Lecture 22 with Textbook Info - Immunology - Dec 8, 2024

Lecture 22 with textbook info Rest of chapter 17- Figure 17.5 Activation of B Cells to Produce Antibodies So here we have the antigen and the monomer IgM is sitting on the outside, it can react the hydrobarital region, it gets internalized, the fragments of the antigen that's critical get displ...

Lecture 22 with textbook info Rest of chapter 17- Figure 17.5 Activation of B Cells to Produce Antibodies So here we have the antigen and the monomer IgM is sitting on the outside, it can react the hydrobarital region, it gets internalized, the fragments of the antigen that's critical get displayed back up on the surface with the MHC-2 complex. And now on the T cells, they don't have an IgM molecule on their surface, they have something called a T cell receptor and the T cell receptor is a protein that mast recognizes this antigen, displayed in the MHC-2. And the T helper now will start secreting cytokines that allows this T cell to expand its cell and ultimately mature to a plasma cell that is the actual antibody secreting cell. ◦This is why the T helper was so critical because the cytokines gave the necessary information to expand this B cell and ultimately don't want to make the antibody. T cell dependent- for the B cell to make it antibody, it absolutely needed help from the T cell. B cell will find its antigen and internalize the antigen and express it on its membrane and mhc2 complex. The B cell wants to get help from T cell. Once the peptide in the MHC 2 complex, the T helper cell can recognize the antigen through its receptor on its cells and once it does recognize and attach it will secrete cytokines that will help the B cells differentate and expand into plasma cells that will be the antibody secreting cells. Immunology works by cell finding one another because therye recognizing the specific antigen and than know what cells to work with, they cells find one another by the common antigen. Figure 17.8 The Results of Antigen–Antibody Binding Agglutination- (being stuck together/clumped tg) ◦Since we have antibodies that combine maybe two antigens, an IgI can combine 10, once we start making antibodies and start grabbing on to whole cells, they start coming out of solutions and they agglutinate. The clumps can be readily picked up by macrophages. The macrophage might ignore one cell just floating around but when you have these clumps of cells attached to antibodies, they're really just going to be recognized very soon by our macrophages. ◦Antibodies attach to something on the outside of the whole cells and once it attaches it makes the organism clump together and it can now be recognized by things like macrophages. Opsonization- ◦The constant region of antibodies can be recognized by the macrophages having a specific receptor for the constant region of the antibodies. So once I see the antibody attached, and this is a capsulated strep pneumonia, now if antibodies are made to the capsule, the macrophage sees it and its called oxidization. ◦The antibody is allowing for the macrophage to see that constant region, because right on the macrophage is the receptor, the protein that can bind to the constant region. ◦Decorating an antigen, with the antibodies attached to it now its lit up. When its decorated with antibodies there’s a receptor for the constant region of the antibody that’s on the membrane of the macrophage and it can now internalize the organism and appropriately digest it. Activation of complement- ◦The complement of the c3b protein can be found, non specifically to the outside of the cell, and there's a receptor on the macrophage for the c3b protein. So c3b is also considered an oxidizing protein, just like the antibodies. We know that complement, the first complement factor, C1, also recognizes something on that constant region of the antibody, and once it binds, it all of a sudden starts eliciting the cascade of complement.  ◦Non specifically bind to organism. Macrophage has receptor for the C3b complement factor, the C3b is acting as an opsidant too.. ◦The constant region plays a role in a healthy immune system. Neutralization- ◦If the antibody grabs the virus before it can attach to our host cells, we just neutralized the virus. If I have an antibody that can grab onto the toxin before it can grab onto my cell, I just neutralized the toxin. It also places role in neutralization. ◦The antibodies bind to virus before it has a chance to bind to our cells. Antibody-dependent cell mediated cytotoxicity- ◦What happens is for those big things like worms, which macrophages cannot ingest, if the worm is attached with a lot of different antibodies and things that can be recognized on its surface than the antibodies start to attract things like macrophages, if I could start mounting an immune response to things on the surface of the worm, make an antibody response, all of a sudden, macrophages are coming to the site, and I have things like eosinophils, which will be attracted to the antibodies attached to this worm, and the eosinophils will go right up to that worm and start secreting chemicals and factors to break up the worm into fragments. So now macrophages have a chance of ingesting those fragments of worms. ◦Nk cells as well. ◦Basically antibody is really attracting cells, the eosinophils, macrophages, even T cells to this site with the idea that this worm is gonna be bombarded by chemicals and things that's gonna destroy it and put it down into smaller fragments so it can at least be digested through the macrophage. ◦Relying on antibodies attaching to worms. So any one of these serves a function, what the antibody is doing, depending on what the antibody needs to do. Cellular Immunity Response Process (2 of 3) Antibodies are effective against pathogens that are circulating freely in the body, where the antibodies can make contact with them. But intracellular pathogens, such as a viruses, certain bacteria, and some parasites, are not exposed to these circulating antibodies because they enter host cells. T cells evolved to combat the issue. Like