Fundamentals: 10:00 - 11:00Scribe: Matthew Davis

Tuesday, October 20, 2009Proof: Susanna Pischek

Dr. BucyImmunopathologyPage1 of 7

Introduction [S1]:
Organ Specific and Non-Organ Specific Autoimmune Diseases [S2]
There are basically two different classifications of autoimmune disease. One is organ specific and the other is nonorgan specific. The idea is fairly straight forward
In organ specific autoimmune disease there is a particular antigen and the idea is that it is an auto-antigen that is localized to particular organ or tissue type. If you have an immune response against that antigen then you get a disease of that particular organ which is specific to the organ that caused the antigen that is localized there.
There are overlap syndromes. One common mechanism of overlap is that the organ is one that is actually widely distributed. For instance, blood vessels or vasculitis. There are blood vessels in all different kinds of organs and therefore an autoimmune disease directed against endothelium is going to be widespread all over the body. In terms of mechanism that is still an organ specific disease with sort of an asterisk definition of organs
Another example of overlap syndromes is rheumatoid arthritis where the synovium of the joints is the target and you have joints all over the body.
Non-Organ specific diseases reduce down fairly well to immune complex mediated pathophysiologic mechanisms and as I mentioned immune complexes deposit in tissue based more on the anatomy and the physical chemistry of the immune complex and therefore don’t focus particularly on organs and the antigen specifictity of the adaptive immune response is not really in any specific way directed to that organ but is directed to something that makes an immune complex that secondarily deposits in that organ.
There are overlap syndromes where you have a little bit of organ specific activity and then you get immune complexes in addition and by that mechanism you can have overlap between these two but by in large they are separate.
Breaking Tolerance [S3]
So over the years the normal ability of the immune response not to respond to self-antigens is a robust process and this process is termed tolerance. So you are tolerant of your own tissues. But tolerance is a classification of a broad set, it doesn’t specify a particular mechanism and there are multiple different mechanistic ways that the body uses to mediate tolerance. Its been a long held view in the field that when you have autoimmunity that must mean there must be a break down in tolerance, so a lot of the idea of what mechanisms can break tolerance that that must underlie the development of autoimmune diseases and most of the time that is focused on organ specific autoimmune type diseases and disease models
Here are four different themes that come from the investigations of how one breaks tolerance in the animal models and that then make implications of how that process might occur in people.
One is the conjugation of self-epitopes to immunogenic determinants. If you immunize with cow tyroglobulin in a rat then some of the epitopes of the cows thyroglobulin are different and you get an immune response to those different sequences but some of those molecules are the same between the rat and the cow and you will get development of so called epitope spreading, so in an immune response they can develop responses to new epitopes based on the facts they are conjugated with different epitopes.
Another principle is the localization of another immune response with another vigorous response. The classic example is called EAE in which you immunize with a protein from the myelin from the central nervous system together with a strong adjuvant by stimulating a local immune response to the adjuvant then you can break tolerance and develop a true autoimmune kind of response.
A third principle is the exposure of hidden self antigens, so lymphocytes and their surface receptors don’t investigate every last immunogenic epitopes that are present, particularly intracellular antigens or antigens that are sequestered from the immune system. In the eye that is the case and in the brain is a immunoprivilidged site. Places where normally the antigen is specific to that site and they are not exposed to the lymphoid tissue the lymphocytes don’t have the chance to learn that it is self antigen that if you get injury to the tissue, release of those hidden antigens, then you can develop an immune response to those antigens that were under the radar screen of normal tolerance.
And finally there are enormous numbers of genetic patterns of responses and those fall into two classes. One is the relationship of the major histocompatibility antigens called HLA in humans that set the context of which T cells recognize antigens as you have learned in immunology the T cells focus on peptides embedded in MHC molecules. Each individual with a particular array of MHC molecules has a little bit different of a fingerprint of how their T cells recognize peptides and that causes different individuals to be susceptible to different kinds of autoreactive responses and therefore one HLA might predispose to this particular disease. The most common of those is a disease called ankylosis spondylitisin which a particular bacterial infection that causes diarrhea induces and immune response to an antigen that is present in that bacteria shigella. That epitope appears to be shared with the collagen that is specific for the spine so if you get an immune response to that particular bacteria because you have diahrea, that particular bacterial species, then you can get autoreactivity to your own collagen in your spine and you develop this disease and that is very tightly related to a particular HLA antigen HLA B27 so the peptide of the bacteria fits in HLA B27 and can induce an immune response. If you don’t have HLA B27 you don’t get autoimmune disease by enlarge to that bacteria. So the different genetic predisposition sets the stage for what types of immune responses in general and in particular what types of self immune response you can develop.
