Chapter 1


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Chapter 1

  1. 1. Immunology Chapter 1: Elements of the Immune System and their Roles in Defense Immunology- study of physiological mechanisms that humans and other animals use to defend their bodies from invasion by other organisms. Origins- practice of medicine. Why did some die and others live and even continue to be exposed. Immune to infection. Bad guys out number the good guys. Microorganisms can reproduce faster than humans can. Collectively the immune system fights for us and for our body. Takes time to put all the players into play. Kids versus adults. EAT dirt. Protective immunity….. in order to have you must first do battle once. Highest risk is at the first infection. Bird flue, Native Americans and chicken pox….. you and chicken pox. Vaccinations. Acquired immunity, passive immunity. Vaccination: Edward Jenner- cow pox, small pox. 1796. Vaccinations are made from a small form of the infectious agent, live versus attenuated. Defenses. The Dark Side….. Those who shall not be named,. All cells originate in the bone marrow. Leave the marrow and circulate some into the lymphoid system. Pathogens. Any organism with the potential to cause disease is known as a pathogen. Wrong place at the wrong time. E. coli….. others, sterile versus normal flora;.
  2. 2. Opportunistic pathogens. Pathogens = four kinds Bacteria Viral Fungi Parasites. We want to consider controlling the infection and the pathogen. Constantly changing. If you die too early not good. We make adjustments. On each side. Healthy population versus compromised. How you get infected. Who are you? Barriers. Time, exposure, temperature, place. Dosing. Where you get the organism or the pathogen. Drying, moist, Skin is the body’s first line against infection. Tough impenetrable barrier. Even a pH advantage that works in our favor. Aseptic technique. Skin, Respiratory, think of anatomy and histology of the cells. Mucosal surfaces. Physical and chemical barrier.
  3. 3. Inflammation at the sites of infection. Two parts. Recognition that there is a pathogen. Recruitment to do something about it. Effector mechanisms that kill and eliminate. Cells and serum proteins… complement. These together are innate immunity or innate immune response. Innate…… what you got is what you get. Your inheritance. MAKE A POINT OF LOOKING AT PAGE 5 = The Diversity of human Pathogens… Figure 1.3 Two step process: 1. Recognition of something as a pathogen 2. Destruction of the pathogen Effector cells and complement. An infection begins and the surrounding cells secrete cytokines (soluble proteins). This triggers the innate immune response = inflammation. Latin words: Calor, dolor, rubor and tumor. Heat, pain, redness and swelling. Not from the infection but from the response. Figure 1.6 Innate mechanism a state of inflammation. Healthy skin. Underlying blood supply and intact skin barrier. Abrasion or invasion of the skin. Release of cytokines also causes vasodilation = fluid comes out of the blood stream, enters the surrounding area, causing edema, swelling, affects nerve endings causing pain. Other effector cells and
  4. 4. inflammatory cells come to engulf and phagocytosis the bacteria and you get redness. Despite your constant barrage and exposure to pathogens, your innate immunity manages to keep most of us healthy , most of the time. Innate mechanism is the same for basically everything you encounter, it is not specific. Doesn’t make any difference the worm, the sliver. Sometimes the innate immune response doesn’t work. The innate response slows things down, but you must have a specific adaptive immune response. The body’s immune response calls upon the WHITE CELLS….. the lymphocytes to increase the power and focus of the immune response. ADAPTIVE IMMUNITY. Provides a highly specialized defense against one pathogen, but is of little effect against infection by a different pathogen. Different effector mechanisms, but similar. The important difference is in the cell-surface receptors used by lymphocytes to recognize pathogens. Make sure you can write a response to this test question: Compare and contrast the different recognition mechanisms of innate immunity and adaptive immunity. See figure 1.7 Only specific cell types with the correct recognition for the pathogen are selected to participate in the adaptive response. Then their numbers are expanded (clonal expansion) to produce huge numbers of effector cells. This process takes time, and therefore the benefits of adaptive immunity only is effective about a week after the infection begins Think of how long it takes to really recover…. 2 weeks. You’re getting sicker during the first week; you’re recovering the second week and getting better.
