Chapter 14 Transcription: Autoimmunity and Transplantation
There are different kinds of autoimmunity, depending on the target organ and the type of immune response which is directed at that target organ. There are some forms of autoimmunity that involve T-cells destroying cells in an organ or tissue, they are doing the same thing they do when they see a virally infected cell, or a tumor cell, or a cell from a transplant, because that is what CTLs do, and both CD4 TH1 and CD8 make lots of cytokines which recruit cells to the area and cause an acute inflammatory response. With type I diabetes, it is T-cells that see an antigen called GAD, and this is an internal protein from the islets of langerhans, the cells that make insulin, that gets processed and presented, because all class I MHC, unless there is viral peptide present, bind house keeping proteins, because you can’t get class I MHC on the surface of cells if they don’t have a peptide, because they don’t get through the ER without a peptide. These autoreactive T-cells see GAD on the pancreatic cells, and they kill those insulin producing cells. Therefore an individual with type I diabetes don’t have insulin because they have no cells producing insulin. There is a theory that these T-cells are elicited by cross reactivity with an infection caused by coxsackie virus type B, there is epidemiologic association, and these individuals have the same MHC I that presented the coxsackie proteins and elicited an immune response.
In MS, there are CD4 cells that recognize a variety of brain antigens, and rarely is it one antigen, but because of a process called epitope spreading, if you start to respond to one antigen and kill the tissue you liberate other antigens which may not otherwise be available to the immune responses. In the inflammatory environment, immune responses can develop against more self-antigens by clones that were not deleted in the thymus. In general the thymus is very good about eliminating self antigens and that is why few people have autoimmune responses. Fortunately, autoimmune diseases are rare.
In other autoimmune diseases, there are autoantibodies against a cell surface molecule. You don’t get an autoantibody without having a T-cell, but the T-cell does not cause the disease associated with for instance, Graves disease, it is an autoantibody against a cell surface receptor. Autoantibodies against a cell surface receptor can either be an agonist or an antagonist, and in the case of Graves disease the receptor thinks its seeing its specific ligand and so it activates the cell and the cell overproduces thyroid hormones. The opposite of that is an antibody that blocks the receptor from its ligand. In myasthenia gravis the antibody blocks the acetylcholine receptor at the neuromuscular junction, so acetylcholine which is normally released by neurons to tell a muscle to move can’t bind and ultimately you get muscle atrophy because the muscles can’t respond to signals.
Thyroiditis is the opposite of Grave’s disease, it is the result of an antibody that blocks binding of a molecule to its receptor. Type I diabetes is very different from type II diabetes which is obesity associated, but type II diabetes is not an autoimmune disease, but a metabolic disease. MS is an attack on the oligodendricytes which provide the insulation for neurons, it is not an attack on neurons per se, but the neurons need to have that insulation around them to enable the efficient depolariziation and signaling of neurons. Systemic lupus erythmatosus is a systemic disease associated with autoimmune antibodies against a lot of intracellular, nuclear proteins. How does an antibody against DNA or a histone result in this disease? Normally, cells are processing and presenting proteins, so some cells present histone on the cell surface. But when you get attacks on a lot of cells, they break down and the nuclear materials are liberated and the antibody can bind. The antibody-immune complexes then cause the disease which is glomerularnephritis, or kidney damage by the immune complexes and complement being deposited on the glomeruli. If your immune complex is inside blood vessels you get inflammation inside blood vessels or vasculitis. Some of vasculitis can result in a rash if it occurs in a capillary that is on the surface of the body.
Remember that most self-reactive T-cells will be eliminated in the thymus, and if you don’t have the second or third signal when a T-cell or B-cell gets activated then you don’t go on to produce a response. The most critical aspect of avoiding autoimmune responses is the deletion of autoreactive cells in the thymus and bone marrow. In the thymus, as you will see, there is a transcription factor called AIRE which is essential for inducing the expression in the thymus of these peripheral gene products so that they can be used to delete the self-reactive T-cells during thymic education. Also it is important that some antigens are kept away from the effector T-cells.
The T-reg cells which express Fox P3 make TGFβ and IL-10 and even if you don’t have a T-reg, if you have an anti-inflammatory TH2 cell then it will make IL-10 which suppresses antigen processing and presentation at the level of the APC. Also, once you expand an immune response, it gets compressed so that you have the resources to respond to something else.
