Lecture 21: Adaptive Immunity PDF

Lecture 21- December 1st- Chapter 17 Innate immunity- responds non specifically to a pathogen nomemoryrapid The same cells of innate immunity work with the adaptive immunity, work together Adaptive immunity- adaptive immunity is designed to recognize self from non self, and it mounts reactions tha...

Lecture 21- December 1st- Chapter 17 Innate immunity- responds non specifically to a pathogen nomemoryrapid The same cells of innate immunity work with the adaptive immunity, work together Adaptive immunity- adaptive immunity is designed to recognize self from non self, and it mounts reactions that are specific to the particular substance or pathogen at hand. The Adaptive Immune System/ acquired Adaptive immunity: defenses that target a specific pathogen after exposure ◦Ability to distinguish “self” from “non self”. Without this ability, the immune system might attack components of the body it is designed to protect. Unfortunately sometimes ppl have problems doing this and they recognize themselves as being foreign and they have an autoimmune diseases. ◦Activated when innate defenses fail to stop a microbe. ◦Acquired through infection or vaccination- a procedure that harnesses the adaptive immune response. A vaccine formulated with a harmless version of a pathogen incites an adaptive response, rendering people immune to the illness without the damage and danger of a full-blown infection that are otherwise needed to obtain these benefits. Ispathogen through aquired bysystem vaccinationbeing tomemory exposed aharmless version Tcells of bcells ◦We want the response to have memory. the which the triggers immune tomake the can cells and quick f e the inthe future m emory respond sothatiw encounter pathogen ◦In our lifetime we well see different pathogens and don’t know what well see but we have to have the ability to recognize a diversity of pathogens, could be virus, fungal cells, bacterial cells or worm like infections. Acquired Diversity immunity has heterogeneity, we have the ability to make the antibody that’s needed at the moment, we make a diversity of antibodies by doing the splicing mechanism. ◦When we respond to a pathogen its a specific response. If its a virus we need to deal with the intracellular organism, if its a worm infection well have a specific response to that. ◦The adaptive immune system comes into play only when innate defenses—physical barriers such as skin and mucous membranes, phagocytes, and inflammation—fail to stop a microbe. ◦The adaptive system tailors its fight to specific pathogens, toxins, or other substances. ◦Specificity- every pathogen that’s going to be dealt with we will have a specific response to it in order to get rid of it. ◦Primary response: first time the immune system combats a particular foreign substance. Involves a lag or latent period of 4 to 7 days. We have signs and symptoms of the disease and we mount an immune response. The first time these cells and chemicals encounter a pathogen, responses can take days or longer to develop. ◦Secondary response: later interactions with the same foreign substance; faster and more effective due to “memory”. Bc we have memory if we see the pathogen again we can get the cells out of memory fast and respond to pathogen quickly so hopefully we wont have signs and symptoms. Dual Nature of the Adaptive Immune System- has dual types of cells Adaptive immunity is described as a dual system, with humoral and cellular components. Cells of the adaptive immune system originate from pluripotent stem cells in the bone marrow or the fetal liver. Although cells of humoral and cellular immunity mature differently, they are all found primarily in blood and lymphoid organs. deal Humoral immunity InvolvesBcellswhich threats withoutside ◦Humoral immunity describes immune actions taking place in these extracellular fluids (blood), brought about by protective molecules called antibodies outside antigeighth makes ◦Humoral immunity primarily involves B cells and neutralizes threats outside mammalian cells. ◦Produces antibodies that combat/react or bind to foreign molecules known as antigens  ‣ Antigens elicits a specific immune response of a virus, bacterium, toxin or other substantial in tissue fluid or blood, can be protein, carb, lipid, or dna or rna, is anything that our body recognizes as foreign and allows us to mount an immune response. The response most often is an antibody. Sometimes we do use T cells to take care of the pathogen. ◦Involves B cells (B lymphocytes) are lymphocytes that are created and mature in red bone marrow. ‣ Recognize antigens and make antibodies. B cells have membrane immunoglobulins (B cell receptors, or BCRs) specific for a particular antigen. Upon antigen binding, the B cell is activated to secrete thousands of Bcell receptors immunoglobulins, which bind to the antigen-bearing substances and target them for destruction. ‣ Named for bursa of Fabricius in birds, organ in birds where researchers first observed these cells ‣ In humans, both B and T lymphocytes are initially produced in the fetal liver. By about the third month of fetal development, once mature the B cells reside in the blood and lymphoid organs/tissue ‣ Make the particular antibody to the pathogen ‣ Maturing and producing antibodies which get secreted out of the cell and the antibody finds the cell. ‣ Because humoral immunity fights invaders outside cells, efforts tend to focus on bacteria that live extracellularly (as well as their toxins) and on viruses before they penetrate a host cell. Dual Nature