  5. 5. Protective or acquired immunity. The lymphocyte populations that expand during as adaptive immune response persist in the body and provide long-term immunological memory of the pathogen. These memory cells allow subsequent encounters with the same pathogen to elicit a stronger and faster adaptive immune response which terminates infection with minimal illness. The adaptive immunity provided by immunological memory is also called acquired immunity or protective immunity. You should be able to write a response to this test question: clearly define these immunities: Innate immunity Adaptive immunity Acquired immunity. Compare and contrast differences and responses. Different pathogens; Measles, mumps,….. one time deal provided life long immunity Influenzae ….. pathogen shifts immune receptors and changes the equation. The system remembers, the pathogen changes. Primary response, Secondary response. Immune system cells with different functions all derive from hematopoietic stem cells. Red cells, white cells, and platelets = magakaryocytes. Pluripotent hematopoietic stem cells. = hematopoiesis. Age dependant as to where this occurs. Fetal versus adult. Bone marrow, iliac crest, sternum. Self renewal of stem cells. They can also become mature and go into three different cell lines. Erythroid, myeloid and lymphoid.
  6. 6. Erythroid = RBC’s and platelets. Myeloid = granulocytes = polymorphonuclear leukocytes. Multi-lobed nucleus Most abundant is the neutrophil. Neutrophil is specialized to capture, engulf and kill microorganisms. Can work under anaerobic conditions = no oxygen. Short lived and die at the site = pus. Eosinophils. = parasitic worms and intestinal parasites. Basophils. So rare that not much is known. Names these based on cell staining techniques. Second group in the myeloid cell line are the monocytes macrophages and dendritic cells. Monocytes are leukocytes that circulate in the blood. Bigger in size and mono nucleus. Once they migrate into a tissue they become Macrophages. These too can capture, engulf and kill cells. They are the general scavenger cells of the body. Phagocytosing everywhere. Long lived commanders and orchestrate the local response to infection. They secrete cytokines to recruit the neutrophils. Myeloid dendritic cells are found in the tissues, Unique star shape. Act as messengers to help in the adaptive immune response. Mast cells. This is found in all connective tissue. Not much known. Lymphoid cell progenitor. Lymphoid cells. Large and small: Large has very granular cytoplasm = natural killer cells. NK cells. Small has almost no cytoplasm. Small lymphs are responsible for adaptive immunity. They are small because they circulate in an immature form that is functionally inactive.
  7. 7. Recognition of a pathogen by small lymphocytes drives a process of lymphocyte selection, growth and differentiation that after 1-2 weeks produces a powerful response tailored to the invading organism. Visually you can’t tell the difference…… they all look small….. But there are very distinctive differences on the cell surfaces and their specific cell surface receptors and the functions that they are programmed to perform. The most important difference is between B lymphocytes or B cells and T lymphocytes or T cells. B cells the cell-surface receptors for pathogens are immunoglobulins T cells are known as t-cell receptors. Immunoglobulins and T-cell receptors are structurally similar molecules that are the products of genes that are cut, spliced and modified during lymphocyte development……. What does that sound like………….. RNA modification anyone???!!!... As a result of these processes each B cell expresses a SINGLE TYPE OF IMMUNOGLOBULIN And each T cell expressed a SINGLE T-CELL RECEPTOR. Within the small lymphocyte population BILLIONS of DIFFERENT IMMUNOGLOULINS and T-CELL RECEPTORS are represented. BILLIONS and BILLIONS and they are all DIFFERENT>>>>>>> AMAZING !!!!! Specialized lymph tissue. They circulate in the blood, but they are found and formed in specialized tissue. Functionally divided into two groups. Primary or central lymphoid tissues = bone marrow and thymus. This is where the lymphocytes develop and mature to the stage where they can fight and engage the pathogen. Secondary or peripheral lymphoid tissues = tonsils, spleen, adenoids, appendix, lymph nodes, and Peyer’s patches. This is where nature lymphocytes become stimulated to respond to invading pathogens.
  8. 8. Lymphatic tissue and system, Nodes. Network. Make sure you understand the way lymph tissue works. Plasma leaking from the blood system into the tissues and then collects back via the thoracic ducts. Left sub clavian and right thoracic. Spleen. While part of the lymphoid system there is no physical connection. It becomes a filter Lymph = fluid that recirculates. Both T and B cells originate from precursors in the bone marrow. B cells complete their maturation I the bone marrow before entering the circulation. T cells leave the bone marrow at an immature stage and migrate in the blood to the thymus. In the thymus they complete their maturation. Lymphocyte maturation is a highly selective process in which the majority of immature lymphocytes are destroyed because they fail to develop immunoglobulins or T-cell receptors that are useful to the immune system. A small fraction of immature B and T cells that successfully complete development depart from the primary lymphoid organs and enter the circulation. They develop in the primary tissue…….. they get activated in the secondary lymphoid tissues. Meeting places where lymphocytes circulating in the blood encounter pathogens and their products brought from a site of infection. They get carried to the nearest lymph node = draining lymph node. Dendritic cells arrive with engulfed pathogens and processed components. Test question. Make sure that you understand the lymph system. It does not have a driving cardiac output. It does not have a pump. Make sure you understand the flow. Lots of potential for infection, for spread, for metastasis. Edema…. Fluid accumulation. Understand the anatomy and histology of the node.
