes are initially formed, some will continue to mature in the bone marrow and become "B" cells. Other lymphocytes will finish their maturation in the thymus and become "T" cells. B and T cells are the two major groups of lymphocytes which recognize and attack infectious microorganisms. The Cells of the Immune System T-Cells -- T lymphocytes are usually divided into two major subsets that are functionally and phenotypically (identifiably) different. The T helper subset, also called the CD4+ T cell, is a pertinent coordinator of immune regulation. The main function of the T helper cell is to augment or potentiate immune responses by the secretion of specialized factors that activate other white blood cells to fight off infection. Another important type of T cell is called the T killer/suppressor subset or CD8+ T cell. These cells are important in directly killing certain tumor cells, viral-infected cells and sometimes parasites. The CD8+ T cells are also important in down-regulation of immune responses. Both types of T cells can be found throughout the body. They often depend on the secondary lymphoid organs (the lymph nodes and spleen) as sites where activation occurs, but they are also found in other tissues of the body, most conspicuously the liver, lung, blood, and intestinal and reproductive tracts. Natural Killer Cells -- Natural killer cells, often referred to as NK cells, are similar to the killer T cell subset (CD8+ T cells). They function as effector cells that directly kill certain tumors such as melanomas, lymphomas and viral-infected cells, most notably herpes and cytomegalovirus-infected cells. NK cells, unlike the CD8+ (killer) T cells, kill their targets without a prior "conference" in the lymphoid organs. However, NK cells that have been activated by secretions from CD4+ T cells will kill their tumor or viral-infected targets more effectively. B Cells -- The major function of B lymphocytes is the production of antibodies in response to foreign proteins of bacteria, viruses, and tumor cells. Antibodies are specialized proteins that specifically recognize and bind to one particular protein that specifically recognize and bind to one particular protein. Antibody production and binding to a foreign substance or antigen, often is critical as a means of signaling other cells to engulf, kill or remove that substance from the body. Granulocytes or Polymorphonuclear (PMN) Leukocytes -- Another group of white blood cells is collectively referred to as granulocytes or polymorphonuclear leukocytes (PMNs). Granulocytes are composed of three cell types identified as neutrophils, eosinophils and basophils, based on their staining characteristics with certain dyes. These cells are predominantly important in the removal of bacteria and parasites from the body. They engulf these foreign bodies and degrade them using their powerful enzymes. Macrophages -- Macrophages are important in the regulation of immune responses. They are often referred to as scavengers or antigen-presenting cells (APC) because they pick up and ingest foreign materials and present these antigens to other cells of the immune system such as T cells and B cells. This is one of the important first steps in the initiation of an immune response. Stimulated macrophages exhibit increased levels of phagocytosis and are also secretory. Dendritic Cells -- Another cell type, addressed only recently, is the dendritic cell. Dendritic cells, which also originate in the bone marrow, function as antigen presenting cells (APC). In fact, the dendritic cells are more efficient apcs than macrophages. These cells are usually found in the structural compartment of the lymphoid organs such as the thymus, lymph nodes and spleen. However, they are also found in the bloodstream and other tissues of the body. It is believed that they capture antigen or bring it to the lymphoid organs where an immune response is initiated. Unfortunately, one reason we know so little about dendritic cells is that they are extremely hard to isolate, which is often a prerequisite for the study of the functional qualities of specific cell types. Of particular issue here is the recent finding that dendritic cells bind high amount of HIV, and may be a reservoir of virus that is transmitted to CD4+ T cells during an activation event. Once mature, some lymphocytes will be housed in the lymphoid organs, while others will travel continuously around the body through the lymphatic vessels and bloodstream. How do lymphocytes fight infection? Although each type of lymphocyte fights infection differently, the goal of protecting the body from infection remains the same. The B cells actually produce specific antibodies to specific infectious microorganisms, while T cells kill infectious microorganisms by killing the body cells that are affected. In addition, T cells release chemicals, called lymphokines, which trigger an immune response to combat cancer or a virus, for example. Other types of white blood cells, such as phagocytes (engulfing cells) and cytotoxic cells (natural killer cells), actually kill the infectious microorganism by "devouring" it.What are lymphocytes? Lymphocytes - a type of infection-fighting white blood cell - are vital to an effective immune system. Lymphocytes "patrol" the body for infectious microorganisms. How are lymphocytes formed? All cells, including immune cells such as lymphocytes, are produced in the bone marrow (the soft, fatty tissue found in bone cavities). Certain cells will become part of the group of lymphocytes, while others will become part of another type of immune cells known as phagocytes. Once the lymphocytes are initially formed, some will continue to mature in the bone marrow and become "B" cells. Other lymphocytes will finish their maturation in the thymus and become "T" cells. B and T cells are the two major groups of lymphocytes which recognize and attack infectious microorganisms. The Cells of the Immune System T-Cells -- T lymphocytes are usually divided into two major subsets that are functionally and phenotypically (identifiably) different. The T helper subset, also called the CD4+ T cell, is a pertinent coordinator of immune regulation. The main function of the T helper cell is to augment or potentiate immune responses by the secretion of specialized factors that activate other white blood cells to fight off infection.

    10. Doug MacDonald PSY 760, 4/7/05 10 Some immune cells have more than one name. For example, the name “phagocytes” is given to the large immune cells that can engulf and digest foreign invaders, and the name “granulocytes” refers to immune cells that carry granules laden with killer chemicals. Phagocytes include monocytes, which circulate in the blood; macrophages, which are found in tissues throughout the body; dendritic cells, which are more stationary, monitoring their environment from one spot such as the skin; and neutrophils, cells that circulate in the blood but move into tissues when they are needed. Macrophages are versatile cells; besides acting as phagocytic scavengers, they secrete a wide variety of signaling cytokines (called monokines) that are vital to the immune response. Neutrophils are both phagocytes and granulocytes: they contain granules filled with potent chemicals. These chemicals, in addition to destroying microorganisms, play a key role in acute inflammatory reactions. Other types of granulocytes are eosinophils and basophils, which degranulate by spraying their chemicals onto harmful cells or microbes. The mast cell is a twin of the basophil, except it is not a blood cell. Rather, it is responsible for allergy symptoms in the lungs, skin, and linings of the nose and intestinal tract. A related structure, the blood platelet, is a cell fragment. Platelets, too, contain granules. They promote blood clotting and wound repair, and activate some immune defenses. Some immune cells have more than one name. For example, the name “phagocytes” is given to the large immune cells that can engulf and digest foreign invaders, and the name “granulocytes” refers to immune cells that carry granules laden with killer chemicals. Phagocytes include monocytes, which circulate in the blood; macrophages, which are found in tissues throughout the body; dendritic cells, which are more stationary, monitoring their environment from one spot such as the skin; and neutrophils, cells that circulate in the blood but move into tissues when they are needed. Macrophages are versatile cells; besides acting as phagocytic scavengers, they secrete a wide variety of signaling cytokines (called monokines) that are vital to the immune response. Neutrophils are both phagocytes and granulocytes: they contain granules filled with potent chemicals. These chemicals, in addition to destroying microorganisms, play a key role in acute inflammatory reactions. Other types of granulocytes are eosinophils and basophils, which degranulate by spraying their chemicals onto harmful cells or microbes. The mast cell is a twin of the basophil, except it is not a blood cell. Rather, it is responsible for allergy symptoms in the lungs, skin, and linings of the nose and intestinal tract. A related structure, the blood platelet, is a cell fragment. Platelets, too, contain granules. They promote blood clotting and wound repair, and activate some immune defenses.

