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Lecture 11

IMM250 Lecture 11 Notes

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Michael Ratcliffe

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IMM250 Lecture 11 – Autoimmunity Autoimmune diseases  1/20 people in Western countries suffer, which is higher than developing country  Non-specific (global immunosuppression  susceptible to opportunistic infections)  Inconsistent efficacy (unpredictable response)  Multiple Sclerosis become wheelchair bound  Glomerulonephritis requires continual dialysis  Type I Diabetes requires daily injections of insulin  Rheumatoid arthritis requires daily therapies to keep the inflammation in joints under control Status of treatment for autoimmune diseases  Not very good therapies  High burden to health care system and economy  Steroids are not good enough Immunobiology  Organ-specific autoimmune diseases attacks particular tissues o Type 1 diabetes mellitus = pancreas o Multiple sclerosis = CNS  Systemic autoimmune diseases attacks common tissue and multiple organs (diseases have stronger role for antibodies  circulate more effectively  target more tissues) o Rheumatoid arthritis = joints + heart o Systemic lupus erythematosus = kidney + heart + CNS Pathogenesis of autoimmune disease  B cells can cause autoimmune diseases as well Layers of self-tolerance: Central tolerance  Four mechanisms of maintaining T cell tolerance T cell precursors migrate from the bone marrow to the thymus  T cells precursors in the bone marrow migrate to the thymus to finish development.  B cells develop and finish development in the bone marrow.  At puberty, the thymus involutes and becomes smaller. A lot of the thymic education takes place in the first decade of life. It continues to take place in adults but not as efficiently. Cellular organization of the thymus  What does the thymus look like? Like the LN, the thymus is also an organ that has compartmentalization to facilitate T cell education. In the LN, compartmentalization facilitates T cell activation. The cells enter the thymus through the sinus. Under the sinus is the cortex. Under the cortex is the medulla. There are discrete steps that take place in T cell education (T cell maturation) that take place in discrete locations. As immature thymocytes mature, they go through the thymus into the medulla and then they leave.  Bone marrow  thymus  periphery  circulation through body  Mature T cells never goes back to the thymus Epithelial cells of the thymus form a 3-D network surrounding developing thymocytes  The thymus is a highly organized structure. Epithelial cells are not cells of the immune system. Epithelial cells form a scaffold for the thymus. Epithelial cells play an active role in the education process of thymocytes. T cell development in the cortex  In the blood, you never find a double-positive T cell. The thymus is the only place where double- positive happens. CD8+CD4+ undergo positive selection. T cell development in the medulla  Thymocyte is an immature T cell that has left the bone marrow. When it enters the thymus, it does not express CD4 or CD8. when it enters the cortex, it expresses both CD4 and CD8 and undergoes positive selection (cortex) then negative selection (cortex medulla boundary). If they pass both tests, the thymocyte is considered a T cell that can patrol the host. It is considered a safe T cell that is not self reactive. Positive Selection (cortex)  CD4 and CD8 both bind to MHC. The epithelial cells in the thymic cortex express MHC I and MHC II. The immature thymocyte will see MHC with peptide. In the thymus during positive selection in the cortex, a thymocyte sees self peptide. The self peptide has very low affinity for the TCR. You do not want to be selecting thymocytes strongly reactive for self peptides. They need to be a little reactive so we know those T cell receptors are good at seeing MHC peptide. If they cannot see it, then they are of no use to the body. When they see foreign antigen in the context of MHC, the T cell should be able to see it. This is an opportunity to test that the T cell will work. Self peptide and MHC allows TCR to be slightly activated. If they get positively selected, it will move to the cortex-medulla boundary to test for autoreactivity.  If there is no peptide interaction, the immature thymocyte does not get a signal. The immature double-positive thymocyte in the absence of signal will not be positively selected and die by apoptosis. This is a thymocyte that fails to see self-peptide in the context of MHC. The bone marrow is making millions of T cells a day. You do not want to pick T cells that cannot recognize antigen.  