of the Adaptive Immune System insidethreats Cellular immunity (cell-mediated immunity)-Dealswith cells infected ginevirally ◦Cellular immunity primarily involves T cells and deals with threats inside cells. ◦Involves T lymphocytes or T cells ‣ Recognize antigenic peptides processed by phagocytic cells ‣ Mature in the thymus ‣ Reside in blood and lymphoid organs/tissue and fluid once they mature ◦The T lymphocytes they respond directly to intracellular parasites like viruses, chlmydia and rikettsia, and they go up to a cells that’s infected and take care of it directly, it’s cell on cell contact. The T lymphocytes releases factors that kill the cell that harbors the intracellular parasites. ◦T cell has T cell receptors (TCRs) ‣ on the T cell surface contact/recognize and serve as receptors to antigens. However, TCRs do not bind to free- floating antigens the way antibodies do. Instead, they recognize a tiny piece of a protein antigen—an antigenic peptide—which is presented by specialized molecules on body cells. When T cells are activated by this presenting cell-peptide combination, some destroy that cell (called a target cell) while other T cells are activated to secrete chemical messengers, called cytokinesAlsthemagarophages ◦TCRs on T cells recognize a fragment of a protein antigen (a peptide), which is presented by specialized molecules on body cells. The kind of body cell that allows T cell activation is known as an antigen-presenting cell (APC) which are usually macrophages, dendritic cells, and even B cells will display an antigen from the T cell that it might want to get help from. n isiE fi isYeiiean'dm'adcr Bcells.magr.ph estsitcaniyetEpntrIne ilatantisenpresenting cells ‣ T helper cells which help B cells produce there antibodiesTheysignalotherimmunecellslikebcellsani.SEhFnFeEtn yy.ae ‣ T regulatory cells help regulate the immune response, when we mount the response we want it to stop when we don’t need it anymore iignygnteippdie They ‣ T cytotoxic cells which respond directly to the intracellular parasites and kill them ‣ Delayed hypersensitivity T cells help macrophages and they secrete factors that allows macrophages to find cells that’s are aberrant and engulf and destroy them ftp.n cytokines rantigensmoreslowly.Theyreleasefactorsline reEP ffer't  ◦When B cells need help from T cells, the T cell helper knows what cell to help because they’re recognizing the same antigen. The antigens are displayed on the outside surface of the cell and the T helper cell provides a chemical to the B cell to help make the antibody. Cells know who to work with because the thing they have in common is the antigen. ◦Cell-mediated immune responses focus on recognizing antigens that have already entered a body cell. This immunity is generally best at fighting virus-infected cells and intracellular bacteria. Both cellular and adaptive immune involve specialized immune cells receptors that recognize antigens, followed by activation and production of cells, chemical messengers, and other factors that help destroy the antigen in question or allow the body to remember it later, for speedier responses in the future. Figure 16.4 Hematopoiesis These cells are part of immune response. Monocytes and neutrophils are the phagocytic cells. They display antigen to the 3 important cells that are part of the acquired immunity. Left side is immunity Lymphoid stem cells mature into T cells, B cells and NK cells NK cells they patrol our bodies and look for anything out of place, infected cells and tumor cells anything that’s abnormally growing and abnormal protein. The NK cells also work to try to prevent tumor growth/cancer. Macrophages and dendritic cells are the antigen presenting cells and they display the antigen to the cell that needs to see it and respond to it. cellsseethis andrespond T Figure 17.1 T Cell and B Cell Development Both B cells and T cells originate from stem cells in adult red bone marrow (or in the fetal liver). Some cells pass through the thymus and emerge as mature T cells. Others remain in the red bone marrow and become B cells. Both B cells and T cells then migrate to lymphoid tissues, such as the lymph nodes or spleen. In bone marrow you’ll be a B cell which will produce antibodies T cells they mature in the thymus and they can become one of the 4 different types of T cells BcellstaysinRed bonemarrow Tcell maturesin thymus Dual Nature of the Adaptive Immune System Cellular immunity- directly attacks antigens that have already entered cells. A T cell will go right up to the infected cell and can even go up to a cancer cell. They make direct contact with the cell and release factors that destroy membrane and destroy cell. ◦Viruses; Deakin some intracellular bacteria such as M. leprae and L. monocytogenes. Chlamydia rikettsia, mycobacteria tuberculosis Humoral immunity- fights invaders and threats outside cells. Involves B cells, the B cells they release antibodies which respond to the pathogen or the toxin, or the virus. As long as the virus didn’t get into our cells and is still out there and hasn’t attached to our cells yet that’s where antibodies come in handy. Getting the viruses before they enter our cells and any extracellular organisms and toxins. The antibody is being released and this destroys the pathogen. ◦Extracellular bacteria and toxins ◦Viruses before they enter a host cell Neutralizing antibodies- once antibody attaches to the spike protein it can’t attach to our cells Cytokines: Chemical Messengers of Immune Cells Adaptive immunity requires complex interactions between