    11. Doug MacDonald PSY 760, 4/7/05 11 B cells work chiefly by secreting soluble substances known as antibodies. They mill around a lymph node, waiting for a macrophage to bring an antigen or for an invader such as a bacteria to arrive. When an antigen-specific antibody on a B cell matches up with an antigen, a remarkable transformation occurs. The antigen binds to the antibody receptor, the B cell engulfs it, and, after a special helper T cell joins the action, the B cell becomes a large plasma cell factory that produces identical copies of specific antibody molecules at an astonishing pace--up to 10 million copies an hour. Humoral immunity An immunocompetent but as yet immature B-lymphocyte is stimulated to maturity when an antigen binds to its surface receptors and there is a T helper cell nearby (to release a cytokine). This sensitizes or primes the B cell and it undergoes clonal selection, which means it reproduces asexually by mitosis. Most of the family of clones become plasma cells. These cells, after an initial lag, produce highly specific antibodies at a rate of as many as 2000 molecules per second for four to five days. The other B cells become long-lived memory cells. Antibodies, also called immunoglobulins or Igs [with molecular weights of 150–900 Md], constitute the gamma globulin part of the blood proteins. They are soluble proteins secreted by the plasma offspring (clones) of primed B cells. The antibodies inactivate antigens B cells work chiefly by secreting soluble substances known as antibodies. They mill around a lymph node, waiting for a macrophage to bring an antigen or for an invader such as a bacteria to arrive. When an antigen-specific antibody on a B cell matches up with an antigen, a remarkable transformation occurs. The antigen binds to the antibody receptor, the B cell engulfs it, and, after a special helper T cell joins the action, the B cell becomes a large plasma cell factory that produces identical copies of specific antibody molecules at an astonishing pace--up to 10 million copies an hour. Humoral immunity An immunocompetent but as yet immature B-lymphocyte is stimulated to maturity when an antigen binds to its surface receptors and there is a T helper cell nearby (to release a cytokine). This sensitizes or primes the B cell and it undergoes clonal selection, which means it reproduces asexually by mitosis. Most of the family of clones become plasma cells. These cells, after an initial lag, produce highly specific antibodies at a rate of as many as 2000 molecules per second for four to five days. The other B cells become long-lived memory cells. Antibodies, also called immunoglobulins or Igs [with molecular weights of 150–900 Md], constitute the gamma globulin part of the blood proteins. They are soluble proteins secreted by the plasma offspring (clones) of primed B cells. The antibodies inactivate antigens

    12. Doug MacDonald PSY 760, 4/7/05 12 T cells contribute to your immune defenses in two major ways. Some help regulate the complex workings of the overall immune response, while others are cytotoxic and directly contact infected cells and destroy them. Chief among the regulatory T cells are helper T cells. They are needed to activate many immune cells, including B cells and other T cells. Cytotoxic T cells (sometimes called killer T cells) help rid your body of cells that have been infected by viruses as well as cells that have been transformed by cancer but have not yet adapted to evade the immune detection system. They are also responsible for the rejection of tissue and organ grafts.  Cell-mediated immunity Macrophages engulf antigens, process them internally, then display parts of them on their surface together with some of their own proteins. This sensitizes the T cells to recognize these antigens. All cells are coated with various substances. CD stands for cluster of differentiation and there are more than one hundred and sixty clusters, each of which is a different chemical molecule that coats the surface. CD8+ is read "CD8 positive." Every T and B cell has about 105 = 100,000 molecules on its surface. B cells are coated with CD21, CD35, CD40, and CD45 in addition to other non-CD molecules. T cells have CD2, CD3, CD4, CD28, CD45R, and other non-CD molecules on their surfaces. The large number of molecules on the surfaces of lymphocytes allows huge variability in the forms of the receptors. They are produced with random configurations on their surfaces. There are some 1018 different structurally different receptors. Essentially, an antigen may find a near-perfect fit with a very small number of lymphocytes, perhaps as few as one. T cells are primed in the thymus, where they undergo two selection processes. The first positive selection process weeds out only those T cells with the correct set of receptors that can recognize the MHC molecules responsible for self-recognition. Then a negative selection process begins whereby T cells that can recognize MHC molecules complexed with foreign peptides are allowed to pass out of the thymus. Cytotoxic or killer T cells (CD8+) do their work by releasing lymphotoxins, which cause cell lysis. Helper T cells (CD4+) serve as managers, directing the immune response. They secrete chemicals called lymphokines that stimulate cytotoxic T cells and B cells to grow and divide, attract neutrophils, and enhance the ability of macrophages to engulf and destroy microbes. Suppressor T cells inhibit the production of cytotoxic T cells once they are unneeded, lest they cause more damage than necessary. Memory T cells are programmed to recognize and respond to a pathogen once it has invaded and been repelled.T cells contribute to your immune defenses in two major ways. Some help regulate the complex workings of the overall immune response, while others are cytotoxic and directly contact infected cells and destroy them. Chief among the regulatory T cells are helper T cells. They are needed to activate many immune cells, including B cells and other T cells. Cytotoxic T cells (sometimes called killer T cells) help rid your body of cells that have been infected by viruses as well as cells that have been transformed by cancer but have not yet adapted to evade the immune detection system. They are also responsible for the rejection of tissue and organ grafts.  Cell-mediated immunity Macrophages engulf antigens, process them internally, then display parts of them on their surface together with some of their own proteins. This sensitizes the T cells to recognize these antigens. All cells are coated with various substances. CD stands for cluster of differentiation and there are more than one hundred and sixty clusters, each of which is a different chemical molecule that coats the surface. CD8+ is read "CD8 positive." Every T and B cell has about 105 = 100,000 molecules on its surface. B cells are coated with CD21, CD35, CD40, and CD45 in addition to other non-CD molecules. T cells have CD2, CD3, CD4, CD28, CD45R, and other non-CD molecules on their surfaces. The large number of molecules on the surfaces of lymphocytes allows huge variability in the forms of the receptors. They are produced with random configurations on their surfaces. There are some 1018 different structurally different receptors. Essentially, an antigen may find a near-perfect fit with a very small number of lymphocytes, perhaps as few as one. T cells are primed in the thymus, where they undergo two selection processes. The first positive selection process weeds out only those T cells with the correct set of receptors that can recognize the MHC molecules responsible for self-recognition. Then a negative selection process begins whereby T cells that can recognize MHC molecules complexed with foreign peptides are allowed to pass out of the thymus. Cytotoxic or killer T cells (CD8+) do their work by releasing lymphotoxins, which cause cell lysis. Helper T cells (CD4+) serve as managers, directing the immune response. They secrete chemicals called lymphokines that stimulate cytotoxic T cells and B cells to grow and divide, attract neutrophils, and enhance the ability of macrophages to engulf and destroy microbes. Suppressor T cells inhibit the production of cytotoxic T cells once they are unneeded, lest they cause more damage than necessary. Memory T cells are programmed to recognize and respond to a pathogen once it has invaded and been repelled.