  9. 9. Afferent lymphatic vessels, several come into the node and only one EEEEEEEEEfferent lymphatic vessel comes out. The filters are macrophages. SO now the pathogen is stuck inside a lymph node ready to be utilized for activation. T-cell areas… Review Figure 1.18. Test Question: Explain the step, by step process of lymph and pathogen as they enter a node. What happens, what gets activated and why? SO the node: T-cells enter the node via afferent vessels, congregate in the T-cell area. Dendritic cells are also coming along. If the receptors on the T-cell surface bind to the pathogen components displayed by a dendritic cell, then the T cell is signaled to divide and differentiate into functional effector cells. 1. Some T cells differentiate into helper T cells that stay in the lymph node and provide soluble proteins and intercellular contacts that drive the differentiation of B cells possessing immunoglobulin receptors that bind the pathogen. 2. Effector B cells called plasma cells can either stay in the lymph node or migrate to the bone marrow via lymph and blood. Plasma cells make and secrete large amounts of antibody, a soluble form of their cell-surface immunoglobulin. 3. A second type of T cells differentiates into helper T cells that leave the lymph node and travel via the efferent lymph and the blood to the infected tissue. These helper T cells interact with macrophages and secrete soluble cytokines to amplify the inflammation. 4. A third type of effector T cell is called the cytotoxic T cell because these cells kill cells infected with viruses or other intracellular pathogens. Make sure you understand this point. Bacteria, fungi, most pathogens are freely associated. Viruses and some intracellular parasites are HIDDEN from cellular presentation.
  10. 10. IN reality only a small minority of the circulating small lymphocytes will be activated, the rest pass through the node and continue to recirculate. Now should they “Miss” the node presentation they can infact find a similar function in the spleen. Remember the spleen acts as a filter for the blood. It also functions as a secondary lymphoid tissue. Infectious agents are removed and used to activate lymphocytes. Only real difference is that both the pathogen and the lymphocytes enter and leave the spleen in the blood ----NO lymph. Know the terms: GALT- gut-associated lymphoid tissues ( tonsils, adenoids, appendix and Peyer’s patches) line the small intestine. BALT- bronchial-associated lymphoid tissue (respiratory tract). MALT. Mucosa-associated lymphoid tissue. Systems act the same way, the differences are chiefly the routes of pathogen entrance. Make sure you understand the Summary on page 20. Know the four key elements of innate immunity: Molecules that noncovalently bond to surface macromolecules of pathogens. Molecules that covalently bond to pathogen surfaces forming ligands for phagocyte receptors. Phagocytic cells that engulf and kill pathogens Cytotoxic cells that kill virus-infected cells.
  11. 11. Principles of Adaptive immunity Know the differences between innate and adaptive immunity. Page 20. Innate – you recognize anything foreign and set patterns that are shared. In adaptive those T and B cells have specific immunoglobulins and T cell receptors. Unique to only one and then it makes a response of stimulation, divide, proliferate and become effector lymphocytes. Found only in vertebrate animals. Evolution with high degree of cellular complexity. Immunoglobulins are expressed on the surface of B cells, Effector B cells are plasma cells and these secrete the soluble form of the immunoglobulin or ANTIBODIES. T-cell receptors are only expressed as cell0surface recognition molecules never soluble proteins. Ay molecule, macromolecule, virus particle of cell that contains a structure recognized and bound by an immunoglobulin or T-cell receptor is known as an antigen. Antigen receptors The particular part of the antigen bound by the immunoglobulin or T- cell receptor is known as the antigenic determinant or epitope. Immunoglobulins can bind to a vast variety of different chemical structures, T-cell receptors recognize a more limited range of epitopes. They are specific. Or have specificity for the antigens that they bind. Immunoglobulins and T-cell receptors are structurally related molecules whose diversity is generated by similar genetic mechanisms. Immunoglobulins are formed from two different polypeptides called heavy and light chairs. Each “Y” shaped immunoglobulin molecule consists of two identical heavy chains and two identical light chains. Both have a variable region that differs from one immunoglobulin from another and a constant region that is identical to the other immunoglobulins.