How do some people get autoimmune diseases? There is a genetic component to this and we talked about the genetic component to allergy, so that for instance, with diabetes, if you have HLA 3 or 4 then that is a genetic predisposition. However, if the right environmental factors aren’t there, that individual won’t get type I diabetes. With ankylosing spondylitis, which is a form of arthritis, having HLA B27 is absolutely critical, however there are lots of people that have HLA-V27that don’t develop the disease. So a combination of genetic factors and environmental affects alter the ability of the immune system and can lead to the development of an autoimmune disease.
There are a number of sites in the body that are privileged, like the brain, the eye or the testes, and in hampsters there is a pouch in the hamster which is also an immune privileged site. Generally, the eye, brain, and testes are not involved in immune responses. However when there is damage to the eye there can be inflammation evoked by that damage and unfortunately, once that cascade has started, both eyes can be targets for further immune attack.
In the thymus there is a transcription factor called AIRE which induces the expression of antigens from everywhere in the thymic cells which present antigen during thymic antigen. If there were to be a T-cell, which might normally attack the retina for instance, because it sees that antigen in the thymus, it undergoes apoptosis during the negative selection phase, and most of us will not respond to ovarian, eye, or muscle antigens because of AIRE. The non-self reactive T-cells leave the thymus and are able to respond pathogens. However, when you don’t have AIRE self-reactive T-cells are not deleted because they are not educated on tissue specific antigens. Individuals lacking AIRE have a higher frequency of developing autoimmune diseases.
We talked a lot about TLRs being important for the response to pathogens. TLR-2 sees gram positive bacteria, TLR-4 sees gram negative bacteria, TLR-3 sees dsRNA, TLR-7 sees ssRNA, TLR-9 sees DNA. Usually however, TLR-9 sees DNA from bacteria or virus, not self DNA. In systemic lupus erythmatosus, APCs get activated by self-DNA and this DNA normally is not naked, it is covered with histones and transcription factors and regulatory factors, and enzyme complexes involved in making RNA and DNA: these proteins get brought in to this APC, and on pg. 3 slide 1, it happens to be a B-cell that hadn’t been deleted in the bone marrow and could see DNA, but the same reaction could be caused by a B-cell that saw histones or one of the other proteins associated with DNA, and the reaction could also be caused by a macrophage that phagocytized apoptotic cytoplasm and in the endosome is where TLR-3, 7 and 9 are found and they see nucleic acids. The rest of the TLRs are on the cell surface. When TLRs bind their specific ligands there is a signal transduction cascade, MyD88 gets activated and ultimately NFκB gets activated, and a series of proteins are produced that facilitate the immune response. One of the proteins induced is IFNβ.
Those B-cells and their somatic hypermutation can also, by mistake, make an antibody that will bind a self-protein better than foreign antigen which elicited the initial response. The somatic hypermutation is a random event once the B-cell gets turned on, and some of those daughter B-cells will make an antibody that is much better at binding the pathogen than the antibody that previously existed, other daughter cells will make antibody that doesn’t bind the flu at all, but if by mistake that antibody that doesn’t bind the flu happens to bind self, then you get an auto antibody. That auto-antibody may or may not get further propogated, and there are a number of transient autoimmune diseases where you have a 6 month period in which you have antibody that in some way compromises normal physiology and there are a number of neurologic diseases that are transient, and these conditions can be treated by plasmaphoresis, because if it is an antibody mediated disease, and you remove antibody from the blood, then that individuals symptoms will wane and ultimately those clones of expanded B-cells will be gone, and as long as they aren’t restimulated that individual can recover. They don’t respond to the self-antigen further because there is no T-cell to turn them on, and you need the T-cell to elicit an antibody response.