    13. Doug MacDonald PSY 760, 4/7/05 13 At least two types of lymphocytes are killer cells--cytotoxic T cells and natural killer cells. Both types contain granules filled with potent chemicals. Both types kill on contact. They bind their targets, aim their weapons, and deliver bursts of lethal chemicals. To attack, cytotoxic T cells need to recognize a specific antigen bound to self-MHC markers, whereas natural killer (NK) cells will recognize and attack cells lacking these. This gives NK cells the potential to attack many types of foreign cells. At least two types of lymphocytes are killer cells--cytotoxic T cells and natural killer cells. Both types contain granules filled with potent chemicals. Both types kill on contact. They bind their targets, aim their weapons, and deliver bursts of lethal chemicals. To attack, cytotoxic T cells need to recognize a specific antigen bound to self-MHC markers, whereas natural killer (NK) cells will recognize and attack cells lacking these. This gives NK cells the potential to attack many types of foreign cells.

    14. Doug MacDonald PSY 760, 4/7/05 14 Cytokines are diverse and potent chemical messengers secreted by the cells of your immune system. They are the chief communication signals of your T cells. Cytokines include interleukins, growth factors, and interferons. Lymphocytes, including both T cells and B cells, secrete cytokines called lymphokines, while the cytokines of monocytes and macrophages are dubbed monokines. Many of these cytokines are also known as interleukins because they serve as a messenger between white cells, or leukocytes. Interferons are naturally occurring cytokines that may boost the immune system’s ability to recognize cancer as a foreign invader. Binding to specific receptors on target cells, cytokines recruit many other cells and substances to the field of action. Cytokines encourage cell growth, promote cell activation, direct cellular traffic, and destroy target cells--including cancer cells. When cytokines attract specific cell types to an area, they are called chemokines. These are released at the site of injury or infection and call other immune cells to the region to help repair damage and defend against infection. Cytokines are diverse and potent chemical messengers secreted by the cells of your immune system. They are the chief communication signals of your T cells. Cytokines include interleukins, growth factors, and interferons. Lymphocytes, including both T cells and B cells, secrete cytokines called lymphokines, while the cytokines of monocytes and macrophages are dubbed monokines. Many of these cytokines are also known as interleukins because they serve as a messenger between white cells, or leukocytes. Interferons are naturally occurring cytokines that may boost the immune system’s ability to recognize cancer as a foreign invader. Binding to specific receptors on target cells, cytokines recruit many other cells and substances to the field of action. Cytokines encourage cell growth, promote cell activation, direct cellular traffic, and destroy target cells--including cancer cells. When cytokines attract specific cell types to an area, they are called chemokines. These are released at the site of injury or infection and call other immune cells to the region to help repair damage and defend against infection.

    15. Doug MacDonald PSY 760, 4/7/05 15 Microbes attempting to get into your body must first get past your skin and mucous membranes, which not only pose a physical barrier but are rich in scavenger cells and IgA antibodies. Next, they must elude a series of nonspecific defenses--and substances that attack all invaders regardless of the epitopes they carry. These include patrolling phagocytes, granulocytes, NK cells, and complement. Infectious agents that get past these nonspecific barriers must finally confront specific weapons tailored just for them. These include both antibodies and cytotoxic T cells. Antibody-mediated Immunity | Back to Top Stages in this process are: antigen detection activation of helper T cells antibody production by B cells Each stage is directed by a specific cell type. Macrophages Macrophages are white blood cells that continually search for foreign (nonself) antigenic molecules, viruses, or microbes. When found, the macrophages engulfs and destroys them. Small fragments of the antigen are displayed on the outer surface of the macrophage plasma membrane.Microbes attempting to get into your body must first get past your skin and mucous membranes, which not only pose a physical barrier but are rich in scavenger cells and IgA antibodies. Next, they must elude a series of nonspecific defenses--and substances that attack all invaders regardless of the epitopes they carry. These include patrolling phagocytes, granulocytes, NK cells, and complement. Infectious agents that get past these nonspecific barriers must finally confront specific weapons tailored just for them. These include both antibodies and cytotoxic T cells. Antibody-mediated Immunity | Back to Top Stages in this process are: antigen detection activation of helper T cells antibody production by B cells Each stage is directed by a specific cell type. Macrophages Macrophages are white blood cells that continually search for foreign (nonself) antigenic molecules, viruses, or microbes. When found, the macrophages engulfs and destroys them. Small fragments of the antigen are displayed on the outer surface of the macrophage plasma membrane.