A second class of genetic patterns are SNP antigens (single nucleotide polymorphisms). They are not antigens but they are genetic differences and an example of that is a particular SNP that is in the promoter region of TNF alpha and that genetic difference makes the gain on TNF alpha control be slightly higher. With a particular stimulus the particular macrophages make 30% more TNF alpha if they get stimulated at the same signal strength. So people who make a little more TNF alpha are a little bit more brittle and their immune response can be kicked off a little easier and sometimes when you kick it off it goes over the edge and you get an auto immune response. That genetic predisposition, although its not that big and you are healthy and its not an overt genetic disease, it makes you more susceptible to an environmental assault that tips the balance and develops autoimmunity.
Figure [S4]
So this is a little cartoon of that. We have genetic susceptibility, you have the activation of the immune response by some exogenous antigen, often an infection perhaps an environmental antigen, then you get regulation of the response that is abnormal because of either of those two things and then you develop an autoimmune disease in which you have tissue injury
The key point is this idea that there are self-reactive lymphocytes that is typically the case if you look hard you can find self-reactive lymphocytes particularly B cells but that alone doesn’t result in a real auto immune disease.
General Scheme [S5]
If you incorporate those ideas into a general scheme for the development of an organ specific autoimmune disease by some mechanism you have induction of a local immune response. That might be a viral infection, drug reaction, even trauma in certain circumstances
There is a virus that affects the beta cells of the islets and that immune response occurs prior to the development or at least there is epidemiological evidence that a viral infection that is specific for the beta cells sort of trips the switch and that is the incident that leads to the development of diabetes. There is a genetic predisposition as well but that comes in when the local immune response would be down regulated, if that down regulation mechanism fails, that failure could be by several different mechanism then you get a progressive immune response to a particular tissue component. Sometimes that progressive immune response bumps along, there is a little activity, then it is suppressed and it isn’t much of a problem. Other times it is sort of a relentless destruction of the tissue and you ultimately get the loss of function of whatever tissue is destroyed by the immune response.
Organ Specific Autoimmune Diseases [S6]
So this list is not meant for you to memorize,
If you pick a different tissue there is a clinical syndrome that’s described in medicine in which there is an autoimmune response to a particular tissue and each one of those causes a different clinical disease and the clinical disease is largely due to whatever function is lost. If you lose the function of the brain that is one kind of disease, if you loose the function of the islets of langerhan that’s a different kind of disease, you lose the function of the adrenal gland is another disease. The mechanism of destruction from immune processes however is the same. The idea is that this is a general point
Multiple Sclerosis [S7]
I am going to spend the rest of the time going over examples of specific diseases, to emphasize some of these same points and also to give you a flavor of the individual differences in different tissue types
One disease that is not uncommon is multiple sclerosis. The basic mechanism is that you have immune destruction of the myelin in the central nervous system. Myelin is produced by cells in the brain called oligodendrocytes which wrap out processes of those cells and makes a sheath around nerve fibers and those sheaths basically make the conduction of the nerve impulse much more efficient. If that sheath is destroyed that doesn’t mean the nerve is not connected and it can’t mediate signal but the signal is sort of dropped because the wiring is not as well insulated and you have neurological deficits.
Depending on the stage of the lesion you look at you see a different morphology in that site.
There’s also a viral antecedent or precursor syndrome where people who get multiple sclerosis there is evidence they have been infected with a particular kind of virus prior to developing that disease.
Probably the best studied animal model of autoimmune disease is one called allergic encephalomyelitis
Figure [S8]
This is a picture of someone who had multiple sclerosis that died and this is their spinal cord and each one of these sections is a different level in their spinal cord as you go down and the dark color is the myelin
At level 3 there is this great big scar hence multiple sclerosis (scars) in the central nervous system
At the next level down there is the tail end of the lesion
The scar is gone by level 6 and picks up again at level 7
There are multiple separated discontinuous scars in the brain and the spinal cord.