The developing fetus is normally an immunologically privileged site. The fetus and the mother’s circulation generally only share metabolites, however if maternal cells cross the placenta and enter fetal circulation, the maternal cells can modify and recognize fetal antigens and you could have a form of graft vs. host disease, which may or may not be transient. If maternal T-cells recognize that there are differences on the B-cells you can have suppression of the ability of the fetus to make its own antibody for about two years of infancy. This never happens in the first child, it happens in subsequent children. The first child primes the mother to differences in paternal antigens and the mother has expanded cells, which if the same paternal antigens are expressed on a following child, can trigger a secondary response. However, fetal cells can also cross the placenta, and it has been found that mothers carrying sons, have cells with y chromosomes circulating. Some of these cells can be found in sites of inflammation. Scleroderma is an autoimmune disease which is really a graft vs. host response. The fetal male cells, and it is only easy to tell when it is a male cell that has crossed the placenta. But largely it is just proteins that cross the placenta, including IgG3, and there is a special IgG3 receptor on the placenta that binds it and allows it to be transported to the fetus; these antibodies protect the fetus from whatever the mother has been exposed to. Until the infant is able to develop its own immune responses it has a transient supply of maternal antibody. A few weeks ago during the discussion on mucosal immunity we discussed colostrum and in colostrum is IgA, which is secreted in breast milk and during the first 3 days of life, IgA is secreted in large amounts and can protect the fetus from pathogens in the GI tract. If the mother responded to another one of the father’s antigens, and that happened to be on a red blood cell, and as you know there are ABO differences and many other red blood cell molecular differences, so that second or third, or later pregnancy, could, if there is a difference in red cell antigens to which an immune response had been developed during the first pregnancy, there might be antibodies that recognize the foreign cell surface molecules and in those cases you can get a type II hypersensitivity, an antibody against a cell surface molecule, and the fetus could have anemia, which is one reason its so important for obstetricians to test the ABO phenotype of the mothers and fathers to know whether this a difference, and if there is, Rhogam is administered to prevent the induction of antibodies against these ABO molecules which can cause a lethal anemia in the fetus. The fetus is protected, but not 100%. Some viruses, like rubella can cross the placenta and cause chicken pox in a developing fetus which can lead to mental retardation or deafness, which is why women who are contemplating pregnancy has to have had bonafide infection with rubella or immunization with MMRs to prevent the woman from getting rubella infection during the course of pregnancy and having the virus transmitted.
We talked about damage to the eye which results in inflammation, which results in an attack on the contralateral eye as well as the damaged eye. (pg. 5 slide 1)
Most of the time you get elimination of the self-reactive cells in the thymus. When that does not occur and you get those cells in the periphery you can develop autoimmune diseases. But T reg cells can suppress cell responses in the periphery and prevent autoimmune reactions.
Inflammatory bowel disease, sometimes referred to as Crohn’s, is a response in which there are T-cells in the lamina propria that see bacterial antigen because there is a mutation in NOD2 remember that NOD 2 is an intracellular recognition molecule that starts a cascade when it sees bacterial gene products. If you have Fox P3 expressing CD4 positive CD25 positive T regs, they can inhibit the response and ultimately lead to the clearance of the inflammation and restore bowel integrity and function. It is hope that for many other diseases like MS, people really try to provoke the Fox P3 regulatory cells to inhibit the activity of these autoimmune T-cells.
There are organ specific diseases and systemic diseases. Scleroderma is an attack generally on the skin, but when you have systemic scleroderma you can get an attack on the lungs.
There are those autoimmune diseases which we can show experimentally are due to the transfer of antibody or the transfer of T-lymphocytes. Typically, this can be demonstrated in a mouse, or you can take antibody from a person and inject it into a mouse. With mice we have studied extensively a model of MS, and this model is experimental allergic encephalomyelitis. There are many attributes to this model but there are lots of short comings. In many ways we can test hypotheses and develop new treatments, but all of the treatments that work in mice do not necessarily work in humans. But the mouse model has allowed us to develop ways of treating MS using the mouse model, and one of them is TSABRI, which is a monoclonal antibody that sees the integrin recognized by VLA-4 on T-cells, so the integrin present on endothelial cells can be blocked by this monoclonal antibody so T-cells can’t bind it and get into the tissue. TASBRI also works in Crohn’s disease, and it would probably work in type I diabetes, but generally we don’t see Type I diabetes until it is too late. MS is in general a chronic progressive autoimmune disease and there are waves of inflammation in the brain which subside in many individuals and periodically there are new waves of inflammation. In many people in MS there is a constant loss of function over time, but it is episodic. Sometimes if there is an attack on part of the visual pathway, people can recover the vision that is temporarily lost during inflammation but it can be attacked in the future. On pg. 7 slide 2 you can see a mouse with EAE, and it is much leaner than the WT mouse, it can’t stand up, it has hind limb paralysis, its tail is floppy and it is leaner because it can’t eat and drink as well as the WT mouse, and with the hind limb paralysis there will be muscle atrophy. From the mouse we have learned a lot and we have generated many designer mice, some of which are engineered to have T cell receptors specific for an antigen present in myelin, which is a product of the oligodendricite and you can evoke that response by injecting monoclonal T-cells into a mouse. You can immunize a mouse with ground up spinal chord and complete freunds adjuvant which will enhance immune responses to the ground up spinal cord. The mouse is immunized and it develops disease, you take the T-cells out, re-stimulate them in vitro and you inject them into another mouse, that has the same MHC and then this second mouse gets the disease. We can see in this case, that if we were to immunize this mouse with one myelin antigen, say myelin basic protein, there is a program in this mouse, where it would respond first to myelin basic protein, and then it would respond to a peptide from oligodendricyte associated glycoprotein, and then it would respond to something different. This is called epitope spreading, where the initial immune response is to one selected peptide and then two months later you see that T-cells are responding to a completely different peptide which is derived from the breakdown of the myelin in the paralyzed mouse.