    16. Doug MacDonald PSY 760, 4/7/05 16 Microbes attempting to get into your body must first get past your skin and mucous membranes, which not only pose a physical barrier but are rich in scavenger cells and IgA antibodies. Next, they must elude a series of nonspecific defenses--and substances that attack all invaders regardless of the epitopes they carry. These include patrolling phagocytes, granulocytes, NK cells, and complement. Infectious agents that get past these nonspecific barriers must finally confront specific weapons tailored just for them. These include both antibodies and cytotoxic T cells. Antibody-mediated Immunity | Back to Top Stages in this process are: antigen detection activation of helper T cells antibody production by B cells Each stage is directed by a specific cell type. Macrophages Macrophages are white blood cells that continually search for foreign (nonself) antigenic molecules, viruses, or microbes. When found, the macrophages engulfs and destroys them. Small fragments of the antigen are displayed on the outer surface of the macrophage plasma membrane. The role of macrophages in the formation of antibodies. Image from Purves et al., Life: The Science of Biology, 4th Edition, by Sinauer Associates (www.sinauer.com) and WH Freeman (www.whfreeman.com), used with permission. Helper T Cells Helper T cells are macrophages that become activated when they encounter the antigens now displayed on the macrophage surface. Activated T cells identify and activate B cells. The display path of an antigen as accomplished by a macrophage. Image from Purves et al., Life: The Science of Biology, 4th Edition, by Sinauer Associates (www.sinauer.com) and WH Freeman (www.whfreeman.com), used with permission. B Cells B cells divide, forming plasma cells and B memory cells. Plasma cells make and release between 2000 and 20,000 antibody molecules per second into the blood for the next four or five days. B memory cells live for months or years, and are part of the immune memory system Antibody-mediated Immunity | Back to Top Stages in this process are: antigen detection activation of helper T cells antibody production by B cells Each stage is directed by a specific cell type. Macrophages Macrophages are white blood cells that continually search for foreign (nonself) antigenic molecules, viruses, or microbes. When found, the macrophages engulfs and destroys them. Small fragments of the antigen are displayed on the outer surface of the macrophage plasma membrane.Microbes attempting to get into your body must first get past your skin and mucous membranes, which not only pose a physical barrier but are rich in scavenger cells and IgA antibodies. Next, they must elude a series of nonspecific defenses--and substances that attack all invaders regardless of the epitopes they carry. These include patrolling phagocytes, granulocytes, NK cells, and complement. Infectious agents that get past these nonspecific barriers must finally confront specific weapons tailored just for them. These include both antibodies and cytotoxic T cells. Antibody-mediated Immunity | Back to Top Stages in this process are: antigen detection activation of helper T cells antibody production by B cells Each stage is directed by a specific cell type. Macrophages Macrophages are white blood cells that continually search for foreign (nonself) antigenic molecules, viruses, or microbes. When found, the macrophages engulfs and destroys them. Small fragments of the antigen are displayed on the outer surface of the macrophage plasma membrane. The role of macrophages in the formation of antibodies. Image from Purves et al., Life: The Science of Biology, 4th Edition, by Sinauer Associates (www.sinauer.com) and WH Freeman (www.whfreeman.com), used with permission. Helper T Cells Helper T cells are macrophages that become activated when they encounter the antigens now displayed on the macrophage surface. Activated T cells identify and activate B cells. The display path of an antigen as accomplished by a macrophage. Image from Purves et al., Life: The Science of Biology, 4th Edition, by Sinauer Associates (www.sinauer.com) and WH Freeman (www.whfreeman.com), used with permission. B Cells B cells divide, forming plasma cells and B memory cells. Plasma cells make and release between 2000 and 20,000 antibody molecules per second into the blood for the next four or five days. B memory cells live for months or years, and are part of the immune memory system Antibody-mediated Immunity | Back to Top Stages in this process are: antigen detection activation of helper T cells antibody production by B cells Each stage is directed by a specific cell type. Macrophages Macrophages are white blood cells that continually search for foreign (nonself) antigenic molecules, viruses, or microbes. When found, the macrophages engulfs and destroys them. Small fragments of the antigen are displayed on the outer surface of the macrophage plasma membrane.

    17. Doug MacDonald PSY 760, 4/7/05 17 Helper T cells only recognize antigen in the grasp of Class II MHC markers. An antigen-presenting cell--such as a macrophage or a dendritic cell--breaks down the antigen it devours, then it places small pieces (peptides) on its surface along with a Class II MHC marker. By exhibiting its catch in this way, antigen-presenting cells enable specific receptors on helper T cells to bind the antigen and confirm (via CD4 protein) that an invasion has occurred. After binding, a resting helper T cell quickly becomes an activated helper T. It assumes command of the immune response, giving orders to increase the number of specific antibody-producing plasma cells and the cytotoxic killer cells needed to quell the attack. Eventually, as this process continues, the number of infectious agents will decrease and we will need to stop the battle. However, all the cells are still activated and the immune system needs to put them to rest. An additional T-cell, the T-suppressor cell (or T8) will send out messages to the other cells and "de-activate" them (Figure 11). If the T-suppressor cell were not there, we would continue trying to fight off a disease that no longer exists (and eventually we would end up fighting our own cells).Helper T cells only recognize antigen in the grasp of Class II MHC markers. An antigen-presenting cell--such as a macrophage or a dendritic cell--breaks down the antigen it devours, then it places small pieces (peptides) on its surface along with a Class II MHC marker. By exhibiting its catch in this way, antigen-presenting cells enable specific receptors on helper T cells to bind the antigen and confirm (via CD4 protein) that an invasion has occurred. After binding, a resting helper T cell quickly becomes an activated helper T. It assumes command of the immune response, giving orders to increase the number of specific antibody-producing plasma cells and the cytotoxic killer cells needed to quell the attack. Eventually, as this process continues, the number of infectious agents will decrease and we will need to stop the battle. However, all the cells are still activated and the immune system needs to put them to rest. An additional T-cell, the T-suppressor cell (or T8) will send out messages to the other cells and "de-activate" them (Figure 11). If the T-suppressor cell were not there, we would continue trying to fight off a disease that no longer exists (and eventually we would end up fighting our own cells).

    18. Doug MacDonald PSY 760, 4/7/05 18 Mounting an Immune Response Your immune system also has a braking mechanism, a checkpoint to prevent immune responses to self. Without this checkpoint, autoimmune disease could flourish. An additional type of immune cells--regulatory T cells--are these critical braking agents. Researchers don’t yet know exactly how regulatory T cells operate. Some think these T cells recognize and compete for the same antigens as those that activate helper and cytotoxic T cells, but that regulatory T cells zero in on a different epitope. Another possibility is that cytotoxic or helper T cells only multiply when regulatory T cells are absent. Your immune system also has a braking mechanism, a checkpoint to prevent immune responses to self. Without this checkpoint, autoimmune disease could flourish. An additional type of immune cells--regulatory T cells--are these critical braking agents. Researchers don’t yet know exactly how regulatory T cells operate. Some think these T cells recognize and compete for the same antigens as those that activate helper and cytotoxic T cells, but that regulatory T cells zero in on a different epitope. Another possibility is that cytotoxic or helper T cells only multiply when regulatory T cells are absent.