B cells, each T cell is specific for only a certain antigen. However, T cells will recognize only antigen fragments (peptides) bound to MHC.Bellswill Magnie free any antigen T cells combat intracellular pathogens and abnormal host cells such as cancer cells ◦Mature in the thymus ◦Is part of lymphoid cell lineage, as well as the B cells and NK cells ◦Thymic selection eliminates immature and self-reactive T cells. About 98% of immature T cells are eliminated in the thymus, which is akin to clonal deletion in B cells. This reflects a weeding-out process, called thymic selection, that allows only those T cells that correctly recognize foreign peptides and self MHC molecules to continue. ◦Once mature the T cells migrate from the thymus by the way of the blood to various lymphoid tissues ◦Attach to antigens via T-cell receptors (T C Rs) Cellular Immunity Response Process Pathogens destined to live intracellularly most frequently enter the body via the digestive canal or respiratory tract. Pathogens entering the gastrointestinal tract pass through microfold cells (M cells) located over Peyer’s patches (aggregaated lymphoid nodules)  ◦Each of these tracts is lined with a barrier of epithelial cells. In the digestive canal, something can pass this barrier only by way of an array of gateway cells called microfold cells, or M cells, scattered among the absorptive, microvilli-bearing epithelial cells ‣ M cells are located over aggregated lymphoid nodules (Peyer’s patches), which are secondary lymphoid tissues located on the intestinal wall. ◦Transfer antigens to lymphocytes and antigen-presenting cells (A P C s)- M cells take up antigens from the intestinal tract and allow their transfer to the lymphocytes and antigen-presenting cells of the immune system found throughout the intestinal tract, just under the epithelial-cell layer but especially in the aggregated lymphoid nodules. ◦It is also here that antibodies, mostly IgA essential for mucosal immunity, are formed and migrate to the mucosal lining. T cells need to be presented with the antigen. The best place for these immune responses are lymph tissue and lymph fluid. Figure 17.9 M Cells M cells are positioned above aggregated lymphoid nodules, which are located on the intestinal wall. Their function is to transport antigens encountered in the digestive tract to contact lymphocytes and antigen-presenting cells of the immune system. B- an antigen can get down through tissue into lymph tissue. We have something in our intestinal tract that can work down through the lymph tissue and this is an area you can present antigen easily. Can see B cells, T cells, and dendritic cells in the lymph tissue. If there’s anything on the antigen coming down through the tissue there will be readily available antigen presentation especially though the T cells Lymph tissue is where the cells can interact and respond to the same antigen. EE tie Antigen-Presenting Cells (A P C s) Antigen-presenting cells (APCs) ◦include B cells, dendritic cells, and activated macrophages. All APCs have class II MHC molecules on their surfaces that present potential antigenic fragments to T helper cells. If the TCR has affinity for the MHC-peptide complex on the APC, T cell activation is initiated. ◦In addition, the APC secretes cytokines that influence the Th cell to develop into a particular type of T helper cell. Dendritic cells (DCs)- antigen presenting cells ◦Have long extensions called dendrites. ◦Dendritic cells are the main APCs that induce immune responses by T cells. ◦Engulf and degrade microbes and transport them to lymph nodes to display them to T cells located there ◦Found in the skin, genital tract, lymph nodes, spleen, thymus, blood, and various tissues except the brain. ‣ Dendritic cells in the skin and genital tract are called Langerhans cells. Macrophages- antigen presenting cells ◦Usually found in a resting state.  ◦The motility and phagocytic capabilities are greatly increased when they are stimulated to become activated macrophages. Activated by cytokines produced by an activated T helper cell or the ingestion of antigenic material. ◦Once activated, macrophages enlarge, become ruffled, and are more effective as phagocytes and as APCs ◦After taking up an antigen anywhere in the body, APC’s tend to migrate to the lymph tissue, presenting antigen to T cells located there. T cells carrying receptors that are capable of binding with any specific antigen are present in relatively limited numbers. ◦Migration of APCs increases the opportunity for these particular T cells to encounter the antigen for which they are specific. B cells ◦Antigen presenting cells because they sometimes they need help from T cells so they need to present the antigen. Classes of T Cells The different classes of T cells have different functions. T cells can be differentiated based on markers on outside of membrane. Clusters of differentiation (CD)- distinguished by surface glycoproteins ◦CD4+ cellThey other likeBcells cells immune and tcellstofightinfection c ytotoxic havea fT conotnhere Areatypeoprotein helper signal which surface them helps with interact amite to antigens molecules recognize class They ‣ T helper cells (TH)- help with the B cells by expressing they’re antibody mainly through cytokine signaling ‣ Cytokine signaling with B cells; interact directly with antigens Th cells also secrete cytokines that help the activation of other immune cells, including T cytotoxic Tc cells, another major T cell type Tc cells are known for recognizing and killing virus-infected cells and cancer cells. ‣ CD4+ molecules on Th cells bind MHC class II molecules on B cells and APCs. MHC2 complex molecules on the B cells and antigen presenting cells (dendritic and macrophages) will always be presenting antigen on MHC 2 pocket ‣ Only the B cells, dendritic and macrophages have the MHc 2 complex which is there to allow for antigen presentation. s.by ainge htign niEas Mittens ◦CD8+referstocytotoxic tcellyth.gg ng ‣ Cytoxic T lymphocytes (CTL)- don’t have CD4, they have CD8. They allow for the toxic event to happen to destroy a cell