Myasthenia gravis has antibody against acetylcholine receptor. Graves disease has an agonist antibody against the receptor thyroid stimulating hormone, and that thyroid cell makes thyroid hormones. If you have anti-platelet antibodies, you will be unable to clot, and you can hemorrhage. Ro is a red cell antibody and in neonatal lupus or congential heart block you can have antibody against Ro. If you have antibody against tight junctions in the skin then the cells in the skin don’t bind together well and you get a blistering rash. If you have an antibody against collagen then antibody is deposited in joints, and there are antibodies that bind to the insulin receptors on cells, and that is a different form of type II diabetes, and unlike type I, insulin is still made.
A fetus can be susceptible to an autoimmune disease that the mother has or autoantibodies that the mom has made against paternal antigens. If the mom has graves disease because the mother has antibodies against her own thyroid stimulating hormone receptor, these can cross the placenta and in an agonist manner turn on the thyroid. This would be an enormous baby to deliver, and if you recognize that the Mom has this disease, you can intervene by giving transfusions to the fetus or plasmaphoresing the Mom during pregnancy to prevent fetal disease. In some of these conditions you can intervene, in others you can’t.
To make pathogenic antibodies you must have a T-cell that recognizes something and is activated. In type I diabetes the T-cells are killing the islets of langerhans. In myasthenia gravis, a T-cell is telling B-cells to make antibody to the acetylcholine receptor and it is the antibody that is pathogenic. Though there may be antibody involved in type I diabetes, no one knows what it does. In MS there is also antibody, and because of the chronic inflammation in the brain a tertiary lymph node is established in the brain, and one of the diagnostic tests for MS, is the presence of antibody and inflammatory cells in the CSF. Some B-cells in this tertiary lymph node will make antibodies against proteins in the brain and others will be B-cells that get activated non-specifically to systemic antigens; it is unclear in humans whether the antibodies are pathogenic or not, in EAE mouse models you can find pathogenic antibodies to brain antigens. The antibodies that are made in the brain during MS cannot be removed by plasmaphoresis because they are not in the blood. In other cases when you have antibody around, it is possible to transfer in IgG. An Ig IV can be a transient therapy for some disorders. It is hoped that you can swamp the pathogenic antibodies with lots of normal antibody and dilute pathogenic antibodies. It may or may not work in many cases, plasmaphoresis is usually the best option.
This (pg. 10 slide 1) could be many different diseases, because many diseases cause tissue breakdown. Some fragments of the tissue will react with the rare B-cell that didn’t have that receptor deleted, or because of the generation in secondary and tertiary antibody responses, of new antibodies from somatic hypermutation, that bind self antigen. That self antigen is taken up by the B-cell and presented and some other protein in the B-cell could be simultaneously presented to a T-cell which may not normally have had that antigen presented to it on the class II MHC of the B-cell, and that B-cell gets turned on by the T-cells and becomes a plasma cell making antibody and that antibody then causes further damage. If instead of a self-antigen being presented, the B-cell bound a self antigen but presented a viral antigen on its MHC, that APC would ultimately be killed and you would remove all the virus, so you would not continue to amplify that response you would get contraction, and deletion by apoptosis of the effector cells, so only the memory cells are left. If it is a self-antigen, there is a large amount of potential antigenic stimuli.