    19. Doug MacDonald PSY 760, 4/7/05 19 Microbes attempting to get into your body must first get past your skin and mucous membranes, which not only pose a physical barrier but are rich in scavenger cells and IgA antibodies. Next, they must elude a series of nonspecific defenses--and substances that attack all invaders regardless of the epitopes they carry. These include patrolling phagocytes, granulocytes, NK cells, and complement. Infectious agents that get past these nonspecific barriers must finally confront specific weapons tailored just for them. These include both antibodies and cytotoxic T cells. Microbes attempting to get into your body must first get past your skin and mucous membranes, which not only pose a physical barrier but are rich in scavenger cells and IgA antibodies. Next, they must elude a series of nonspecific defenses--and substances that attack all invaders regardless of the epitopes they carry. These include patrolling phagocytes, granulocytes, NK cells, and complement. Infectious agents that get past these nonspecific barriers must finally confront specific weapons tailored just for them. These include both antibodies and cytotoxic T cells.

    20. Doug MacDonald PSY 760, 4/7/05 20 Macrophage Attacking E.coli (SEM x8,800). This image is copyright Dennis Kunkel at www.DennisKunkel.com Macrophage Attacking E.coli (SEM x8,800). This image is copyright Dennis Kunkel at www.DennisKunkel.com

    21. Doug MacDonald PSY 760, 4/7/05 21 When the immune system is lacking one or more of its components, the result is an immunodeficiency disorder. These disorders can be inherited, acquired through infection, or produced as an inadvertent side effect of drugs such as those used to treat cancer or transplant patients. AIDS is an immunodeficiency disorder caused by a virus that destroys helper T cells. The virus copies itself incessantly and invades helper T cells and macrophages, the very cells needed to organize an immune defense. The AIDS virus splices its DNA into the DNA of the cell it infects; the cell is thereafter directed to churn out new viruses. When the immune system is lacking one or more of its components, the result is an immunodeficiency disorder. These disorders can be inherited, acquired through infection, or produced as an inadvertent side effect of drugs such as those used to treat cancer or transplant patients. AIDS is an immunodeficiency disorder caused by a virus that destroys helper T cells. The virus copies itself incessantly and invades helper T cells and macrophages, the very cells needed to organize an immune defense. The AIDS virus splices its DNA into the DNA of the cell it infects; the cell is thereafter directed to churn out new viruses.

    22. Doug MacDonald PSY 760, 4/7/05 22 AIDS is an immunodeficiency disorder caused by a virus that destroys helper T cells. The virus copies itself incessantly and invades helper T cells and macrophages, the very cells needed to organize an immune defense. The AIDS virus splices its DNA into the DNA of the cell it infects; the cell is thereafter directed to churn out new viruses. AIDS Interferes With Normal Response In AIDS, this procedure does not work adequately. Initially, macrophages recognize HIV, T-helper cells initiate the response, and B-cells produce antibodies. However, although effective at first, the antibodies do not eliminate the infection. Although some HIV might get killed, many more viruses will actively infect T-helper cells, the very same cells that are supposed to coordinate the defense against the virus. Infected T-cells become virus factories which, if activated, will produce virus instead of triggering the production of more antibodies against it. Besides T-cells, HIV is capable of infecting other cells (macrophages, B-cells, monocytes) and to cross the brain-blood barrier, infecting nervous system cells. Most immune cells cannot cross that barrier, which surrounds the brain and spinal cord, so HIV can retreat where the immune system cannot follow. AIDS is an immunodeficiency disorder caused by a virus that destroys helper T cells. The virus copies itself incessantly and invades helper T cells and macrophages, the very cells needed to organize an immune defense. The AIDS virus splices its DNA into the DNA of the cell it infects; the cell is thereafter directed to churn out new viruses. AIDS Interferes With Normal Response In AIDS, this procedure does not work adequately. Initially, macrophages recognize HIV, T-helper cells initiate the response, and B-cells produce antibodies. However, although effective at first, the antibodies do not eliminate the infection. Although some HIV might get killed, many more viruses will actively infect T-helper cells, the very same cells that are supposed to coordinate the defense against the virus. Infected T-cells become virus factories which, if activated, will produce virus instead of triggering the production of more antibodies against it. Besides T-cells, HIV is capable of infecting other cells (macrophages, B-cells, monocytes) and to cross the brain-blood barrier, infecting nervous system cells. Most immune cells cannot cross that barrier, which surrounds the brain and spinal cord, so HIV can retreat where the immune system cannot follow.

    23. Doug MacDonald PSY 760, 4/7/05 23 You do not need to have an MD or a Ph.D. in human physiology to make some general observations about the connection between the mind and body when it comes to getting sick. Think back on the times within the past 3 years when you came down with an illness of one sort or another. If you are like most people, you were probably more likely to become ill during or just after a stressful period of time (e.g. exams, big job presentation, when your in-laws visited) than during times of low-stress (e.g. vacation, kids go to camp for the week, spouse takes over the cooking and cleaning). The fact that phrases like "you’re worrying yourself sick" exist suggests that we experientially and/or intuitively know that there is some link by which our thoughts, feelings, and behaviors can have an effect on our susceptibility to becoming sick. Such a causational connection would require that the nervous system and the immune system be linked in some way so as to allow for communication between the two systems. You do not need to have an MD or a Ph.D. in human physiology to make some general observations about the connection between the mind and body when it comes to getting sick. Think back on the times within the past 3 years when you came down with an illness of one sort or another. If you are like most people, you were probably more likely to become ill during or just after a stressful period of time (e.g. exams, big job presentation, when your in-laws visited) than during times of low-stress (e.g. vacation, kids go to camp for the week, spouse takes over the cooking and cleaning). The fact that phrases like "you’re worrying yourself sick" exist suggests that we experientially and/or intuitively know that there is some link by which our thoughts, feelings, and behaviors can have an effect on our susceptibility to becoming sick. Such a causational connection would require that the nervous system and the immune system be linked in some way so as to allow for communication between the two systems.

