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Unformatted text preview: Cell:Cell Communication There's three majjor classes of cytokines which is autocrine which is self-stimulating. An activated cytokine can stimulate a receptor on itself. Paracrine is when it is used to stimulate adjacent cells. Most cytokines will be autocrine and paracrine. There's also endocrine such as hormones, which interact with cells far away. They can provide differentiation signals. they can bring a cell to another location. they can turn a cell on and bring more effector molecules. They are involved with T and B cell collaboration. T and B cell get a long with each other. historically, cytokines were first noted in the 1960s. They used these allogeneic mixed culture supernatatns. An allogeneic system is where you mix two different cells from two different species. People mixed cells in a dis.... I'll just talk about the important interleukins. These first two cytokines are just by numerical orcder. Il1 and Il2 are important especially Il2. it's shown here coming out and communicating. it does a lot of different things. It causes fever (endogenous pyrogen). It acts on T cells and B cells as well as cells that workin fevers. There's a lot of different pleiotrophic effects. Th1 cells. This is why it's called T cell growth factor. i tcauses ... and another cell type called NK cells. Importantly, this can be autocrine. It can stimulate itself to replicate. These guys can also cause macrophage activation. IL4 cause cells to be more phagocytic. If you give it Il4, it'll be able to gobble stuff. MHC2 will increase the ability of T cells to recognize peptide. IL10 is secreted by the same cell. this is an example of antagonistic cytokines. Theere's a yin and yang thing. When you look at cytokine responses. We backed upa nd said it's a microenvironemtn. That'll be an answer. Here's Th1 versus Th2. The first two we'll talk about are Thelper 1 and Thelper 2. Typically Th1 is called an inflammatory cell... etc. stimulates tc cell that's good for ... IL2 causes T cells to proliffereate. TNFbeta activates macrophage. IFNgamma is antiviral and inhibits TH2. TH2 secretes IL 4, 5, 10. If these cytokines Importantly IL12, it'll polarize to a Th1. In contrast, if this Interleukin sees IL4, you polarize the guy to a TH2. It's going to secrete these cytokines. What do these cytokiens do? They regulate surrounding cytokines and what they do. Black arrow is increasing activity and White arrow is inhibiting. Th1 is going to turn on B cell and mnake IgG2a. At the same time, it's going to make IFNgamma and stimulate TH2. TH2 will secrete IL4 and it tells B cells to make IgE, an Ab found in allergic reactions. This is gonna lead to allergy. At the same time, TH2 will suppress the other functions. it's a battle to influence which way the immune system will go. Th1 is generally ogoing to influence B cells to make IgG wheras Th2 is going to get B cell. Th1 is for viral infections, TH2 will be for antigen and soluble infections. if you overly skew to one side, ... autoimmune diseases. This is an innappropriate TH1 response to itself so you get nervous system disorder. Leprosey is an inappropriate Th2 response. Allergies are pretty overt TH2 responses so they switch to IgE. In AIDS you get Th1 which fights the viral, but you switch to TH2 can skew disease pahtogenesis. There have been other subsets that helpidentify. They become more and more important as time goes by. It turns out, (not on exam) there are various TF that turn on, but they skew them over. You do'nt have to memorize them but that's acutally how it happens. The thir kind is a Tfh. it's found iin lymphoid follicles and regulates some Ab isotypes. This is one I'm not going to focus on too much. Th17 are all the rage now and it's found at mucosal surfaces. They're probably there .... they have a class of defensins. Bascially IL22 induces defensins that knockout ... HIV infection deplets Th17. One of my favorite subsets is Tregs. They'll be more important when we talk about tolerance after the midterm. It's thought to instead of preventing your autoimmune, it can shut down your immune system so that you don't attack yourself. Back to cytokines, these guys are inflammatory, TNFalpha increases vascular permeability. The endothelial cells separate so cells and liquid can leak out of the blood vessel. This leads to swelling. You get an accumulateion of Ig and complement. This also induces expression of adhesion molecules. It recruits cells. It's very harmful during sepsis. It is tightly regulated. Because you increase vasopermeability, you lose bloodpressure and youg et shock and can die. Il8 causes inflammation and cell migration. It's also chemoattractant. Chemokines Cause cells to move to a particular site. Cells will migrate will move towards an increasing concentration gradient. .... Don't have to remember something from infecting cell.s. Interferon, thhey get turned on by dsRNA and activates endoribonulcease, tit also stops some cell function, and it kills the cell. IFNgamma, is made by activated T cells and NK cells and increase MHC I and II. Aside from singaling cells, cytokines can promote differentiation for example what happens in the bone marrow. This is controlled largely by cytokines. Erythropoietin to a HSC you'll get RBC. It's a factor that works far away from the kidney. Endocrine. MCSF induces formation of macrophage colonies. GM-CSM (Favorite!) It does both MCSF and GCSF. IL3 induces proliferation, differentiation of granulaoctyes and macrophages. There's a redundancy. If you look at cytokine receptors.. you don't have to remember this Appreciate e chemokien receptor. They acutlaly go across the membrane 7 times and form a snake like structure and G coupled proteins. There's very diffent cell structure proteins. Many receptors have more than one chain. There's one chain that binds the cytokine and another chain that transmit the signal.. It's unusual for them to both transmit. We have GMCSF, IL3, and I5. They each have a specific receptor, but they share the same beta component. These chains have singals that transmit sinals into the cell to promote gene expression. ify ou think abou it, if you signal through the beta chain you get the same effect becuse it's the same signal. here's another sereis, where there's 3 different molecules, they all share a common