Pg. 10 slide 2 is basically how lupus starts. There is a DNA complex with the histones and transcription factors bound, and there might be a B-cell that can see one of those components. This can lead to the development of anti-histone1 antibodies.
Pg. 11 slide 1, we’ve talked about most these already, hemolytic anemias can occur as a response against Rh antigen. We talked about platelet responses that can result in abnormal bleeding. If your immune system recognizes the basement membrane then among other things, glomerular nephritis and good pasture’s syndrome can occur. We talked about tight junctions on the skin cells and blistering. One example of molecular mimicry can be seen when people develop a response to strep infections which can lead to an attack on the cardiac muscle because of the cross reactivity between some antigen in strep, and some antigen on cardiac muscle. This leads to myocarditis which is an acute rheumatic fever that follows strep infection.
Type I hypersensitivy is IgE antibody mediated and type II hypersensitivities are antibodies against cell surface molecules, type III involve immune complexes and the first that was recognized was serum sickness, type IV are all the T-cell responses. So type I diabetes is a type IV hypersensitivity.
This (pg. 12 slide 2) shows how you can eliminate red blood cells by having an antibody against the red cell surface; the red cells can be phagocytized or they can be lysed. Either way, you are depleted of red blood cells.
Normally the pituitary in the brain makes TSH, and normal individuals make thyroid hormone, and some of it returns to the brain and results in negative feed back. If you have an agonist antibody against the TSH receptor, it doesn’t matter how much TSH the pituitary is making, the thyroid is going to make lots of thyroid hormone, and this can shut off the pituitary. Tissues will have a higher metabolism due to the Thyroid hormone.
In good pasture’s syndrome you have an immune complex. On this picture these immune complexes are visualized by a secondary antibody that has been conjugated to flurocine, which is why you see the ftz green in the micrograph. So you use a UV light and shine it on the immune complex and it will fluoresce green, and if you stain with HNE you see the tissue damage and the break down of the glomeruli. In lupus instead of the immune complex you have immune complexes in many other places, they can be in kidneys, blood vessels, tissues, and that is what makes lupus systemic.
In a normal pancreas there are islets of langerhans that are stained with an antibody that recognizes insulin, and in people that have type I diabetes those islets of langerhans are destroyed and you can see only a few cells that are still capable of producing insulin. (pg. 15 slide 1). Now what would happen if you transplanted in the pancreas from a cadaver, and the pancreas was autologous? The islets of langerhans would again be destroyed by the self-reactive T-cells. If you want to transplant in the islets of langerhans they have to be in some sort of capsule where they are not available to T-cell attack, but can get all the perfusion of metabolytes they need and can secrete insulin. That is the only way you can deal with a transplant, unless you are able to delete the clones of T-cells that react against the islets of langerhans.
In MS you have T-cells that cross the blood brain barrier and attack the neurons. There are also innate immune factors that can also attack the myelin from the oligodendrocytes which prevents the neurons from functioning. Sometimes in these neurons, when there are high levels of inflammation and there is no myelin sheath, they can be truncated.
If instead of an attack on the pancreas or an attack on the oligdendrocyte, or an attack on the red blood cell, there is recognition of a collagen associated protein, which is present in cartilage and joints, then you get a local inflammatory response in that joint and you have the inflammatory cells which make inflammatory mediators which interact with nucleated cells in the joint and they further respond with their own set of inflammatory mediators, and this can affect the balance of the deposition and removal of bone which we normally have. Bone is in constant flux, it is always being remodeled. There are osteoclasts which destroy bone and osteoblasts which make bone. As long as these cells are in a good interaction and neither is dominant bones won’t grow or be destroyed. If you don’t have osteoclasts and an excess of osteoblasts you have very strong bones, in fact it can be a problem. In osteoporosis, which is not an attack on a joint, but rather all the bones of the body, if the osteoclasts are excessively active you get sponge-like bones, which is why people need to take enough calcium and be cognizant of their bone density. Especially after menopause for women, estrogen decreases, which positively regulates the osteoblasts, osteoporosis can occur. This can occur in joints, and the osteoclasts get activated and joints get remodeled, there is destruction of cartilage, and you end up with bone on bone, and there is also an antibody component to the disease.