    24. Doug MacDonald PSY 760, 4/7/05 24 Psychoneuroimmunology - background The term was first used in 1974 by Robert Ader. In his classical conditioning experiment, Ader paired a conditioned stimulus (saccharin solution) with an unconditioned stimulus, a drug called Cytotaxan, which is known to decrease the number of T-lymphocytes in rats. After several pairings, the rats were presented with the saccharin solution (CS) in the absence of Cytotaxan (US), and a blood sample was taken so the rat’s T-lymphocytes could be counted. The result was a decline in the T-lymphocyte count, indicating that conditioned immunosuppression had occurred. The term was first used in 1974 by Robert Ader. In his classical conditioning experiment, Ader paired a conditioned stimulus (saccharin solution) with an unconditioned stimulus, a drug called Cytotaxan, which is known to decrease the number of T-lymphocytes in rats. When the immune system is compromised by a decline in the T-lymphocyte count, it is referred to as immunosuppression; therefore, Cytotaxan can be classified as an unconditioned stimulus for immunosuppression. After several pairings, the rats were presented with the saccharin solution (CS) in the absence of Cytotaxan (US), and a blood sample was taken so the rat’s T-lymphocytes could be counted. The result was a decline in the T-lymphocyte count, indicating that conditioned immunosuppression had occurred(3). The term was first used in 1974 by Robert Ader. In his classical conditioning experiment, Ader paired a conditioned stimulus (saccharin solution) with an unconditioned stimulus, a drug called Cytotaxan, which is known to decrease the number of T-lymphocytes in rats. When the immune system is compromised by a decline in the T-lymphocyte count, it is referred to as immunosuppression; therefore, Cytotaxan can be classified as an unconditioned stimulus for immunosuppression. After several pairings, the rats were presented with the saccharin solution (CS) in the absence of Cytotaxan (US), and a blood sample was taken so the rat’s T-lymphocytes could be counted. The result was a decline in the T-lymphocyte count, indicating that conditioned immunosuppression had occurred(3).

    25. Doug MacDonald PSY 760, 4/7/05 25 Psychoneuroimmunology - background George F. Solomon, M.D., of the University of California in Los Angeles, defines psychoneuroimmunology as having "to do with the complex bidirectional interactions between the central nervous system and the immune system and their clinical implications. Psychoneuroimmunology attempts to unravel biological mechanisms by which emotions, attitudes, and coping mechanisms affect the course of disease." Solomon believes that "neuroendocrine influences modulate specific aspects of the immune response. Central nervous system-immune interaction appears to play a role in psychosocial influences on immunologically resisted and mediated diseases (like cancer)," he said. During the last two decades, Solomon said, "there has been a growing body of scientific evidence that the mind and the body are inseparable." Solomon believes that "neuroendocrine influences modulate specific aspects of the immune response. Central nervous system-immune interaction appears to play a role in psychosocial influences on immunologically resisted and mediated diseases (like cancer)," he said.

    26. Doug MacDonald PSY 760, 4/7/05 26 Background - additional suggestive evidence: 1970s, Guillemin: endorphins, neuropeptides that bind to opioid receptors in the brain and also appear to have receptors on lymphocytes, suggesting a relationship between the brain and the immune system. In 1988, Irwin, UCSD: emotional stress induces release of corticotropin-releasing factor (CRF). This triggers the release of NE from the SNS, which appeared to reduce the ability of natural killer cells to destroy cancer cells in vitro. Bovbjerg and Redd, chemotherapy patients seemed to develop conditioned immune suppression as a result of repeated hospital visits for chemotherapy. 1970s, Roger Guillemin, M.D., of the Salk Institute, discovered that endorphins, neuropeptides that bind to opioid receptors in the brain and that appear to mediate pain perception, also appear to have receptors on lymphocytes, suggesting a relationship between the brain and the immune system. In 1988, Michael Irwin, M.D., of the University of California in San Diego, found that emotional stress induces the release of corticotropin-releasing factor, or CRF, in the hypothalamus area of the brain. This, in turn, triggers the release of norepinephrine from the sympathetic nervous system, which appears to reduce the ability of natural killer cells to destroy cancer cells in vitro. Dana H. Bovbjerg, Ph.D., and William H. Redd, Ph.D., of Memorial Sloan-Kettering Cancer Center in New York, suggest that chemotherapy patients may develop conditioned immune suppression as a result of repeated visits to the hospital for chemotherapy treatment. SMALL n = They assessed immune function in 20 ovarian cancer patients before their hospital visit and during chemotherapy. 1970s, Roger Guillemin, M.D., of the Salk Institute, discovered that endorphins, neuropeptides that bind to opioid receptors in the brain and that appear to mediate pain perception, also appear to have receptors on lymphocytes, suggesting a relationship between the brain and the immune system.

    27. Doug MacDonald PSY 760, 4/7/05 27 Background - Stress evidence Human studies suggest stressors such as decreased sleep, tension, varied eating patterns that occur during final exams can put stress on the immune system and result in more students becoming ill. It is possible that the immune system may respond in a similar way during exams the next year, even in the absence of physical stressors, indicating that the perception of stress has become a conditioned stimulus for immunosuppression