and it recognizes the cell it needs to interact with and kill through the MHC 1 class of proteins that are all on all of the nucleuses cells. CD8 molecules on Tc cells bind to MHC class I molecules present on all nucleated cells. All of our cells that have a nucleus have MHC class 1 proteins. This is what the cytotoxic T cells need to see to respond to the cells that are aberrant. ‣ T cells that have not encountered antigen are called naïve. ‣ Bind MHC class I molecules After specific contact with an MHC-peptide complex, the T cell is activated to form effector cells: Th cells, which secrete cytokines; T regulatory cells, which are a subset of Th cells; Tc cells, now referred to as cytotoxic T lymphocytes (CTLs), which kill abnormal body cells; and memory T cells. T Helper Cells T helper cells recognize antigen presented by a class II MHC molecule of an APC. If the APC is a macrophage, it becomes activated, making it more effective in both phagocytosis and in antigen presentation TCR on the cell recognize and bind to the antigen fragment and M H C class 2 on A P C CDaos A P C or Th secretes a costimulatory molecule, activating the Th cell Th cells produce cytokines and differentiate into: CD4differentiatsto  They infections produce cytokines Ienywhich like the enhance thatqgtiyqtmathgyiag.ve to intracellular cellsfight ofhelper Areatype teeth ◦Th1 cells- when in the right environment and they’re seeing they’re antigen they will respond by producing certain cytokines and TH1 cells will release cytokines that work with our macrophages. Help macrophages. ‣ The cytokines produced by Th1 cells, especially IFN-y, activate cells related to delayed hypersensitivity (such as a poison ivy rash) and are responsible for activation of macrophages. They also stimulate the production of antibodies that promote phagocytosis and are especially effective in enhancing the activity of complement, such as opsonization and inflammation immune ordinate against responses in evqiityarenlegsegytpi.in I activate like parasites and worm role playa neo ◦Th2 cells- cells that work with our B cells and help the B cells proliferate making antibodies. ‣ Th2 cells produce cytokines, including IL-4. They are associated primarily with the production of antibodies, especially IgE, that are important in allergic reactions. They are also important in the activation of the eosinophils that defend against infections by extracellular parasites, such as helminths ◦Th17 cells- not made in great amounts, they seem to be involved with inflammatory response. Seem to be involved with a lot of auto immunity problems. ‣ Excessive amounts of Th17 cells probably contribute to the inflammation and injury to tissue found in certain autoimmune diseases ◦Memory cells- when T cells are activated there is a small portion that goes into memory so if there’s a second infection it’ll respond fast. Figure 17.12 Activation of CD4+ T Helper Cells This shows the activation of a naïve T helper cell by a dendritic cell. The Th cell recognizes antigen fragments held in a ADC complex with MHC class II proteins on the surface of the dendritic cell. This is the initial signal for activation of the Th cell. However, notice that a second, costimulatory signal is also required. This signal comes from the dendritic cell in the form of a cell surface protein known as B7. B7 binds to a protein on the Th cell surface called CD28.The APC-T cell interaction also involves cytokines secreted by the APC, which cause the proliferating cells to differentiate into populations of Th cell subsets, such as Th1, Th2, and Th17. These subsets act on different cells of the body’s defensive systems. They also form a population of long-lived memory T cells. Figure- To activate a T helper cell, at least two signals are required: the first is the binding of the TCR to the processed antigen-MHC complex, and the second involves another protein (B7) on the APC surface binding to CD28 on the Th cell surface. This costimulation triggers the Th cell to secrete IL-2 and other cytokines. These cytokines affect the functions of multiple cell types of the immune system. When we see our T helper cells, we see that the T cell that is going to respond to the MHC 2 complex holding the antigen that can bind to the T cell receptor. Based on what the antigen is the cytokines start getting released and there’s an activated T cell and now the activated T cells might be asking for a specific T helper cells. T helper cells can help with cytotoxic T lymphocytes. T helpers do a lot of work. When HIV binds to our cells, they see cd4 receptor which is on all of our T helper cells , when they enter that cell and destroy it than we become immunocompromised because the T helper cells can’t help do anything, can’t helper with B cell response, macrophage response, T cell cytotoxic response and this is why ppl become immunocompromised. The fact that the virus wants to enter the CD4 cells, and they enter a critical cell and it makes us immunocompromised. This is why ppl are monitoring to see if they have healthy T cell numbers in they’re body, iiiiiiii.mn ii E i iIEiiii E.EE Eii EI.IE Figure 17-13 Killing of Virus-Infected Target Cell by Cytotoxic T Lymphocyte 1- virus infected cells has MHC 1 protein on it. With viruses proteins are displayed on membrane so the T cell sees the viral protein in association with the mHC 1 complex and it gets activated and once it’s activated it’ll look for any cell that has the particular antigen it can recognize and its looking at the mHC complex too. Once it makes contact it secretes things like perforin to kill the cell. The cell isn’t serving any purpose so its killed so the virus doesn’t keep replicating. T Regulatory Cells T regulatory cells (T reg/T suppressor cells)- not made in great numbers. It helps regulate our immune responses. It seems to turn off a response. If we get rid of antigen we don’t need the response anymore. It suppresses responses when they’re no longer needed. And helps us ignore our normal flora and not attacking it. cells own Attach Their primary function is to combat