During the process of positive selection developing T cells (thymocytes) interact with thymic epithelial cells which express MHC class I and II molecules in association with self-peptides. Thymocytes interacting with no sufficient but not too high affinity with MHC plus peptide receive survival signals (therefore the use of the word "positive"), proceed in their maturation steps and then leave the thymus as mature naive T cells to circulate in the (body) periphery. These are the T cells that will be able to mount an immune response because they have passed the "positive selection" checkpoint, in other words they have been tested for their ability to recognize MHC molecules. The cells that are not able to "see" MHC molecules are eliminated because they do not receive survival signals. Negative Selection (medulla)  Negative selection happens after the thymocyte has been positively selected. This happens at the boundary of the medulla and cortex. A double positive thymocyte has been positively selected. Epithelial cells will present self peptide in the context of MHC. If the TCR is good at seeing the MHC self peptide, then it is going to die by apoptosis. You do not want T cells leaving the thymus that have strong reactivity to self antigens. This is a chance to test whether your thymocytes are self reactive. If they are, they get killed off.  If the double positive thymocyte does not have a strong reaction with the self peptide in the medulla region, the thymocyte will become a single positive T cell. It will leave the thymus and patrol the body.  Negative selection gets rid of thymocytes interacting too strongly with MHC molecules and/or self-peptides. This process is called "negative" because the cells are "deliberately" killed. If these cells were left free to go to the periphery, they would attack self organs and create autoimmunity. T cell selection  Death by neglect because the thymocytes do not get the same survival factors that other thymocytes would.  If the TCR has intermediate affinity for the antigen, positively selected and fails to be negatively selected, then it can leave the thymus and enter the periphery. What is programmed cell death?  The visualization of apoptosis. Apoptosis is important because the way the cells die does not cause inflammation. Apoptosis happens in the thymus at high levels. You see the same amount of apoptosis in the GC. Life and death is an important part of thymocyte selection and the immune response.  Apoptosis occurs through a complicated pathway. FAS triggers this pathway and sends a signal to the cell to die by apoptosis. This method of inducing apoptosis is important in the thymus. If you mess with this, you end up with an individual that has profound autoimmunity. You want to preserve death pathway to kill off thymocytes you do not want. Problem #1: All T cells are to a certain extent “Autoreactive”  To leave the thymus as a mature T cell, you have to be a little autoreactive. To leave the thymus, you have to undergo successful positive selection in the cortex of the thymus. The T cell leaves the thymus with the capacity to see self peptide to an extent. All the T cells in the body have reacted to self peptide at some point. Every foreign antigen specific T cell binds at least to one cross reactive self peptide that they saw when they were positively selected in the thymus. Solution #1: Affinity for selecting self peptide is insufficient to trigger full activation of a mature T cell (ie, Signal 1 is too weak)  A TCR that recognizes MHC in the context of self peptide can get a weak signal 1. It is probably not going to get signal 2 because you need inflammation. If a DC has a self peptide drains into the LN and presents it to an autoreactive T cell, if there is no inflammation, this is the end of the story. The slightly self reactive T cell is not going to do anything. They get a weak or abortive signal 1. This is the obvious way to prevent massive autoimmunity. Problem #2: How do T cells get negatively selected to not react to ALL peripheral peptides?  How is it that all the self peptides in the body can be seen in the thymus, if you want to teach thymocytes to not respond to peptides that come from all over the body?  In humans, within the thymus medullary region, the epithelial cells have the capacity to de- repress gene expression. Normally if you are a cardiac cell, you express cardiac genes. If you are a big toe cell, you express big toe genes. The thymus medullary epithelial cells have the capacity to express a whole bunch of different genes that a normal cell would not express. Your cells express only the genes that dictate their function and not other genes. How can this be changed?  Transcription factors bind to the gene that you want to be expressed. The medullary epithelial cells express a broad range of genes through an enzyme called AIRE. Expression of AIRE in a medullary epithelial cell in the thymus  The red is staining for AIRE. APECED  AIRE was mapped to a chromosome region in humans. People who had recessive mutations in this gene got a disease called APECED. APECED is a rare disease. If you have mutations in both copies of the AIRE gene, you get APECED. This is a very serious, debilitating disease. AIRE  People get APECED because they lack the machinery to express all of these different peptides in the thymus to achieve negative selection. They end up with a deflective negative selection protocol.  