different cell types. This communication is mediated by chemical messengers called cytokines. We have the cells in the immune system that are communicating through chemical messengers. Actas attractantstoo Cytokines are soluble proteins produced by nearly all types of activated immune cells. They are chemical messengers produced in response to a stimulus. Cytokines function to activate nearby immune cells bearing the corresponding cytokine receptors. Cells that are working together communicate and help each other by releasing cytokines or interleukins that tell those cells what needs to be done ◦Interleukins (ILs):Theypromotecell immune growthactivating responses ‣ serve as communicators primarily between (inter-) leukocytes (-leukins). Is cytokines between leukocytes. ILs often target immune cells to stimulate cell proliferation (increase), maturation, migration, or activation during an immune response. This type of cytokine may sometimes be useful as a drug treatment designed to stimulate the immune system and treat certain infectious diseases or cancers. ◦Chemokines: cells WBCimmune ‣ induce migration of leukocytes to areas of infection or tissue damage where they contribute to their activation. Things that are released that attract cells to the site of infection. ◦Interferons (IFNs): ‣ interfere with viral infections of host cells. They are specific to virally infected cells. The interferons get secreted and help the next door neighbors start making anti viral proteins so the virus can’t replicate in the next door neighbor. ◦Tumor necrosis factor alpha (TNF-α): ‣ direct toxic effect on tumor cells ‣ involved in the inflammation of autoimmune diseases. ‣ Monoclonal antibodies that block the action of TNFs are an available therapy for some of these conditions. ◦Hematopoietic cytokines: ‣ control stem cells that develop into red blood cells and white blood cells. Cytokines that help build up RBC or WBC depending on what we need to be expressed at the moment.  Overproduction of cytokines leads to a cytokine storm. ◦During covid some people responded and made the cytokines and were supposed to help there immune system but it was too much of a cytokine response. ◦This overabundance of cytokines can do significant damage to tissues and appears to be a factor in the pathology of certain diseases such as influenza and COVID-19. Antigens- anything that elicits an immune response/substances that induce production of antibodies. Antigens: substances that cause the production of antibodies. Usually proteins but can be carbohydrates ◦Most antigens are either proteins or large polysaccharides. ◦Usually components of invading microbes or foreign substances are antigenic sites ‣ Capsules, cell walls, flagella, fimbriae, toxins, viral capsids, viral spikes, nucleic acids (DNA or RNA). Lipids and nucleic acids are usually antigenic only when combined with proteins and polysaccharides. ◦Nonmicrobial antigens may include egg white, pollen, blood cell surface molecules, serum proteins from other indivuals or species, and surface molecules of transplanted tissues and organs are still antigenic. Allergic response, abnormal immune response. ◦Detection of an antigen provokes production of highly specific, corresponding antibodies. Antigens that cause such a response are often known as immunogens. ◦Antibodies interact with specific regions on antigens called epitopes, or antigenic determinants. The nature of the interaction depends on the size, shape, and chemical structure of the binding site on the antibody molecule. A bacterium or virus may have several epitopes that cause the production of different antibodies. ‣ When we think about an antibody reacting to an antigen we refer to the area that’s acting on the antigen as an epitope or antigenic determinants. ‣ Can have more than 1 epitope being discovered by the antibody. Were usually making multiple different antibodies to the pathogen, one antibody might be looking at something on the capsule, another on the flagella. ‣ Polyclonal- different antibodies recognizing the pathogen ‣ Monoclonal- 1 antibody looking at 1 specific sequence. Haptens: ◦A foreign substance that has a very low molecular mass (1000 Da or less) is generally not antigenic unless it is attached to a carrier molecule. ◦molecules too small to be antigenic and have a low molecular mass; Once an antibody against the hapten has been formed, the antibody will react with the hapten independent of the carrier molecule. ◦It attaches to carrier molecules and provoke an immune response. Antigen comes into our body and its too small to be seen but once inside us it non specifically attaches to a protein in our body and it lights up and now becomes an elicitaresponse itdoesn't antigen. By itself the small molecule is a hapten. The firsttime itsseen 2ndtimeit animmuneresponse elicits Itattachestoacarrier and ◦Example- penicillin, first time is fine but second time you can be allergic to it. First time the penicillin attached itself to a protein in a body and now you mount an immune response to it and if u take it again it was a hapten but now its being recognized as foreign and you have an allergy. When penicillin combines with host proteins, the proteins act as carriers, initiating an immune response against penicillin. Figure 17.2 Epitopes (Antigenic Determinants) In this illustration, the antigens are components of the bacterial cell wall. Each antibody molecule has two binding sites that attach to identical epitopes on an antigen Example of mounting a good immune response. Multiple antibodies