autoimmune reactions by suppressing autoreactive T cells that escape deletion in the thymus. They are also useful in protecting the resident microbiota that live in our intestines and aid digestion. In pregnancy they may play a role in protecting the fetus from rejection as nonself. ◦Subset of T helper cells; carry an additional CD25 molecule which is a receptor and is used to distinguish. ◦Suppress T cells against self; protect intestinal bacteria required for digestion; protect fetus by being rejected even though its not identical to the mother. Helps ignore normal flora. Cytotoxic T Lymphocyte (C D 8 super plus T Cells) (1 of 2) The activation of a naïve Tc cell requires interaction between its T-cell receptor and a class I MHC-peptide complex on the surface of another body cell. This interaction plus costimulatory signals results in an activated cytotoxic T lymphocyte (CTL) that will recognize and kill this and other cells that have the same antigen displayed. Activation of a naïve cell: T cell receptor must interact with class 1 M H C and antigenic peptide (endogenous antigen) presented on another body cell. Will see antigen on MHC complex which is on all of our cells critical bc we don’t know where a virus might be, if it’s in our I liver cell we don’t have MHC 2 in our liver cells but we do have MHC 1. Cytotoxic T cells can see that problem through the MHC 1 complex. Activated cytotoxic T lymphocyte (C T L) will recognize other cells expressing the same antigen. ◦Target cells (body cells) may harbor an intracellular pathogen such as a virus or may be tumor cells or cells in transplanted tissue ◦CTL takes care of intracellular pathogens. ◦Recognize unusual things on tumor cells and unfortunately they do look for transplant tissue/ nonself cells of transplanted tissue and see it as non self, that’s why we have to suppress Immune system so it’ll ignore the differences on the cells. Because MHC class I molecules are found on all nucleated cells, our diverse CTLs are poised to attack almost any cell of the body that has been altered Activated CTL attacks and attaches to target cell and releases perforin (forming a pore), and granzymes (proteases) causing apoptosis, are then able to enter the cell as it endocytoses the pore death normal ◦Pore formation contributes to the subsequent death of the cell and is similar to the action of the complement membrane attack complex. ◦Once the CTL recognizes there’s something on the outside of the cell that’s not right it will come right up to it and it starts pushing in things Iike perforin which cause the organ to die, its punching holes into the membrane and the proteases trigger cell death or apoptosis. Cytotoxic T Lymphocyte (CD8+ T Cells) Apoptosis- ◦Programmed cell death ◦It is a necessary process in multicellular organisms ◦Apoptosis is also an infection-fighting mechanism of last resort: if a cell cannot clear a pathogen any other way, it may die by apoptosis. This helps prevent spread of pathogens, particularly viruses, to nearby healthy cells ◦Cells that die from apoptosis first cut their genome into fragments, causing the membranes to bulge outward via blebbing. Signals are displayed on the cell’s surface that attract circulating phagocytes to digest the remains before any significant leakage of contents occurs. Nonspecific Cells and Extracellular Killing by the Adaptive Immune System Natural killer (NK) cells- ◦Part of lymphoid cell lineage. ◦NK cells can destroy certain virus-infected cells and tumor cells and can attack large, extracellular parasites. ◦They don’t need to presented with the antigen. Do not look to see anything to due with antigen presentation. ◦Destroy virus-infected cells, tumor cells, and attack large, extracellular parasites.  ◦Make up 5–20% of all circulating lymphocytes ◦Dont have TCR’s, they do not need to be stimulated by antigen. NK cells are able to distinguish normal cells from tumor cells, or from cells infected with intracellular pathogens. ◦Detect unusual things/target cells based on whether those cells express M H C class ‣ Viral-infected cells and tumor cells may no longer express M H C class or proteins are missing ‣ Make pores in the target cell leading to apoptosis ◦With tumor cells we start expressing fetal proteins that were made during fetal development. ◦Play a role in extracellular killing. Figure 17.16 Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) (1 of 2) If an organism—for example, a parasitic worm—is too large for ingestion and destruction by phagocytosis, it can be attacked by immune system cells that remain external to it. 1 The target cell is first coated with antibodies. 2 Cells of the immune system, such as eosinophils, macrophages, and NK cells, bind to the Fc regions of the attached antibodies. 3 The target cell is then lysed by substances secreted by the cells of the immune system. Nk cell want to break up the worm into smaller fragments so macrophages can digest it. NK cells will see transplant and cytotoxic T cells will see difference on outside of transplant cells and the organ will fail. All of these different chemicals are attacking cells to the area because we have to get rid of it so only thing to do it break it up so macrophages can take of it. NK cells first contact the target cell and determine whether it expresses MHC class I self-antigens. If it does not—which is often the case in viral infections—they kill the target cell by mechanisms similar to that of a CTL. Tumor cells also have a reduced number of MHC class I molecules on their surfaces. Like CTLs, NK cells cause pores to form in the target cell, which leads to apoptosis. Nonspecific Cells and Extracellular Killing by the Adaptive Immune System (3 of 3) With the help of antibodies produced by the humoral immune system, the cell-mediated immune system can stimulate natural killer cells and cells of the innate defense system, such as macrophages, to kill targeted cells. In this way, an organism such as a fungus, protozoan, or helminth that is too large to be phagocytized can be attacked by immune system cells. This is referred to as