    28. Doug MacDonald PSY 760, 4/7/05 28 What is the mechanism? Evidence supports the existence of bi-directional pathways connecting the brain and the immune system. Psychoneuroimmunology (a.k.a. Neuro-endocrino-immunology) is a point of intersection. cells of immune system and inflammatory systems communicate directly with the peripheral and/or central nervous system. This communication is also mediated via the bloodstream, and therefore involves hormonal communication. Thus, the brain and the nervous system are part of a neuroimmuno-regulatory network in which each of the various components not only communicate with each other, but also regulate additional sites in the body. Biological links between the immune system and the central nervous system exist at several levels. Hormones and other chemicals such as neuropeptides, which convey messages among nerve cells, have been found also to “speak” to cells of the immune system--and some immune cells even manufacture typical neuropeptides. In addition, networks of nerve fibers have been found to connect directly to the lymphoid organs. Central Nervous System & Immune system Neuro-endocrino-immunology is a point of intersection in the field of immunology. It is also referred to in scientific literature as psychoneuroimmunology. The emerging concept is that the cells of the immune system and inflammatory systems communicate directly with the peripheral and or central nervous system. This connection or communication pathway is also mediated via the bloodstream, and therefore involves hormonal communication. The term hormone not only signifies classical endocrine systems, but also molecules released by the nervous and immune systems which have functional effects from some distance. Thus, the brain and the nervous system are part of a neuroimmuno-regulatory network in which each of the various components not only communicate with each other, but also regulate additional sites in the body The picture that is emerging is of closely interlocked systems facilitating a two-way flow of information. Immune cells, it has been suggested, may function in a sensory capacity, detecting the arrival of foreign invaders and relaying chemical signals to alert the brain. The brain, for its part, may send signals that guide the traffic of cells through the lymphoid organs. Biological links between the immune system and the central nervous system exist at several levels. Hormones and other chemicals such as neuropeptides, which convey messages among nerve cells, have been found also to “speak” to cells of the immune system--and some immune cells even manufacture typical neuropeptides. In addition, networks of nerve fibers have been found to connect directly to the lymphoid organs. Central Nervous System & Immune system Neuro-endocrino-immunology is a point of intersection in the field of immunology. It is also referred to in scientific literature as psychoneuroimmunology. The emerging concept is that the cells of the immune system and inflammatory systems communicate directly with the peripheral and or central nervous system. This connection or communication pathway is also mediated via the bloodstream, and therefore involves hormonal communication. The term hormone not only signifies classical endocrine systems, but also molecules released by the nervous and immune systems which have functional effects from some distance. Thus, the brain and the nervous system are part of a neuroimmuno-regulatory network in which each of the various components not only communicate with each other, but also regulate additional sites in the body The picture that is emerging is of closely interlocked systems facilitating a two-way flow of information. Immune cells, it has been suggested, may function in a sensory capacity, detecting the arrival of foreign invaders and relaying chemical signals to alert the brain. The brain, for its part, may send signals that guide the traffic of cells through the lymphoid organs.

    29. Doug MacDonald PSY 760, 4/7/05 29 Tuesday’s class - Stress The Brain's Response to Acute Stress Hypothalamic-pituitary-adrenal (HPA) system is activated. Release of Steroid Hormones Glucocorticoids Cortisol

    30. Doug MacDonald PSY 760, 4/7/05 30 Tuesday’s Class - HPA Axis The Brain's Response to Acute Stress Activation of HPA Axis. Cell Interactions: Cytokines a) communication by cell-cell contact b) communication by secretion of cytokines Cytokines are basically polypeptide hormones but the term is often used to denote those molecules which are the products of cells of the immune system or which act upon such cells. In common with other hormones, cytokines exert their effects by binding to specific cell-surface receptors which signal to their target cells. Cell Interactions: Cytokines a) communication by cell-cell contact b) communication by secretion of cytokines Cytokines are basically polypeptide hormones but the term is often used to denote those molecules which are the products of cells of the immune system or which act upon such cells. In common with other hormones, cytokines exert their effects by binding to specific cell-surface receptors which signal to their target cells.

    31. Doug MacDonald PSY 760, 4/7/05 31 HPA Axis HPA axis is a central link between the central nervous system and the immune system. An increased expression of corticotropin-releasing hormone (CRH) through the hypothalamus results in the formation of adrenocorticotropin hormone (ACTH), which subsequently… signals the adrenal cortex to increase levels of glucocorticoid hormones, which act to downregulate parts of the immune response axis (HPA) is a central link between the central nervous system and the immune system. An increased expression of corticotropin-releasing hormone (CRH) through the hypothalamus results in the formation of adrenocorticotropin hormone (ACTH), which subsequently signals the adrenal cortex to increase levels of glucocorticoid hormones, which act to downregulate parts of the immune response axis (HPA) is a central link between the central nervous system and the immune system. An increased expression of corticotropin-releasing hormone (CRH) through the hypothalamus results in the formation of adrenocorticotropin hormone (ACTH), which subsequently signals the adrenal cortex to increase levels of glucocorticoid hormones, which act to downregulate parts of the immune response

    32. Doug MacDonald PSY 760, 4/7/05 32 Mechanisms . The immune system is composed of lymphoid tissues, and the fact that these tissues are innervated with sympathetic nerve fibers adds support to the theory that the central nervous system can directly influences the immune system. Not only do nerve fibers form neuroeffector junctions with lymphocytes and macrophages (crucial components of the immune system, i.e. white blood cells), but certain neurotransmitters secreted from these nerves are able to have effects on far off lymphocytes and macrophages, which have receptors for the neurotransmitters. An example of one such neurotransmitter is noradrenaline, which binds to beta adrenergic receptors on lymphocytes Cell Interactions: Cytokines a) communication by cell-cell contact b) communication by secretion of cytokines Cytokines are basically polypeptide hormones but the term is often used to denote those molecules which are the products of cells of the immune system or which act upon such cells. In common with other hormones, cytokines exert their effects by binding to specific cell-surface receptors which signal to their target cells. . The immune system is composed of lymphoid tissues, and the fact that these tissues are innervated with sympathetic nerve fibers adds support to the theory that the central nervous system can directly influences the immune system. Not only do nerve fibers form neuroeffector junctions with lymphocytes and macrophages (crucial components of the immune system, i.e. white blood cells), but certain neurotransmitters secreted from these nerves are able to have effects on far off lymphocytes and macrophages, which have receptors for the neurotransmitters. An example of one such neurotransmitter is noradrenaline, which binds to beta adrenergic receptors on lymphocytes Cell Interactions: Cytokines a) communication by cell-cell contact b) communication by secretion of cytokines Cytokines are basically polypeptide hormones but the term is often used to denote those molecules which are the products of cells of the immune system or which act upon such cells. In common with other hormones, cytokines exert their effects by binding to specific cell-surface receptors which signal to their target cells.

    33. Doug MacDonald PSY 760, 4/7/05 33 NTs receptor found on Ts, Bs, monocytes Thus, the nervous system is able to… Induce T cell function, including cytokine secretion, proliferation, migration. Modify T cell membrane potential and thereby affecting the gating of specific voltage gated channels. Modulate antigen driven T cell function. Anatomically, all of the lymphoid organs are innervated and there is a regular pattern of close spatial relationships between nerve fibers and T lymphocytes, mast cells and macrophages. In addition, specific receptors for several neurotransmitters have been detected on T cells, B cells, and monocytes. Thus, the nervous system is able to: Induce T cell function, including cytokine secretion, proliferation, integrin-mediated adhesion and migration. Modify T cell membrane potential and thereby affecting the gating of specific voltage gated channels. Modulate antigen driven, CR mediated, T cell function. Anatomically, all of the lymphoid organs are innervated and there is a regular pattern of close spatial relationships between nerve fibers and T lymphocytes, mast cells and macrophages. In addition, specific receptors for several neurotransmitters have been detected on T cells, B cells, and monocytes. Thus, the nervous system is able to: Induce T cell function, including cytokine secretion, proliferation, integrin-mediated adhesion and migration. Modify T cell membrane potential and thereby affecting the gating of specific voltage gated channels. Modulate antigen driven, CR mediated, T cell function.