recognizing specific antigens on the organism, we don’t just mount a monoclonal response. Figure 17.3 Haptens A hapten is a molecule too small to stimulate antibody formation by itself. By combining with a larger carrier molecule (often a serum protein) the hapten and its carrier form a conjugate that can stimulate an immune response. Isnow seenasforeign If this was penicillin, initially we wouldn't have mounted an immune response, we never saw it before, but if it had the opportunity the penicillin just non specifically is binding to this carrier, and now this is recognized as foreign, and you start making antibodies to the penicillins. An allergy response arises. Humoral Immunity: Antibodies Secreted antibodies (the secreted versions of B cell membrane immunoglobulins), are compact, relatively soluble proteins. They are designed to recognize and bind to a specific antigen, and cause the antigen to become a target of destruction by various means. Are compact soluble proteins called immunoglobulins (I g) Recognize and bind to specific antigens, targeting them for destruction Each antibody has at least two identical antigen-binding sites that bind to identical epitopes. The number of antigen-binding sites on an antibody is called the valence of that antibody. anti has glance qu ◦Valence is the number of antigen-binding sites on an antibody ‣ Bivalent antibodies have two binding sites. Because a bivalent antibody has the simplest molecular structure, it is called a monomer (A small molecule that collectively combines to form polymers). The Y shaped molecule has a valance number and the valance number means that the antibody can bind to the number of antigens that are identical depending on what the valance number is. So if you're a Y-shaped molecule, each arm of the Y can bind to the same identical antigen, and so we say has a balance of two. Some antibodies though can bind more than two, they're more complex Humoral Immunity: Antibodies An antibody monomer has four protein chains and form a Y-shape ◦Two identical light chains (is shorter chain) ◦two identical heavy chains (made up of more amino acids) joined by disulfide links/bridges  ◦Light and heavy refers to the relative molecular masses. The chains are joined by disulfide links to form a molecule that is often depicted as Y-shaped. However, these two “arms” have flexible hinge regions in their heavy chains and can bend. Variable (v) regions are at the ends of the arms; bind epitopes- ◦On the arm, at the tips is what’s recognizing the antigen. The very tip of each arm forms an antigen-binding site. ◦It has to vary because each unique antibody can see each unique antigen, vary greatly antibody to antibody. Basically recognizes specifically the antigen. ◦The amino acid sequences and, therefore, the three-dimensional structure of these two variable regions are identical on any one antibody. So theybindto identical epitopes and the determines typeoantibody f itwill be Constant (Fc) region is the stem, which is identical for a particular Ig class.This doesn't change Itbindsto immune ocomplement cells r proteins the helping immune orremove destroy system marked pathogens the by antibody ◦Determines the class of antibody it’ll be. Depending on the sequence of the constant region. The area that the macrophage-recognized, complement-recognizes. ◦Fc regions play a crucial role in immune responses. When both antigen-binding sites of an antibody attach to a target, such as a bacterium, the exposed Fc regions can interact with complement proteins. This interaction activates the classical pathways complement system, which ultimately destroys the bacterium. ◦Certain immune cells, like macrophages, have Fc receptors on their surface. These receptors enable them to bind easily to antibodies attached to antigens, enhancing their ability to engulf and eliminate the targets through phagocytosis. ◦There are five major types of C regions, which account for the five major classes of immunoglobulins. Five classes of Ig (IgG, IgM, IgA, IgD, IgE) ◦Each class of antibody has a particular job to do. ◦IgG, IgD, and IgE molecules are secreted as monomers ◦IgA is secreted either as a monomer or as a dimer (two molecules linked together) ◦IgM is secreted as a pentameric ring, with five antibodies linked together Figure 17-4 Structure of a Typical Antibody The antibody molecule is composed of two light chains and two heavy chains linked by disulfide bridges (S—S). The amino acid sequences of the variable regions (V), which form the two antigen-binding sites, differ for each B cell. The constant regions (C) are the same for all antibodies of the same class. light chain blue is shorter and heavy chains are made up of more amino acids The 2 arms are held together of disulfide bridges. The rest of the antibody is the constant region (C), The area that the macrophage-recognized, complement-recognizes. We generate the diversity of antibodies that we need in our lifetime, because when we're bringing together and splicing together the variable region and the appropriate constant region, we're generating the diversity. So in our genes, we're bringing a variable region and genes for the constant region. Those are being stuck together, and then ultimately you're making the mRNA and the protein. With this Y-shaped IgG molecule here, we're picking up two identical, in this case, it's something on this particular cell. So theepitope we have a valance of two, and the antibody here can recognize something on these two cells. And if this is a monoclonal antibody, these monoclonal