antibody dependent cell mediated cytotoxicity. Antibody-Dependent Cell-Mediated Cytotoxicity- ◦The target cell is first coated with antibodies. A variety of cells of the immune system bind to the Fc regions of these antibodies and, thus, to the target cell. The attacking cells secrete substances that then lyse the target cell. ◦NK cells will look at worms and parasites and see things on the outside and they’ll secrete things like perforin and ultimately they want to break up the worm into smaller fragments so macrophages come in and clean up the debris. ◦Protozoans and helminths are too large to be phagocytized  ◦Protozoan or helminth target cell is coated with antibodies ◦Immune system cells (N K cells, macrophages) attach to the Fc regions of antibodies ◦Target cell is lysed by chemicals secreted by the immune system cells Immunological Memory Primary response: ◦immune response on first exposure to an antigen. We’ve never seen the pathogen before, so we mount an immune response and it involves a B cell response and the B cell response it’ll provide the antibodies. For our first response the first antibody is IgM that’s expressed in the B cell and depending on what is needed IgM will go through a class switch and we either make IgE, IgA or IgG. The class switch happens right in the cell, because the variable is the same just switching the constant region and we can do this through splicing. Secondary (memory or anamnestic) response occurs after the second exposure to an antigen ◦Class switching, where initial I g M response shifts to I g G, I g E, or I g A, occurs. Keeping a few B cells to the side to keep for memory so when we see antigen again we can go through secondary response which is quicker and produces antibodies in a short time so no signs and symptoms see. ◦More rapid, lasts many days, greater in magnitude than the primary response. ◦Memory cells produced in response to the initial exposure are activated by the secondary exposure ◦The secondary response is due to the portion of activated B cells that, instead of transforming into antibody-secreting plasmocytes, become memory cells. Memory cells do not reproduce, but they are long lived. Years or even decades later, if these cells are stimulated by the same antigen, they very rapidly differentiate into antibody-producing plasmocytes. Antibody titer is the relative amount of antibody in the serum. Is the concentration of the antibody in the serum (fluid) of the blood. ◦During a primary immune response, the exposed person’s serum contains no detectable antibodies against an antigen for 4 to 7 days. Then there is a slow rise in antibody titer: first, IgM class antibodies are produced, followed by IgG peaking in about 10 to 17 days, after which antibody titer gradually declines. This pattern is characteristic of a primary response to an antigen. ◦Reflects intensity of the humoral response Figure 17.17 The Primary and Secondary Immune Responses to an Antigen Figure- IgM appears first in response to the initial exposure. IgG follows and provides longer-term immunity. The second exposure to the same antigen stimulates the memory cells (formed at the time of initial exposure) to rapidly produce a large amount of antibody. The antibodies produced in response to this second exposure are mostly IgG. Shows the primary response, have to allow some time for igm to get secretaed from the B cell and over time theres a class switch to igg. Pulling off some B cells for memory. The primary response needs the help from t helper cells. T helper secrete cytokines into B cells to proliferate and differentiate it also secrete factors for the class switch and also the factors that the T cells release help the B cells have memory. T cell that needs to help is being presented with the antigen that is needed at the moment. T cells also support memory T cells. There is also memory T cells and memory B cells. If you see the pathogen for a 2nd time the memory cells will do its job and the expression of igm will happen faster and class switch will happen faster and no signs and symptoms might not be seen. Types of Adaptive Immunity (2 of 2) Immunity is acquired actively when a person is exposed to microorganisms or foreign substances and the immune system responds. Immunity is acquired passively when antibodies are transferred from one person to another. Passive immunity in the recipient lasts only as long as the antibodies are present—in most cases, a few weeks. Both actively acquired immunity and passively acquired immunity can be obtained by natural or artificial means Naturally acquired active immunity naturally infection Through ◦Resulting from infection ◦develops from exposure to antigens, illness, and recovery. Once acquired, immunity is lifelong for some diseases such as measles. In other cases, especially for intestinal diseases, immunity may last only a few years. Subclinical infections can also confer immunity. antibodies Naturally acquired passive immunity meaning Passive to transferaseaereen ◦Transplacental or via colostrum ◦Get presented when were a fetus. Is natural, getting antibodies from mother. ◦Is the transfer of antibodies to a fetus during pregnancy. These antibodies cross the placenta (transplacental transfer). ◦If the parent is immune to diphtheria, for example, the newborn will be temporarily immune to diphtheria as well. ◦Certain antibodies are also passed to a nursing infant in breast milk, especially in the colostrum. ◦Passive immunity generally lasts only as long as the transmitted antibodies persist—usually a few weeks or months— but it is essential for defending newborns until their own immune system matures. Artificially acquired active immunity ◦Injection of vaccination (immunization) Artificially acquired passive immunity ◦Injection of antibodies into the body. These antibodies come from an animal or a human who is already immune to the disease. In this approach, plasma from a person who has recovered from an infection (so-called convalescent plasma), is introduced into a recipient ◦We can get antibodies passively. ◦Antibodies will attach to cells