This (pg. 16 slide 2) is a mouse model for type I diabetes, and in this model there is a mutation in one of the class II molecules for that mouse. This mutated class II molecule presents GAD very well. As you can see, 80% of females and 40% of males of this mouse strain, by the time they are half a year old, have type I diabetes. Understanding that, people have looked for associations between MHC in humans and type I diabetes.
There are a number of inbred mutations which are strongly associated with a variety of autoimmune diseases. Earlier we discussed AIRE and the ability of the thymus to delete in negative selection, autoreactive cells, and if you don’t have AIRE many autoimmune diseases can develop. CTLA4 is the negative molecule that offsets the B7 CD28 interaction and if you have a CTLA4 deficiency, you can get autoimmune diseases. Fas-Fas ligand interactions are important for apoptosis, and in humans if you don’t have Fas or Fas ligand, you have systemic lupus and lymphoproliferative diseases. There are two mouse models which were spontaneous mutants that demonstrate how important Fas is. C1q deficiency leads to antibody that doesn’t work properly. C1q is the first component in the classic pathway. We have made designer mice in which we can overexpress these traits associated with autoimmunity, and this can help to piece together what is happening in autoimmunity.
Overexpression of TNF gives you many inflammatory diseases, and this is another reason why there are many diseases in which TNF is targeted by treatments. In rheumatoid arthritis, remicaid is used, as are a number of other drugs that block TNF action. There are two monoclonal antibodies and a soluble receptor for TNF which are licensed for both rheumatoid arthritis and Crohn’s disease. IL-3 is normally important in inflammation and it alerts the bone marrow to make more cells because there is a reaction occurring. If you make too much IL-3, and you make it in the wrong place, you can have a demyelinating syndrome. STAT 4 is the signal transduction molecule for IL-12 signaling in TH1 cells, so if STAT 4 is overly activated those TH1 cells can be overly activated. If you don’t make IL-1 receptor antagonist then you can’t compensate for a lot of IL-1 which is an inflammatory cytokine, and you get arthritis, and this is why one of the new therapies will be to infuse IL-1 receptor antagonist into individuals with arthritis. TGFβ compensates for TNF α a lot of the time and TGF β is also one of the cytokines made by T regs, so not having enough results in many inflammatory diseases. If you can’t process and present antigen properly or if you can’t delete properly in the thymus then you get autoimmune diseases, if you can’t signal properly you get autoimmune diseases. If you have a knockout for programmed death 1, PD-1 which is a TNF family molecule and it is important for the induction of apoptosis, you have a proliferative disease, similar to a CTLA4 deficiency. BCL-2 is important in protecting the mitochondrion from Bcl-x and other molecules which, in excess will attack mitochondria and cause it to break down so Ox-Fox isn’t happening and cytochrome C gets liberated which activates the apoptosome which results in cellular apoptosis. So if you have an overexpression of Bcl-2, your mitochondria will be protected and that aspect of apoptosis will not occur, so you get excess proliferation and no deletion.
Earlier we mentioned the incredibly high association of the expression of HLA B27 with ankylosing spondylitis. This is a disease that affects more men than women, however there are other diseases in which women are more prone then men. These are diseases in which CD4 cells are more important than CD8 cells in the disease pathway. There is an estrogen response element in the promoter for IFNγ and this is thought to be a major player in the sex skewing of these autoimmune diseases where CD4 TH1 cells are involved. In other diseases, like good pastures, there is no sex skewing. Some diseases are associated with HLA DR2, some are associated with Class I molecules and we mentioned HLA DR3/4 heterozygotes in type I diabetes. (Pg. 20 slide 1) Pg. 20 slide 2 shows the frequency of HLA DR3/4 heterozygotes being 40% of type I diabetics, vs. 2% of the normal population.
This slide (pg. 21 slide 2) should have been shown when we were discussing the NOD mice. Remember there is the floor and the walls of the Class I and Class II molecules and peptides bind in the cleft, and anchor residues on the peptides interact with different residues. If there is a point mutation in one of the sites that binds anchor residues, it will determine and change what peptides are able to bind. In the NOD mouse, and in people with type I diabetes, there is a specific change which enables them to bind GAD more efficiently. In normal individuals there is hydrogen bonding between two residues and in the mutant that is not present, that molecule can bind to the peptide.
