CLASS: 10:00 – 11:00 Scribe: Allison O’Brien
DATE: November 19, 2010 Proof:
PROFESSOR: R. Pat Bucy Immunopathology II Page 1 of 6
I. Introduction [S1]
a. Today we are going to talk about autoimmune diseases. (Yesterday was the way that immune system causes damage from an exogenous antigen or infection)
b. We think these diseases are due to a response to an auto-antigen (Remember that this is the definition of an autoimmune disease-that the Antigen is an auto-antigen). However, a lot of times we don’t know what the antigen is. How do we know its an auto-antigen? There is Circularity in the definition.
c. Best we can say is that in an autoimmune disease its the effector parts of the immune system causing the tissue damage and that an antigen has not been identified as an infectious agent.
II. Organ Specific and Non-Organ Specific Autoimmune Diseases [S2]
a. Autoimmune diseases are divided into two categories: Organ specific and non-organ specific.
b. Lesions are either specific to one organ or found throughout.
c. Non-organ specific: Immune Complexes (Type III Hypersensitivity)-skin, joint, and kidney (particularly glomerular nephritis) are the primary targets. Damage is done by the immune complexes. Antigen specificity in immune complex are not particular to organs but to antigens that can be anywhere and cause immune complexes to deposit anywhere.
d. Organ specific-a particular antigen localized to tissue type/organ. The Target of immune attack is against Ag so the lesion is in the organ where the Antigen is.
e. Can have an overlap situation and start in the organ (specific) and then stimulate immune complex to get whole non-specific reaction and the two happen together basically (co-incidental).
III. Breaking Tolerance [S3]
a. Tolerance is the normal mechanisms to maintain the lack of any self responses.
b. One of these is to covalently link self epitopes to immunogenic epitopes (if you modify protein with external chemical) OR
c. Another Classical example-in thyroid disease you can immunize another species thyroid (thyroglobulin) to get an immune response to that epitope. This occurs because of the differences in species. Because its also linked with shared sequences (thyroglobulin has homology), you get an autoimmune response to animal’s own thyroglobulin, but the target is the animal’s own thyroid gland. We haven’t manipulated the thyroid gland, but Induction of an active immune response to a linked epitope causes cross-over and development of reaction to self Ag.
d. Another principle is the Localization of a self Ag together with an immune response with strong adjuvant. Immunization with adjuvant that has heat-killed mycobacteria in a viscous oil that holds Ag tightly in one injection site, causes inflammatory response. Inflammatory microenvironment response to self Ag is lessened, and you develop immune responses to self Ag, which alone wouldn’t cause autoimmune response. Inflammatory microenvironment-you can overcome normal mechanisms that maintain unresponsiveness to self antigens.
e. Some body compartments-eye-don’t normally have lymphocytes recirculating-like the cornea, because don’t want blood vessels circulating because you need it to be clear. Uvea also protected. If you get injury to one eye, autoimmune uveitis attacks injured eye and the other eye. Tolerance maintained by unavailability of self antigen in re-sequestered compartment, release Ag that normally wasn’t present, this is enough to activate an autoimmune response.
f. Multiple Genetic patterns of responsiveness-linked to major histocompatibiltiy complex, HLA. Control structure, T cells control peptide Ags, causes T cell repertoire to have different structure, have a different kind of both positive and negative selection, difference in pattern translates into some individuals might have ankylosing spondylitis than if you don’t have HLA B 27 -100% more likely to get it. Among HLA B27+ people, much higher incidence rate of AS, not complete penetrance of gene but they are clearly related.
g. Another example of genetic pattern=Promoter polymorphism makes macrophages 30% more responsive given the same level of stimulus. Add different doses of LPS, bacterial endotoxin that activates TLR4, MQs produced TNF alpha. 30% higher at the same doses for people caring particular allele of that polymorphism at same doses. Gain is higher for pro-inflammatory cytokine, and given a stimulus more likely to develop rheumatoid arthritis that have excess TNF alpha production. You can treat RA with TNF alpha blockers. Our genomes are littered with different genetically polymorphisms. This is a really complex pattern of immune regulation and modifications in any one of those different molecules might alter immune sensitivity to immune diseases.