before the pathogen enters and attaches to our cells. ◦When an individual is given artificially acquired passive immunity, it confers an immediate passive protection against the disease. However, this immunity is short-lived because antibodies are degraded by the recipient. The half-life of an injected antibody (the time required for half of the antibodies to disappear) is typically about 3 weeks. Figure 17.18 Types of Adaptive Immunity Different types of adaptive immunity. Figure 17.19 The Dual Nature of the Adaptive Immune System Shows how all the cells are responding and how hummoral immunity works with cellular immunity. The adaptive immune system is divided into two parts, each responsible for dealing with pathogens in different ways. These two systems function interdependently to keep the body free of pathogens. Humoral immunity, also called antibody-mediated immunity, is directed at freely circulating pathogens and depends on B cells. Cellular immunity, also called cell-mediated immunity, depends on T cells to eliminate intracellular pathogens, reject foreign tissue recognized as non self, and destroy tumor cells. The adaptive immune system provides specificity, clonal expansion, and memory. Chapter 18 Vaccines (3 of 3) Variolation: smallpox prevention procedure involving inoculation of material from dried smallpox scabs into the respiratory tract or skin (1400s in China–1700s). Occasionally did result in a serious case of smallpox. Jenner inoculated people with cowpox scab material to prevent smallpox (17 98) ◦Termed vaccination by Pasteur ‣ vacca = cow Vaccine: suspension of organisms or fractions of organisms which stimulate the body’s immune defenses against the pathogen. ◦Introduce a harmless form of antigens, such as tetanus toxoid, to the body. For example, killed or inactivated bacteria can be injected into the body resulting in an immune response without causing infection. Principles and Effects of Vaccination Provokes a primary immune response- what were doing when were getting vaccinated were given the antigen without having to suffer through signs and symptoms and were depending on making the memory cells. ◦Leads to the formation of antibodies and long-lived memory cells, b and t memory cells to the antigen so if wee the real antigen well mount a secondary response quickly and less intense and less signs and symptoms and faster. Produces a rapid, intense secondary response Herd immunity: immunity in most of the population. Want to get population about 95% immune or vaccinated so that the few ppl that are susceptible wont be in contact with the pathogen because theres no spread since a good amount is immune to it. Protects few susceptible ppl. ◦Outbreaks are sporadic due to the lack of susceptible individuals Types of Vaccines and Their Characteristics (1 of 6) Attenuated vaccines ◦Uses a living pathogen with reduced virulence. ◦Weakened pathogen, reduced virulence. Seeing live virus but its been crippled but allows you to mount a strong immune response as if you saw the wild type. ◦Closely mimic an actual infection. The pathogen in the vaccine reproduces within the host, and cellular, as well as humoral, immunity usually is induced. Lifelong immunity, especially in the case of viruses, is often achieved without booster immunizations ◦Long term effectiveness due to the vaccine organisms replicating in the body, magnifying the effect of the original dose ◦Confers lifelong immunity (both humoral and cellular) ◦Not given to immunocompromised patients. Because the organism can start growing more that what you want it to and mutate back to pathogenic form and the person doesn’t have an immune response that will stop it. ◦Risk of mutating back to virulent form. Risk of going back to wild type due to mutation. ‣ Problem with the oral polio vaccine. Was attenuated strain. Some cases the wild type came back. Going back to killed vaccine. Types of Vaccines and Their Characteristics (2 of 6) Inactivated vaccines ◦Whole microbes are killed or inactivated. Heat killed or formaldehyde treated after being grown in the laboratory. This keeps the pathogen intact so the immune system can recognize it, but it destroys the pathogen’s ability to replicate. ◦Safer than attenuated vaccines. There is a risk of incomplete inactivation., inactivated vaccines often require repeated booster doses because its not as strong since it doesn’t replicate within the host. No long lasting immunity. ◦Induce mostly humoral immunity, which makes them less effective than attenuated vaccines. Inducing antibody response not T cell response. ◦Won’t cause disease because its dead. Types of Vaccines and Their Characteristics (3 of 6) Subunit vaccines- contain only selected antigenic fragments of a microorganism that best stimulate an immune response. ◦This avoids the dangers associated with the use of live or killed pathogenic organisms. ◦Subunit vaccines can be components of bacteria or viruses. ◦Recombinant vaccines: subunit vaccines produced by genetic modification of yeast or insects to produce the desired antigenic fraction ‣ You get the antigen and the gene for the protein to make capsid protein and put it into rDNA and you grow it up and you express a lot of the protein and this is going into vaccine. It’s the protein that’s isolated through rDNA. No side effects through it. ‣ Hepatitis B vaccine: capsid grown in recombinant yeast. For example, the hepatitis B vaccine is produced by yeast that has been engineered to contain genes encoding hepatitis B viral proteins. Those proteins are then isolated from the yeast and used as vaccines ◦Toxoids: contain inactivated toxins produced by a pathogen and elicit an antibody response against that particular toxin. Getting toxin from it. ‣ Getting toxin that will protect us from Diphtheria, tetanus ‣ Many older adults have not received boosters and likely have low levels of protection. ◦Virus-like particle (V L P) vaccines: resemble intact viruses but do not contain viral genetic material. ‣ Taking particles from protein of virus and its put into lipid particle so it sort of looks like