  12. 12. The variable region contains the sites that bind antigens. You anchor these into the cell membrane by Transmembrane regions located at the carboxyl ends of the heavy chains. Antibodies are identical, but they circulate so they do not have the trans membrane region. The T-cell receptor consists of am alpha chain and a beta chain. Both areas anchored in the T-cell membrane. Like the heavy and light chains of the immunoglobulins, the alpha and beta chains of T-cell receptors each consist of a variable region and a constant region. The variable regions form an antigen binding site. The differences in the amino acid sequences of the variable regions of immunoglobulins and T-cell receptors create a vast variety of binding sites that are specific for different antigens and thus for different pathogens. This is the hallmark of an adaptive immune response. The diversity of immunoglobulins and T-cell receptors is generated by gene rearrangement. You can have gene rearrangement in the heavy and light chain loci only in B cells. There is diversity in the variable regions. When B cells go through the secondary lymphoid tissue they can initiate a process of somatic hyper mutation which introduces nucleotide substitutions into the heavy and light chains of immunoglobulins. B cells recognize intact pathogens, whereas T-cells recognize pathogen- derived peptides bound to proteins of the major histocompatibility complex. Figure 1.24 REVIEW Antibodies made by B cells are the soluble pathogen-binding molecules of adaptive immunity. By circulating in the body fluids, antibodies can bind to bacterial cells and intact viral particles in extracellular spaces, targeting them for phagocytosis. To fulfill this function, the binding sites of antibodies interact with intact components of the pathogen surface such as glycoproteins and proteoglycans. The epitopes bound by
  13. 13. antibodies most commonly include carbohydrate groups, or clusters of amino acids on the protein surface or combinations of the two. Whereas antibodies bind directly to the native structures of biological macromolecules, T-cell receptors can bind only to short peptides that have been assembled into a complex with a membrane glycoprotein called a major histocompatibility complex (MHC) molecule. T-cell antigens are therefore peptides. They are produced within human cells by the breakdown of pathogens or their protein products, a process called antigen processing. This processing occurs inside the cell where the antigen was processed. It presents antigens in a complex with MHC. The cell becomes an antigen presenting cell. The MHC antigens are presented to the cell surface for the T-cell receptors. There are two classes of MHC molecules: Class I Class II Class I molecules present peptide antigens derived from pathogens that replicate intracellularly, such as viruses and some bacteria. CD8 glycoprotein on their cell surfaces is the distinguishing factor for the T cells that can function by killing infected cells. Since all nucleated cells can be infected by viruses, MHC class I molecules are present on almost all cell types. Cytotoxic T cells. MHC class II present peptides obtained from pathogens and their products that are present in the extra cellular fluid and have been taken up in the endocytic vesicles of phogocytic cells. These are presented to helper T cells, which then go on to activate B cells or macrophages. Helper T cells have CD4 glycoproteins on their surface. These MHC class II molecules are present on only a few cell types. These antigen-presenting cells are dendritic cells, macrophages and B cells. The variability and immense variety of MCH molecules is the chief cause of rejection of tissue transplants. Donor and recipient are of different MHC types. Figures 1.26 = MHC Class I Figure 1.27 = MHC class II.
  14. 14. Soooooo While we have a HUGE variety of antigens and antibodies, once we have an infection we get clonal selection. All of these cells are identical …. All expressing the identical immunoglobulin or T-cell receptor. = clonal selection. For this chapter you will not be held responsible for self-tolerant selection. We will cover this more later. But you should know that there is a process for self selection. Only a few T cells make it out to circulate. Extracellular pathogens and their toxins are eliminated by antibodies. Immunoglobulins are divided into five classes. IgA. IgD, IgE, IgG, and IgM IgM is the first antibody to be secreted in the immune response. Immunity due to antibodies is often known as humoral immunity. IgM, IgA, and IgG are the main antibodies present in blood, lymph and the fluid in connective tissues. Antibodies can also have the effect of neutralization. If they bind tightly to a site on a pathogen, it can prevent growth, replication, inhibit bacterial toxins. The most important function of IgG antibodies is to facilitate the engulfment and destruction of extracellular microorganisms and toxins by phagocytes. Neutrophils and macrophages have cell- surface receptors that bind to the constant regions of the IgG heavy chains. A bacteria coated with IgG is more efficiently phagocytosed than an uncoated bacterium = opsonization. Adaptive immune responses generally give rise to long-lived immunological memory and protective immunity. Vaccinations.
  15. 15. The immune system can be compromised by inherited immunodeficiencies or by the actions of certain pathogens. You can have one defective gene copy and the other takes care of the immune response. Immunodeficiency diseases. HIV – AIDS – CD4 T lymphocytes. Death comes from an opportunistic infection. Unwanted effects of adaptive immunity cause allergy, autoimmune disease and rejection of transplanted tissues. Allergy = IgE antibodies against substances in the environment, foods, grass pollen, house dust….etc. Autoimmune diseases, = rheumatoid arthritis, Grave’s disease, MS, Known and review the summary. Practice and complete the review questions. Very beneficial.