antibodies are recognizing a same identical antigen on themselves. And eventually, these complexes can grow very large, and sometimes when we see an antibody on a whole cell, we refer to this as an agglutination reaction, because you're sort of pulling and making a complex of cells that are pulled together. toantigenson bind Agglutination reaction- creating a complex of cells Isaprocesswhereantibodies surfaceof the cells causing toclump them together  other can cells immune cross to newborns placentaprotect IgG Themain aretoneutralizepathogenstag for functions them by destruction Is derived from the part of blood, called gamma globulin, that contains antibodies. Is the dominant antibody that you can find is someone’s blood. Monomer- its just the Y shaped molecule Accounts for 80% of serum antibodies In regions of inflammation, these antibodies readily cross the walls of blood vessels and enter tissue fluids. In the blood, and get into lymph, and intestine/tissue Actions: ◦Cross the placenta and protect the fetus. The IgG is small enough that it can cross the placenta. This is what’s protecting the baby along the fetal development. ◦Trigger complement activation. C1 protein recognizes something on the constant region of IgG ◦When bound to antigens, enhance the effectiveness of phagocytosis. When sometime is decorated with antibody’s, macrophages can recognize it like a capsule because the macrophages sees something on the constant region of the antibody. ◦Neutralize toxins and viruses before they enter our cells. the Eye it system the from body complement ftp.nktinmakrlbes an infection and recognize Q uickly neutralize trigger pathogens IgM Thefirstantibodiesproducedby the immune during system More complex. 5 monomers coming together, they are identical and can pick up 10 antigens. Pentamer ring made of five monomers linked by disulfide bonds. The structure also includes a protein called joining (J) chain, which serves like the clasp of a bracelet to close the ring. Valence of pentamer is 10. Can pick up 10 antigens. Makes up 6% of serum antibodies Remains in blood vessels because they’re so big and can’t can’t get out of blood. Causes agglutination (clumping) of cells and viruses because they can attach to 10 different identical antigens. Because the antibody has 10 antigen-binding sites, it is much more effective than IgG in causing the clumping of cells and viruses and in reactions involving the activation of complement. Activates complement When we mount an immune response the first antibody igM than we switch to the other classes. IgM is the predominant type of antibody produced upon first exposure to an antigen, and is the class of antibody involved in the response to the ABO blood group antigens on the surface of red blood cells. Will be found as a monomer on B cells. B cells know what antigen to respond to because the IgM monomer sitting on its membrane can recognize the antigen. Helps the B cells identify which antigen is can respond to.  Released as a first response to an infection; short lived which makes it uniquely valuable in diagnosing disease. If high concentrations of IgM against a pathogen are detected in a patient, it is likely that the symptoms observed are caused by that pathogen. The detection of IgG, which is relatively long-lived, may indicate only that immunity against a particular pathogen was acquired in the more distant past. attaching and from to these invading surfaces by pathogens preventing IgA Secreated thebody's Protects asamonomer adimer membranes mucous Monomer in serum and is attached to the secretory component; dimer in secretions Accounts for 13% of serum antibodies The form of IgA that circulates in serum, serum IgA, is usually in the form of a monomer. Found in secretions. Common in mucous membranes, saliva, tears, and breast milk. Sometimes referred to as secretory IgA, not all IgA have the secretory piece. The most effective form of IgA, however, consists of two monomers linked by disulfide bonds via a J chain, forming a dimer called secretory IgA. It is produced in this form by plasmocytes in the mucous membranes—as much as 15 grams per day, mostly by intestinal epithelial cells. Each dimer then enters and passes through a mucosal cell, where it acquires a polypeptide called secretory component that protects it from enzymatic degradation. The main function of secretory IgA is to prevent the attachment of microbial pathogens to mucosal surfaces. This is especially important in resistance to intestinal and respiratory pathogens. Because IgA immunity is relatively short-lived, the length of immunity to many respiratory infections is correspondingly short. IgA’s presence in breast milk, especially the earliest milk called colostrum, probably helps protect infants from gastrointestinal infections. IgD Actsasareceptor on igif antibodies other Eiabg'flattanatiface imgmnqtfg.gg Monomer Make up only 0.02% of serum antibodies Structure similar to IgG molecules Found in blood, in lymph, and also play a role as membrane immunoglobulins on mature B cells. No well-defined function in serum other than antigen binding. May play a role as a membrane immunoglobulin on B cells. IgE andplaya inallergic role imiml the from gi parasites Entemmbiiatit Fainter.fm protect helps body n ggn monomer Only make up0.002% of serum antibodies On mast cells, on basophils, and in blood They have been shown to be potent inducers of erythema (superficial reddening or rash of the skin). Their Fc regions bind tightly to receptors (Fc receptors) on mast cells and basophils, specialized cells that participate in defense against large parasites such as helminths and in allergic reactions Cause the release of histamines when bound to antigen; and lysis of parasitic worms- when an antigen such as pollen links with the IgE antibodies attached to a mast cell or basophil, that cell is triggered to release histamine and other chemical mediators. These chemicals provoke a response—for example, an allergic reaction such as hay fever ◦In the case of a helminth infection, these chemicals are damaging to the organism because they attract complement and phagocytic cells to the site.  