outside of virus and this is put into vaccine and we recognize it and have a strong immune response. ‣ H P V vaccine- human papilloma virus- For example, the human papillomavirus vaccine consists of viral proteins produced by a genetically modified yeast or viruses grown in insect cells. The proteins assemble themselves into a VLP. Types of Vaccines and Their Characteristics (4 of 6) Polysaccharide vaccines: made from molecules in pathogen’s capsule; not very immunogenic. ◦Include polysaccharide and Pneumococcal vaccine ◦Some pathogens, most notably S. pneumoniae (pneumococcus), are virulent primarily because their polysaccharide capsule makes them resistant to phagocytosis. Conjugated vaccines: polysaccharide antigen is attached to a protein. Protein antigen is conjugated with something like a lipid that makes it more seen from the immune cells. combinesaweak with antigen astrong to the antigen enhance immune response ◦Children < 2 years old, do not respond to T-independent antigens like capsular polysaccharides ◦Attaching polysaccharide to a protein carrier (conjugate): makes the vaccine immunogenic in babies as young as 2 months Types of Vaccines and Their Characteristics (5 of 6) DNA vaccines ◦Injected naked or encapsulated D N A that encodes specific protein antigens into muscle ◦Upon injection, the DNA enters muscle cells where the introduced genes are transcribed (mRNA is synthesized) and the mRNA is translated (antigenic proteins are synthesized). The antigens encoded by the DNA vaccine are expressed on the cell to stimulate both humoral and cellular immunity. ◦D N A directs the synthesis (transcription, translation) and produces the protein antigen encoded in the D N A ◦Put in DNA into our cells so the DNA will express spike protein which we recognize as foreign and we mount an immune response to it. ◦We did see DNA vaccine as a virus. We were reacting to the nucleic acid and it didn’t do what it was supposed to do. They fixed this by manipulating the amino acids ◦Stimulates humoral and cellular immunity mRNA vaccines ◦mRNA enclosed in a lipid nanoparticle is injected into muscle where it directs the synthesis of the encoded antigen ◦Put in mRNA into our cells so the mRNA will express spike protein which we recognize as foreign and we mount an immune response to it. These are harmless, but serve as antigens that trigger the immune response. Unlike DNA vaccines, which require gene transcription in the cell nucleus followed by protein synthesis in the cytosol, mRNAs need only enter the cytosol where protein synthesis takes place. ◦This and dna vaccines has a lot of issues because our body sees the mRNA as foreign and it though it was viral RNA and it triggers an interferon response and an immune response. We were reacting to the nucleic acid and it didn’t do what it was supposed to do. They fixed this by manipulating the basis in the nucleic acids so we ignored it and accepted it. ◦COVID-19 vaccines direct synthesis of spike protein antigen These vaccines were being used for tumors and cancer prevention and treatment. Figure 18-1 m R N A Vaccines Figure- The messenger RNA vaccines developed in response to the COVID-19 pandemic encode antigens from the viral spike protein. These are incorporated into a lipid nanoparticle shell. Upon injection, this mRNA preparation is taken up by cells, where it is translated in ribosomes into the antigenic spike protein. The antigens then stimulate humoral and cell- mediated immune responses by B cells and T cells. We get shot of mRNA and we express spike proteins, the antibody’s grab onto spike proteins so that the spike protein can’t grab onto our receptors on our cells. Vaccine production- Vaccine production often required growing the pathogen in animals, embryonated eggs, or cell cultures. Recombinant vaccines, DNA vaccines, mRNA vaccines, and recombinant vector vaccines do not need a cell or animal host to grow the pathogen. This avoids the problems involved in using attenuated virus, including the presence of egg protein in a vaccine, or the difficulty of propagating certain viruses in cell culture. The very successful subunit vaccine for hepatitis B was the first of these recombinant vaccines. Plants are also a potential production system for doses of antigenic proteins that would be taken orally as pills or as an injection. Tobacco plants are a leading candidate for this use because they are unlikely to contaminate the food chain Vaccine Production, Administration, and Safety Adjuvants ◦Additives to a vaccine that improve its effectiveness ◦Alums and a derivative of lipid A (from LPS) called monophosphoryl lipid A are the only adjuvants approved for use in humans in the United States ‣ Alum (aluminum salts)- added to improve the ability for us to react and form a good immune response. The mercury that was added into vaccines by Marisol was in there only because it was a preservative, but people believed it was a cause of autism but it wasn’t and it will removed though. ‣ Monophosphoryl lipid A (derivative of LPS)- ◦Improve the innate immune response, activation through Toll-like receptors Vaccine Production, Administration, and Safety (3 of 4) Vaccine Administration Oral vaccines: favored due to ease of administration and effectiveness against pathogens that enter through the G I tract ◦Vaccines for rotavirus, adenovirus, cholera, typhoid Nasal vaccine: attenuated influenza vaccine. Will be released in the next year or 2. Skin patch vaccines: (NanopatchT M). Makes it easier for ppl to be willing to be vaccinated. Helps with the lack of training and resources with injected vaccines. Doesn’t require refrigeration. Multiple-combination vaccines- combined vaccines Vaccine safety- Minor side effects vary according to vaccine, but may include tenderness at the injection site, headache, fever, mild rash, and fatigue. Occasionally, a vaccine is linked to more severe outcomes; for example, on rare occasions, the oral polio (Sabin) vaccine may cause the disease. Diagnostic Immunology We have diagnostic tests that can pinpoint various diseases with a high degree of