Figure [S9]
This is a higher power section through the brain stem and the white areas are places where all of the myelin has been destroyed because that was an inflammatory focus.
Figure [S10]
In the live cut frontal section of the brain, this lesion on the left would be negative for the myelin while over on the other side is what normal white matter looks like. This lesion is a so called plaque
Microscopically that plaque shows an inflammatory focus with lymphocytes activated macrophages, activated microglial cells, and they are digesting the remnants of a bunch of oligodendrocytes
Figure [S11]
Interestingly, studies were done where someone with multiple sclerosis underwent a CT scan every month for two years. So you have a time series of these kind of lesion and what you see is that 1 month there will be a lesion here and the next month it is smaller and the next month it could be gone. At the same time there can be a new lesion popping up in another part of the brain.
On a constant basis, each of these lesions are coming and going and jumping around and they are completely out of sink
One out of ten can be correlated with clinical symptoms. If you have a lesion that is superficial to the motor cortex you might lose movement in your right arm and that can be correlated with one of these lesions and then you will have a bunch of other lesions that don’t have a specific neural anatomic defect and then you might have one in the brainstem and loose control of your bladder. That lesion will get better over time as the inflammation goes down in that local spot but you are then left with the residual deficit.
You can imagine that as those things accumulate over time, as you get more and more you will get more and more incapacitated with people in wheel chairs where people can’t control their bowel disease
It is a serious disease and people die from multiple sclerosis
Other individuals who appear to have the same disease have a much more benign clinical course. They will have an episode but it won’t get worse for a couple of years, they basically do ok by taking immunosuppressant during the acute episodes
Figure [S12]
That disease is very much like an animal model called EAE in which you take a protein, a myelin basic protein, and emulsify it in an adjuvant in which in this case is complete oil adjuvant which is basically a very viscous oil together with microbacteria. You immunize the rat in the foot or in the tail, you can then collect lymph-node cells from about ten days after the immunizations, culture them with the antigen, take the activated T cells completely void of B cells so there is no antibody production and put it into a normal animal of the same strain so they are genetically identical and the cells will induce the lesions of EAE just like was present in that animal.
That kind of experiment is called a passive transfer in which the T cells can mediate that disease and show that even though the T cell s develop in the lymph nodes based on a peripheral immunizations, when you put them into a different animal, even though you didn’t do anything to the brain, the T cells can find the antigen that is hiding in the brain and induce an immune response against that antigen and cause neurological deficits.
Figure [S13]
In mice the animals typically get hind limb paralysis that is correlated with a lesion in their spinal cord, specifically why they get that lesion as opposed to others is not clear, but the hind limb paralysis is easy to measure, just go in and look at the animal and they are crawling around as best they can and you score that chronically
Insulin Dependent Diabetes Mellitus [S14]
Another model that shares many of the features of EAE or multiple sclerosis is insulin dependent diabetes mellitus which is an immune mediated destruction of the beta cells in the islets. Again the histopathology is different depending on the stage you look at it but unlike the myelin which there is a large volume of and you can take a hit and not be dead, there are not many beta cells in the pancreas and typically once the immune process starts and starts killing off the beta cells it will kill of them in a particular islet and the immune respone in that local spot goes away because all the beta cells are gone. It will then attack another islet and over, in people, a year all of the islets or almost all will be destroyed and you will be left deficient in beta cells and insulin production
There are both viral species that have been associated with the development in people as well as MHC antigens and there are several different animal models in particular the non-obese diabetic mouse which is a mouse strain that spontaneously gets autoimmune diabetes
Islets of Langerhans [S15]
This is a lesion (figure on right) where you have lymphocytes primarily T cells and macrophages that invade the islet and basically destroy the islet tissue. In somebody who has had juvenile diabetes for ten years, if you look at their pancreas all you see is the scar, you don’t see inflammation because that lesion has been burned out and you see the same kind of scar that you saw in the brain with multiple sclerosis
Autoimmune Thyroiditis [S16]
Autoimmune thyroiditis is another example of an organ specific autoimmune disease in which most people that have this disease is called lymphocytic thyroiditis. A guy in Japan named Hasimoto described it first but most people are moving away from diseases named after people but in this case both of these guys were physicians that described the disease
The lesion is typically the same chronic inflammatory infiltrates i.e.