Plays an important role in treating large worm infections and plays a major role in allergy’s. hypersensitivity reactions (allergies) The concentration of IgE, which is greatly increased during some allergic reactions and parasitic infections, is often diagnostically useful. Table 17.2 A Summary of Immunoglobulin Classes- don’t need to know half life, %, or location IgM has this J-chain which joins five monomers. And so IgM can potentially bind 10 identical antigens. And theres the secretory piece with your IgA. Humoral Immunity Response Process Humoral immune actions take place in the extracellular spaces within the body. So-called free antigens found here need to be recognized by the immune system so that specific antibodies can be generated to neutralize them. These antigens need to be remembered so that future interactions with them result in a quicker immune response. B cells are key to these processes. B cells reside in, and interact with antigen in, lymphoid organs such as the spleen and lymph nodes. bcellreceptors Each B cell has more than 100,000 membrane-bound immunoglobulins on its surface that serve as receptors for antigen. The majority are IgM and IgD, all of which are specific for the same epitope. Some B cells have other immunoglobulin classes on their surfaces. For example, B cells in the intestinal mucosa are rich in IgA Clonal selection- a B cell is activated when its BCRs bind to antigen. This causes the B cell to proliferate, an event known as clonal expansion, and to differentiate, generating memory B cells as well as plasmocytes that secrete antibodies, all specific Clonalselectionprocess where immune specific cellsBcells orci ellsthatrecognizeaparticularantigenare activated and m ultiply copies p roduce for that same antigen. B after a Clonal cells immune expansionspecific T like or cells cells rapidly m ultiply recognizingpathogen Activation and Clonal Expansion of Antibody-Producing Cells BcellssometimesTcells Activation of a B cell can occur in two ways. T-dependent antigen ◦Some antigens require a type of T cell called a T helper cell to activate a B cell. This kind of antigen is known as a T- dependent antigen. Antigen that requires a TH cell to produce antibodies ◦T-dependent antigens are mainly proteins of the type found on viruses, bacteria, red blood cells, and hapten-carrier conjugates. ◦For antibodies to be produced in response to a T-dependent antigen, both B and T cells must recognize and interact with different epitopes of a given antigen. This ensures specificity of the attack and also helps prevent an unintentional autoimmune response  T-independent antigens ◦B cells can be activated directly by some antigens, called T-independent antigens, without assistance of T cells. ◦Stimulate the B cell without the help of T cells ◦Provoke a weak immune response, usually producing IgM. The T-independent response is composed primarily of IgM, and no memory B cells are generated. ◦No memory cells generated ◦These are repetitive structures like peptidoglycan or a capsules. T-independent antigens tend to be molecules consisting of repeating subunits, such as polysaccharides or lipopolysaccharides or capsules. The repeating sub units can bind to multiple B cell receptors which is probably why this class of antigens does’nt require T cell assistance. ◦The B cell doesn’t need help and it will respond to the antigen and mount a B cell and than and antibody response. Because its not getting help from T cells, the immune response is weak and only produces IgM because the T cells help make the switch from IgM to the other classes called class switch, but it can’t do this bc its not getting help from the T cells and there’s no memory. ◦For some antigens we don’t need a strong response. And IgM is enough. Activation and Clonal Expansion of Antibody-Producing Cells TCRs on T cells recognize a fragment of a protein antigen (a peptide), which is presented by specialized molecules on body be can macrophages cells. The kind of body cell that allows T cell activation is known as an antigen-presenting cell (APC) and the specialized molecule on the APC that presents the peptide is a major histocompatibility complex (MHC) class II protein.The senting ftp.qptitpc Antigen-presenting cells must display antigen on their surface in association with the major histocompatibility complex (MHC) protein. ◦Antigens being displayed on the surface of antigen presenting cells. The antigen presenting cells is presenting antigen to a cell that can respond to that antigen. ◦ Antigen-presenting cells are thought of as a macrophages, dendritic cells and B cells can also display antigens on they’re surface because they’re need to display it to T cells. Major histocompatibility complex (M H C) genes encode molecules on the cell surface. On our cells we have a complex of i inii i amine t.EEi proteins called MHC. aimi S Two types of M H C ◦Class I MHC on the membrane of nucleated cells ‣ Identifies a cell as “self” ‣ Antigen-presentation to T cytotoxic (Tc) cells ‣ On all of our nucleated cells we have the Class MHC 1 found in all of our cells. Function to present peptide antigens to T cells called T cytotoxic (Tc) cells Responds them tointracellularparasiteskills directly ◦Class II MHC on the surface of antigen-presenting cells Are on found surfaceofA the PCThey the present toT antigens helper to cells the fight infection proteins ‣ APCs bind to, internalize, and break down antigens to form peptides which are then loaded onto the MHC class II signals molecule and are transported to the surface of the presenting cell. There they are accessible to TCRs on Th cells. they ‣ (A P Cs) including B cells, macrophages, dendritic cells which are displaying antigens to the T cells and B cells cells need to display the antigen to the T cell they need help from and this is displayed in a complex of proteins that supports the antigen. ‣ A B cell can serve as an APC, first binding specifically to a T-dependent antigen, then internalizing it. The antigen is broken down to peptide fragments that are presented by MHC class II to a T cell. The T cell makes contact with the fragment presented on the APC. This interaction, along with a stimulatory signal from the T cell, induces the T cell to secrete cytokines that help activate the B cell, which divides into a large clone of cells.  ‣ Some of the B cells differentiate into antibody-secreting plasmocytes. Others become long-lived memory B cells responsible for the enhanced secondary responses to that antigen. ‣ Only on the surface of antigens presenting cells Activation and Clonal Expansion of Antibody-Producing Cells Our B cells are more or less in active until, they’re not making antibodies until they see the antigen and they internalize the antigen and they see the antigen because the IgM which is a monomer that can react to the antigen at the hydrobarital region, is saying it can attach and it more or less internalizes that whole complex and the antigen is more or less broken down into fragments and displayed with the MHC-2 complex sitting on the membrane, the outside membrane of our B cells. Inactive B cells contain surface Ig that bind to antigen B cell internalizes and processes antigen Antigen is broken down into fragments and are displayed on MHC class II molecules B cell wants to display the antigen to get help from the T helper cells that will release cytokines that will allow the B cell to expand and go from one to cell to others and than ultimately well have the antibody made which will get secreted from the cell. T helper cell (TH) contacts the displayed antigen fragment and releases cytokines that activate B cells. Will help with clonal expansion because that one cell that can react with that one antigen will expand in number and so that will be can secrete a lot of antibodies from each one of those cells. B cell undergoes proliferation (clonal expansion) Figure 17.5 Activation of B Cells to Produce Antibodies In this illustration, the B cell serves as an APC, presenting antigen to a T cell. The T cell then helps activate the B cell to proliferate and differentiate. 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 B 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. Activation and Clonal Expansion of Antibody-Producing Cells When we have an antibody producing cell, we also take a few B cells and keep them into memory. So we always have memory that we take that antigen before. And so if I see that antigen a second time, those memory cells are gonna come out of memory and expand much faster than the original primary response. The T helper cells also help the B cells to do that. The T cells secreting some of those cytokines not only by expanding B cells, but also giving information to say, set aside a few and put into memory and your T cells will also be sent aside some T cells to go into memory too. Because for a correct B cell response, u need a T cell. So they both have to be in memory. So there can be a good secondary response if needed. Clonal selection differentiates activated B cells into: ◦Antibody-producing plasma cells ◦Memory cells Clonal deletion- the elimination of B and T cells that react with self. Eliminates harmful B cells. During fetal development, if any B cell can recognize a protein on the outside of our cells as the tissue is being developed, that's where tonal deletion occurs. Getting rid of B cells during fetal development. So if we recognize ourselves as foreign and we're never gonna be able to survive, but we get rid of those cells during development. Figure 17.6 Clonal Selection and Differentiation of B Cells B cells together can recognize an almost infinite number of antigens, but each B cell recognizes only one particular antigen (epitope). An encounter with that antigen triggers B cell proliferation (here, B cell “II”) into a clone of cells with the same specificity, hence the term clonal selection (by the antigen) and expansion (B cell proliferation). The initial antibodies produced are generally IgM, but later the same cell might produce different classes of antibody, such as IgG or IgE; this is called class switching. The IgM is reacting to an antigen and well have an immune response and mature into a plasma cell that secretes antibodies and IgG is small enough that it can get out of blood vessels and this is why this is the antibody seen that can cross the placenta because its small enough. And we always portion some off the cells for memory. T cells are supporting the whole process. Figure 17-7 Activation