    34. Doug MacDonald PSY 760, 4/7/05 34 Direct and indirect effects Direct: synapsing of neurons with white blood cells in lymphoid tissues. Indirect: through blood-borne neurotransmitters and hormones, which activate receptors on white blood cell surfaces. Also, the immune system acts upon the nervous system through cytokines released by immune cells within the brain, immune-related information causes glia cells and neurons to secrete cytokines such as interleukin (IL)-1, IL-2, and IL-6, interferon gamma, and tumor necrosis factor, which influence activation of the hypothalamic- pituitary-adrenal (HPA) axis and are, in turn, influenced by glucocorticoid secretion. These cytokines are regulated by the presence of glucocorticoids. Recent research has revealed that glucocorticoids help inhibit the production of cytokines, and thus minimize the behavioral effects of cytokines (i.e. sickness behavior). directly and indirectly. The direct effect is via the synapsing of neurons with white blood cells in lymphoid tissues, while the indirect effect is through blood-borne neurotransmitters and hormones, which activate receptors on white blood cell surfaces(5). In addition, it has been established that the immune system acts upon the nervous system through cytokines released by immune cells Cytokines released by activated immune cells, in addition to their role in regulating cellular interactions, are one means by which the immune system communicates with the CNS and thereby influences behaviour. Interleukin (IL)-1, IL-2, IL-6, interferon-gamma, and tumour necrosis factor influence activation of the hypothalamic- pituitary-adrenal (HPA) axis and are, in turn, influenced by glucocorticoid secretion directly and indirectly. The direct effect is via the synapsing of neurons with white blood cells in lymphoid tissues, while the indirect effect is through blood-borne neurotransmitters and hormones, which activate receptors on white blood cell surfaces(5). In addition, it has been established that the immune system acts upon the nervous system through cytokines released by immune cells Cytokines released by activated immune cells, in addition to their role in regulating cellular interactions, are one means by which the immune system communicates with the CNS and thereby influences behaviour. Interleukin (IL)-1, IL-2, IL-6, interferon-gamma, and tumour necrosis factor influence activation of the hypothalamic- pituitary-adrenal (HPA) axis and are, in turn, influenced by glucocorticoid secretion

    35. Doug MacDonald PSY 760, 4/7/05 35 Bidirectional pathways Besedovsky: activation of the immune system is accompanied by changes in hypothalamic, autonomic, and endocrine processes. Immune system activation increases the firing rate of neurons in the ventromedial nucleus of the hypothalamus at the time of peak antibody production; sympathetic activity, indexed by noradrenaline turnover, is increased in the spleen and the hypothalamus; and immune responses initiated by viral infections, are associated with dramatic increases in blood levels of adrenocorticotropic hormone (ACTH) and corticosterone Pathways between the brain and the immune system are bidirectional. For example, Besedovsky and colleagues n 19 observed that activation of the immune system is accompanied by changes in hypothalamic, autonomic, and endocrine processes. Immune system activation increases the firing rate of neurons in the ventromedial nucleus of the hypothalamus at the time of peak antibody production; sympathetic activity, indexed by noradrenaline turnover, is increased in the spleen and the hypothalamus; and some immune responses, including those initiated by viral infections, are associated with dramatic increases in blood levels of adrenocorticotropic hormone (ACTH) and corticosterone. Such data indicate that signals generated by an activated immune system are being received and acted upon by the CNS. Pathways between the brain and the immune system are bidirectional. For example, Besedovsky and colleagues n 19 observed that activation of the immune system is accompanied by changes in hypothalamic, autonomic, and endocrine processes. Immune system activation increases the firing rate of neurons in the ventromedial nucleus of the hypothalamus at the time of peak antibody production; sympathetic activity, indexed by noradrenaline turnover, is increased in the spleen and the hypothalamus; and some immune responses, including those initiated by viral infections, are associated with dramatic increases in blood levels of adrenocorticotropic hormone (ACTH) and corticosterone. Such data indicate that signals generated by an activated immune system are being received and acted upon by the CNS.

    36. Doug MacDonald PSY 760, 4/7/05 36 PNI research Most PNI research is Stress research E.g. PNI and HIV: Stressful life experiences (loss, deaths of friends); bereavement Depression Coping style and Adaptation [Perceived] Social support CB stress reduction Therapy Exercise Results suggest that expected links exist.E.g. Robinson, et al. 2003,8-wk. MBSR may have improved immunity. Best evidence: Hypnosis and Conditioning (Miller, Cohen, 2001)

    37. Doug MacDonald PSY 760, 4/7/05 37 Methodological issues Confounding factors: Health related behaviors CNS impairment – HIV infection in the brain? Physical Symptoms – e.g. swollen lymph glands ? Change in immune status or a sign of distress? Treatment effects – correlation between distress and immune status may be mediated by use of immune altering treatment regimens.

    38. Doug MacDonald PSY 760, 4/7/05 38 Design Issues Sample selection – such variety of participants that “explaining variance” difficult. Age, sex, alcohol, tobacco, other drugs, nutrition, sleep… Time period assessed – longer longitudinal studies needed. Lack of agreement on how to measure immune function – what validly reflects “immunocompetence?”

    39. Doug MacDonald PSY 760, 4/7/05 39 Is there practical significance? Much evidence for stress-related immune impairment in humans, yet what remains uncertain is the clinical significance of the altered immunity that accompanies psychological stress. Yet, popular belief in a link between beliefs, behaviors, optimism, mood… exists

    40. Doug MacDonald PSY 760, 4/7/05 40 In Conclusion “The association between stressful life experiences and changes in immune function do not establish a causal link between stress, immune function, and disease. This chain of events has not yet been definitively established. However, major links between these "systems" have been described and a new understanding of interactive biological signaling has begun. Psychoneuroimmunology is developing the means to explore these relations and their clinical and therapeutic implications.” Ader, Robert; Cohen, Nicholas; & Felten, David , Psychoneuroimmunology: interactions between the nervous system and the immune system. Lancet 1995; 345 (8942). P.103

    41. Doug MacDonald PSY 760, 4/7/05 41

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