We talked about molecular mimicry with respect to type I diabetes and coxsackie and strep and rheumatoid pneumatic heart disease. We talked about cross-reactive antibodies, rheumatic fever and arthritis. Lyme arthritis is thought to be the same basic mechanism as strep rheumatic heart disease. One of the kinds of designer mice made, has been to stick a viral protein in a cell with a certain promoter, so that there is constitutive expression of viral proteins. Although every cell has this, it is expressed only where the promoter is active. One specific mouse has the LCMV nucleoprotein in front of the insulin promoter. So LCMV NP is constitutively expressed in the islets of langerhans. Nothing happened to the mouse until it was injected with T-cells from another mouse that were specific for that gene product. Those T-cells circulated around the body and didn’t find any LCMV except in the pancreas, and those T-cells destroyed the β islets and the mouse became diabetic.
Now we are switching gears to graft vs. host disease. We really talked about this a lot when we introduced T-cell recognition. If you have an autologous graft, a syngeneic graft, nothing happens. There are people who are burned, and they take skin from other parts of the body to protect and graft on the burn. If someone is burned cadaver skin can also be used to cover the area and enable the individual to breathe and survive that acute burn, but that cadaver skin will be rejected in about 10 days. If in this individual that has just rejected the cadaver skin and you do a second skin transplant a month later, and it’s the same as the one just rejected, the graft will be rejected more rapidly because the response is secondary it is a memory response. If you take cells from one mouse that has just rejected foreign skin and you put them in another mouse that has just received foreign skin there are T-cells that recognize the foreign MHC and reject it. This can happen with any transplant if the organ is different. Next week you will learn about some of the strategies used to suppress immune responses. You can’t selectively say you want this graft of skin to stay but simultaneously allow the host to respond to infection.
MHC antigens have six loci and hundreds of alleles at those loci, but there are also minor antigens, and these are allelic variants of all of the other molecules you have in your cells. There are people who are blue eyed vs. brown eyed, there are allelic variants of many other proteins. Some of those proteins are expressed and are presented as self on MHC. Those are the minor antigens, the self, housekeeping proteins. You can have a kidney transplant that has all the same MHC but you can have minor differences. The nomenclature is the same but one is in capital letters for major and lowercase letters for minor, mhc. A graft that is incompatible in mhc will be rejected more slowly than one incompatible for MHC. For the minor antigens there are fewer T-cell clones committed to those minor antigens, but once you have one clone that is activated it will divide and differentiate and expand because you have constant presence of the antigen. Once the antigen is removed by skin graft rejection then the immune response will be compressed, but there will be memory cells.
If you have a skin graft, the langerhaans cells in the skin will travel to the draining lymph node and trigger an immune response and the T-cells get activated and divide and they leave the lymph node and they identify the activated endothelium and they attack the skin. When the graft is rejected there is no more foreign skin and hopefully the skin will heal, and the clones will compress and there will be memory cells.
In a kidney transplant rejection, rejection occurs at the level of the blood vessel. When you transplant a solid organ like a kidney you connect its blood vessels to the blood vessels of the host. So all you need is to recognize is the foreign antigens on the blood vessels.
There is an enormous need for transplanted organs for a variety of different diseases. Cystic fibrosis can require the replacement of lungs, heart disease can require the replacement of an entire heart. Some people need new livers because of alcohol cirrhosis but there are also acute and chronic infections of the liver, and if you have hepatitis C virus infection and you transplant a new liver in, the new liver is infected and destroyed. There are many causes of kidney failure, and there are more kidney grafts than anything else. For bone marrow, there are a number of cancers or acute failure of different cells in the bone marrow, not to mention people that have mutations in some gene product from a bone marrow derived cell. So sickle cell anemia for instance could be treated by a bone marrow transplant, and there many other diseases that could be treated that way.
If you have allogeneic bone marrow come in and you haven’t cleaned up the T-cells, the mature cells in that individual, induce an immune response. These cells can induce graft vs. host disease or host vs. graft disease.
Remember that the baby is a hybrid, it has maternal and paternal antigens, and the placenta must be able to separate the mom from the baby or the baby will be rejected. Sometimes infertility is associated with recognition of paternal antigens on the gametes or early embryos.