of B Cells Against a T-Independent Antigen T-independent antigens have repeating units (epitopes) that can cross-link several antigen receptors on the same B cell. These antigens stimulate the B cell to develop into antibody-secreting plasmocyte without the aid of T helper cells. However, no memory B cells are generated. The polysaccharides of bacterial capsules are examples of this type of antigen. This is a repetitive polysaccharide carbohydrate, and we just really don't need any help. And so the B cell can recognize the epitopes and it can mature to being able to secrete IgM. The Diversity of Antibodies We have a diversity of antibodies we have for our whole life and we can generate the diversity by splicing together variable regions with different constant regions so we can generate a diversity without needing so much DNA. By being able to splice and taking a variable region and putting it together with a constant region we can generate a diversity. The human immune system is capable of creating a number of specific antibodies, the estimated extent of antibody diversity: 10^11 (100 billion) ◦different antibodies can be made by one individual The number of genes required for this amount of diversity is actually relatively small, thanks to random rearrangement of gene segments that code for antigen receptors, resulting in variations of the amino acid sequence at the antigen-binding site (V region). These random rearrangements occur before antigen is present, during the early stages of B cell development in the bone marrow. Because of this randomness, some of the B cell antigen receptors made would ultimately lead to antibodies specific for our own tissues. However, these potentially harmful B cells are usually eliminated in the bone marrow by a process called clonal deletion. Immunoglobulin genes have segments that can rearrange to produce this diversity in the antigen-binding section of the antibody molecule Results of the Antigen-Antibody Interaction antibodies are being secreted from the plasma cells. An antigen–antibody complex forms when antibodies encounter and bind to antigens. ◦Affinity- strength of the bond. ‣ In general, the closer the physical fit between the epitope and the antigen-binding site, and the stronger the attractive forces between their amino acids, the higher the affinity. The antibody molecule itself is not damaging to the antigen. Rather, the binding marks foreign cells and molecules for destruction by phagocytes and complement. Thebindingattractstheimmunecells ◦Antibodies render foreign agents harmless by five primary mechanisms- ◦Protects the host by tagging foreign molecules or cells for destruction ‣ Agglutination Clumping ‣ Opsonization PuttingOpsoninsonitwhichhelpimmunecellsfindit ‣ Antibody-dependent cell-mediated cytotoxicity ‣ Neutralization neutralizesthethreat ‣ Activation of the complement system Figure 17.8 The Results of Antigen–Antibody Binding The binding of antibodies to antigens forms antigen–antibody complexes that tag foreign cells and molecules for destruction by phagocytes and complement. Agglutination- ◦In agglutination, antibodies cause antigens to clump together. For example, the two antigen-binding sites of an IgG antibody can combine with epitopes on two different foreign cells, aggregating the cells into clumps that are more hasatotal easily ingested by phagocytes. Because of its more numerous binding sites, IgM is more ofIositesat cross-linking and effective aggregating particulate antigens. IgG requires 100 to 1000 times as many molecules for the same results. ◦Since we have antibodies that combine maybe two antigens, an IgIycan 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. Opsonization- ◦Opsonization is the coating of antigens with antibodies or complement proteins. This enhances ingestion by phagocytic cells ◦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 opsonization. ◦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. Activation of complement- ◦either IgG or IgM antibodies may trigger activation of the complement system. For example, inflammation is caused by infection or tissue injury. One aspect of inflammation is that it will often cause microbes in the inflamed area to become coated with certain proteins. This, in turn, leads to the attachment to the microbe of an antibody–complement complex. This complex lyses the microbe, which then attracts phagocytes and other defensive immune system cells to the area ◦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. Neutralization- ◦In neutralization, IgG antibodies inactivate microbes by blocking their attachment to host cells. IgG can neutralize toxins in a similar manner. By surrounding specific pathogenic components of a microbe, the antibodies can reduce pathogenicity or toxicity. ◦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. Antibody-dependent cell mediated cytotoxicity- ◦Antibody-dependent cell-mediated cytotoxicity resembles opsonization in that the target organism becomes coated with antibodies; however, in this case the target cell is not engulfed but remains external to the phagocytic cell attacking it ◦What happens is for those big things like worms, which macrophages cannot ingest, 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 to break up the worm into fragments. So now macrophages have a chance of ingesting those fragments of worms. ◦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. So any one of these serves a function, what the antibody is doing, depending on what the antibody needs to do. Clumping tg Bet geysers