accuracy. Since we have antibodies and they are sensitive and specific, we have an ability to diagnose diseases through looking at the serum from patients to see if they made the antibody for that specific virus. Two essential elements of diagnostic tests are sensitivity and specificity Sensitivity: probability that the test is reactive if the specimen is a true positive  ◦For example, if 100 people are known to have a disease but the test finds only 72 of them positive, the test has a sensitivity of 72% How matters's Specificity: probability that a positive test will not be reactive if a specimen is a true negative ◦if 100 people are known not to have the disease, and the test reveals that 72 of them are negative but 28 of them are positive, the test has a specificity of 72%. Immunologic-based diagnostic tests I ◦Based on interactions of humoral antibodies with antigens ◦Known antibody can identify an unknown pathogen ◦Known pathogen can determine the presence of an unknown antibody. A known pathogen can be used, for example, to determine the presence of an unknown antibody in a person’s blood—which would determine whether they have immunity to the pathogen. Use of Monoclonal Antibodies (1 of 3) We have specificity of the antibody and we can deliver it to something like a cancer cell, we have specificity of the antibody recognizing some antigen on a cancer cells, what we can do is on the constant region of the antibody add either a radioactive molecule or bacterial toxins into the cancer and it wont be spread to our cells. This was the “magic bullet”. There is success in using antibodies in treating cancer. As soon as it was determined that antibodies were produced by B cells, it was understood that if a B cell producing a single type of antibody could be isolated and cultivated, it would be able to produce the desired antibody in nearly unlimited quantities and without contamination by other antibodies. A B cell reproduces only a few times under the normal cell culture conditions, but this limitation was largely removed by tapping cancerous plasma B cells for culture. These cancerous plasma B cells, known as myelomas, no longer make antibodies but can be isolated and grown indefinitely in cell culture. Fusing this “immortal” myeloma cell with an antibody-producing normal B cell creates a hybridoma that, when grown in culture, produces the type of antibody characteristic of the ancestral B cell indefinitely This allows us to procure immense quantities of identical antibody molecules. Because all of these antibody molecules are produced by a single hybridoma clone, they are called monoclonal antibodies, or Mabs andcancerousmyeloma regularBcell see Hybridoma: that had “immortal” cancerous B cell (myeloma) and they could take the antigen they wanted to make an antibody too and inject it into mice, the idea was to take the immortalized cell line and combined/fuse with an antibody- producing normal B cell that’s making the specific antibody and now there is an immortal cell line specifically making only 1 antibody, this is monoclonal antibody. Only recognizing 1 antigen and it’s highly specific and you can grow up a lot and enough to make magic bullets and that’s what’s being used in the clinics now. ◦Hybridoma produces monoclonal antibodies (Mabs)- ‣ Nearly unlimited quantities of identical antibody, same specificity as the ancestral normal B cell ‣ No contamination by other antibodies iiii i ‣ Highly specific EEE Use of Monoclonal Antibodies (2 of 3) Mabs are uniform, highly specific, and produced in large quantities ◦Used in diagnostic tools ◦Used in human therapy  ‣ Treatments for multiple sclerosis, Crohn’s disease, psoriasis, cancer asthma, arthritis, COVID-19- ppl were treated when diagnosed with monoloclomal antibodies and this could be treating them. ◦Commercial kits use them to recognize several bacterial pathogens, and home pregnancy tests use them to indicate the presence of a hormone excreted into the urine only during pregnancy; moreover, home COVID-19 tests use Mabs specific for the viral spike protein. ◦Often derived from mouse B cells, leading to side effects bc we see the mice antibody as being foreign and not human. But its been humanized so we accept them and don’t see them as foreign. The modes of therapeutic action of monoclonal antibodies vary. Some neutralize tumor necrosis factor (TNF), which certain inflammatory diseases such as rheumatoid arthritis require. One such Mab is infliximab. Other Mabs block a receptor site; an example is omalizumab. This drug treats allergic asthma by preventing the binding of IgE to Fc receptors on mast cells and basophils Foundation Figure 18-2 The Production of Monoclonal Antibodies Have antigen and the mouse has different B cells. Physically will take lymph tissue and have different types of techniques to fuse B cells from mouse with the myeloma cell line that will grow and you’re asking for the myeloma cells to produce antibodies that you’re interested in. Now have a supply of antibodies. This is monoclonal antibodies. All tests like covid test use monoclonal antibodies. The fusion of cultured myeloma cells (cancerous B cells) with antibody-producing spleen cells forms a hybridoma. Hybridomas can be cultured to produce large quantities of identical antibodies, called monoclonal antibodies. Monoclonal antibody production is an important advancement in medicine and also is integral to common diagnostic and therapeutic tools. A monoclonal antibody can attach to a target cell while carrying a diagnostic marker or an anticellular toxin. The therapeutic use of monocolonal antibodies had been limited because they were once produced only by mouse (murine) cells. The immune systems of some patients reacted against the foreign mouse proteins, leading to rashes, swelling, and even occasional kidney failure, plus the destruction of the antibodies. The more human the antibody the more successful it is likely to be. Antibodies- Umab means human-derived, omab are from mice, ximab are chimera (genetically modified mice to make a human–murine hybrid), and zumab are humanized.