gp130. This one down here is very important , a group of IL2 receptor and share a common gamma subunit. Why is it important? There are natural mutations, if there is a mutation it iwll inhibit all the responses to all of these cytokines, IL2,4,7,9, 15,21. If you have amutation in common gamma chain, you get a disease called xlinked scid. You cannot make B cells, T cells, or NK cells. It's bubble boy diseease. With this mutation, you have no immune system. You can "cure" some patient by adding in through stem cell gene therapy. The disadvantage was that 11 children and 4 of them got leukemia due to the viral vector or because of the gene therapy. It was the first success and failure for gene therapy. There's a second type of SCID defect and that is a mutation in the chain of the IL7 receptor. They have B and NK cells but no T cells. TNFalpha - there's a TNFalpha . What causes the dsRNA to be seen? There's certain sequences that induce IFN better than others. We were talking about soluble cytokines. Let's switch to cell surface communicators. They can influence cell adhesion. The conformation of those molecules can change. There are molecuels outise the cell in the ECM which tran cytokines and conncentrate and maintain them therel. That can influence them. Chemokines, because of their charge, they stick to ECMs and make a gradient because otherwise they're very small. The idea is that these swirly guys are ECM, it can trap chemokines that that cell makes, it can be trapped by different cells that are getting them, or on the other side and help them migrate. It helps maintain gradient so it doesn't just dissolve away. Surface interactions can induce differentiation. We can see how it inducces T cell differentiation. if it sees MHC1 it'll make CD8 and when it meets MHCII, it becomes CD4. If a B cell that gets a strong binding to TCR, it will die. The surface interactions can do lots of things. We're going to talk about neuroendocrine interactions. somethi secreted in one site can travel to anoter site. Stress may correlate with susceptiblity to disease. it turns out, some of the signaling molecules that are made by the lymph nodes are neuroendocrine. ... Hypothalamus releases a molecule called corticotropin-releasing hormone which induces the pituitary to make another molecule ACTH. That molecule travles all the way to the adrenal gland located above the kidney. It causes the dadrenal gland to realase glucocorticoids to suppress the immune system and that feeds back to stop that process. These guys can influence lymphoctye migration.l The interaction of the nervous system... Back to the brain, it turns out, IL1 is an endogenous pyrogen. It can get in the brain from periphery or ... if you induce an electric shock to your brain, you can cause immune suppression. As an example how the immune system can function. This study where investigators took subjects where they put a little device to sample their blood every 10 min and took their blood. Then they told them to jump out of the airplane. These stress hormones will ... There are these some high stress ... they have different disease progressions compared to other people. green is a nerve fiber and red are lymphnodes. Youc an see how closely lymphocytes associate with the nerver. they change how lympoctyes progress. It causes incrased HIV ... high stress individuals die off easier. They don't .... That's neuropeptides. Circulation and extravasation. How do they move aorudn in the body and get out of the bloodl. G are ... and M are APCs. Anythign fluid outside the blood stream is considered lymph. It's controlled by specific receptors by both lymphocytes and on target tissues. when cells try to levave the blood vessel. if there's an infection, certain innate responses to that response alters the adhesion molecuels of the enndothelium celsl. It causes the cells to lightly stick to the endothelial cell. That signal between the adhesion molecule activateas that cause tighter binding molecules in 2. This causes tighter binding. it causes them to sit down on each other and squeeze through. Once they come out, that's where chemokines come in. There are different types of activation states for lymphocytes. They either leave the thymus or the bone marrow. it hasn't seen antigen, we've called that a virgin lymphoctes. They have different surface types. When the virgin lymphocytes will elave the bone marrow and leave the thyjumus. They are in the lymphatics and come in contact with post-capillary venule. Then at the end of the cappilary is the vein system. It's jsut at the end of the capillary stystem. They ahve special adhesion molecules at the surface. It allows virgin cells to squeze out of the blood into the lymph node. once they're in the lymphnode, they're in lymph and they'll stay there until they see an antigen. Activated T cells they can find the site of infection or not. If they find it, endothelial cells of capillary by the infection will be altered. it will allow T cells to squeeze through. But it's diffferent from earlier. Once the antigen is cleared, some will die some willb ecome memory cells. The lymph brings them down to the lymph node and keep there. If the cells odn' tfind the infection, they can become deactivated and are converted to memory cell. There are certain adhesion molecules on post-capillary venules in the skin that are recognized by deactivated t cells. They bind to them, come out of the circulation and go to a lymph and go to the skin and stay out in the periphery. Summary: Naiive ce cells awit for a signal. Once they're activated, if they find... It'as all controlled by adhesion molecuesl on Ec as well as ligands. pro-adhesion molecuels are induced on EC. They trap them at the site. This induces true adhesion molecules. In additional signals ni the form of chemokines, to move it towards the site of inflammation. Some of the bacteria can also bring complement activation. Here's an exajmple of thow this works. It will activate to change conformation of the top moleeculeso it can stick down and extravasate out. Here's just someof the adhession molecules. They bind to different molecules on the surface. As the sighanals progress, they get better adhesion...
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This note was uploaded on 12/31/2009 for the course MIMG 185 taught by Professor Zack during the Fall '06 term at UCLA.
- Fall '06