In A, a developing thymocyte has entered the thymus. It has undergone positive selection. It is time for negative selection. It will interact with thymic medullary cells that express AIRE. AIRE induces the expression of all of these different self peptides. The self peptides get loaded on MHC and presented to the developing thymocyte. If the developing thymocyte has strong affinity for self peptides, they will be negatively selected. If the developing thymocyte has no affinity for self peptides, they will escape negative selection.  In B, they have a thymus medullary epithelial cell where AIRE does function properly. All these proteins are not expressed. All self-reactive thymocytes escape negative selection and leave the thymus. They will attack the host. This is why they get autoimmunity. Individual organs of the body express tissue-specific antigens  This individual has proteins expressed all over the body. Even though they are far from the thymus, they are expressed in medullary epithelial cells and presented to thymocytes so those thymocytes can be deleted.  The transcription factor AIRE in the thymus allows the transcription of proteins that function elsewhere. This expression of "peripheral" proteins in the thymus is necessary to allow their interaction with developing thymocytes. Thymocytes that interact too strongly with these proteins are eliminated, because if allowed to go to the periphery they would cause autoimmunity. An engineered mouse model  These mice do not get diabetes because the virus specific T cells are naïve and will not go to the pancreas. They go from LN to blood and they will not see the antigen. If it does not see the antigen, then it will not get activated. Infection with virus induces autoimmunity  When you infect the mice with virus, you get active draining of antigen from the pancreas. Because there is inflammation, DC upregulate B7. The virus specific T cell sees antigen and gets CD28 signal to activated the T cell. The inflammation caused by the virus leads to diabetes.  In the normal state, the mice have no diabetes.  In the inflammation state, the mice have diabetes.  Obviously we do not have virus specific proteins in the pancreas. This is an engineered model. This indicates that one of the environmental triggers to autoimmune disease could be getting a virus and you happen to have one of the autoreactive T cells floating around in the wrong place and wrong time. This is one theory for a potential trigger of autoimmune disease. This explains why most autoreactive T cells do not respond because they are segregated away from the antigen. Layers of self-tolerance: Peripheral anergy  Another mechanism for preventing autoreactive T cells is anergy. In the thymus, if you encounter a self antigen and you have a high affinity for the self antigen, then the thymus is negatively selected. Another outcome can be anergy which happens in the periphery. A T cell that sees self antigen does not die and does not cause any harm. T cell activation (Signal 1 + 2 + 3)  In the normal situation where you have an immune response to a pathogen, DC are activated through inflammation through PAMPs. The DC will upregulate B7 and present peptides on MHC. The foreign peptide in the context of MHC and inflammation will be good at delivering signal 1 and signal 2 through the expression of B7. You need signal 1 and signal 2 and cytokines to activate T cells. What are the different effector mechanisms of activated T cells?  T cell activation happens during infection. T cell tolerance (Signal 1)  This happens most of the time.  T cell tolerance is when there is a self-peptide presented by MHC but there is no PAMPs. In absence of PAMPs, you do not get signal 2 and you do not get cytokines. You get some T cell activation but the T cell is crappy and is not going to exert effector functions. It is either going to die or become anergic (T cell unresponsiveness). There are a lot of thymocytes that escape negative selection because you cannot display all self-peptides in the thymus. This is a second check to get rid of self-reactive T cells in the periphery. DC sample antigen all the time and drag it back into LN. In the absence of inflammation, it does not have an outcome other than to induce anergy or deletion.  This happens on mature T cells that have been educated in the thymus but not good for us.  DC are not smart. They will pick up antigen no matter what. They do this in the presence and absence of inflammation. They take in all these antigens all the time and go to the draining LN. Most of the time, you get DC that pick up self antigen in a non-inflammed tissue, drag to draining LN, if there is a self-reactive T cell that sees antigen, it will get signal 1 but not signal 2. The T cell will become tolerant (die or anergic).  If there is inflammation, the DC is ready to prime T cells. Hopefully, the antigen is foreign antigen. This is likely because inflammation was c
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