IV. General Scheme [S4]
a. Induction of a local immune response (might be infectious agent, drug, hypersensitivity, trauma- a number of different things it could be) if you break mucosal barrier-infection that’s persistent, periodontal disease. Think there might be some component of auto-antigen response as well as hypersensitivity and damage by infectious organisms themselves. Then, based on genetic predisposition, normal immune response is somehow altered, many different alteration of mechanism can take place-two factors combined can lead to progressive immune response to an antigen.
b. Have to have genetic susceptibility as well as environmental insult not dictated by gene. Gene doesn’t directly cause disease.
c. People can get insult or have gene but must have right combination of both to get a progressive immune response.
d. You can get epitope spreading, both B and T cells can respond to Ags present in local environment.
e. Tissue destruction in Bile ducts caused initially by T cell infection, can get Abs to intracellular Ag that you wouldn’t have normally and cause further destruction of bile ducts and can get new T cell responses.
f. Rumbling type of infection/hypersensitivity/overexposure of auto-ags leads to progressive tissue destruction, loss of function of whatever target involved.
g. What this looks like is widely variable and depends on the particular organ physiology.
V. Organ Specific Autoimmune diseases [S5]
a. This slide indicates there are many organ specific autoimmune diseases that have similar characteristics. Infection might start it and get autoimmune responses but might wax and wane periods of episodes and recovery.
b. Some are relatively common like Type 1 insulin dependent diabetes, others are not so common like idiopathic hypophysitis has many of same characteristics in terms of physiology.
c. Outcome of loss of function is completely different for the different target tissues.
VI. Multiple Sclerosis [S6]
a. Immune mediated destruction of myelin in the CNS.
b. Histopathology of lesion depends on stage of the lesion.
c. Acute phase can last only a month, 6 weeks, In local microenvironment the lesion resolves and results in a scar.
d. Later on, Person might have another attack in a local spot in the brain and then it resolves.
e. Over time the person develops multiple different scars In the central nervous system that are the end result of local inflammatory type response.
f. Evidence that Viral infections that are tropic for CNS oligodendrocytes might initiate that lesion-Some investigators believe that it is a result of an infection not an immune defect, Simply Collateral damage (like in leprosy) tissue damage as secondary consequence.
g. Animal model-EAE, talk about it later.
VII. Cross Sections of Spinal Cord [S7]
a. Gross photographs of spinal cord from cervical to lumbar to caudal region
b. Myelin is stained dark blue color
c. See lesion where myelin is gone, the lesion gets smaller in successive sections and then disappears
VIII. [S9]
a. This also occurs in the brain-MS plaque, name for acute lesion in brain
b. T cell infiltrate and Destruction of oligodendrocytes (make myelin to insulate nerves in CNS)
c. Lesion in different spots cause problems in different parts of body (arm numbness, bladder control loss)
d. This is by chance where it will be
IX. [S10]
a. MRI of a person with MS looks like this
b. Lesions pop up and go back down if you take them over time
c. Get more lesions than you actually have individual symptoms
d. Immune response has normal inhibitory mechanisms, also get rid of myelin in lesion area (taking away the Ag, so immune response will also go down because of this)
X. Experimental autoimmune encephalomyelitis (EAE) [S11]
a. Occurs when you inject myelin protein and rat develops hindlimb paralysis
b. Haven’t done anything to CNS (relatively protected), if you get a strong response in lymph nodes, Tcells find myelin in CNS
c. We don’t know the mechanism of how the Tcells find the Ag in CNS
d. Take T cells out in vitro and stimulate
e. Inject into normal animal can directly cause EAE
f. Don’t have to transfer Abs/T cells to cause exact same disease
g. Another case can transfer Abs to cause disease (passive transfer experiment)
h. Can’t do direct transfer of T cells in humans obviously
i. Pasteur used rabbit SC to do rabies vaccine, this contained a lot of myelin, people developed syndrome similar to EAE, so not just a mouse/rat phenomenon, however not clear that this model is what MS is
XI. Mouse pic [S12]
a. Picture of a mouse with hindlimbs dragging because has been injected with EAE
XII. Type 1 Diabetes [S13]
a. Autoimmune disease, destruction of Beta islet cells
b. Not much islet cell mass, possible for immune response to wipe out all islets, so people could have no insulin producing cells
c. Now we can inject insulin, but it is still hard to control the levels so people still have the disease, this still works much better than before=death in two weeks
XIII. Islet of Langerhans [S14]
a. Pathology of pancreas of someone who has had diabetes for 20 years-no evidence of diabetes just a Lack of islets, a little bit of fibrosis. This is because once you get rid of Ag, all that’s left is deficient function of target tissue
b. Also evidence for tropic viral infection growing specifically in beta islet cells might initiate immune response
c. Predisposition of genetics also-MHC linkages.
d. Animal models-non-obese diabetic mouse (NOD). 10 different genes present in NOD mice separated by breeding experiments, about 80% of animals develop lesion (insulitis) at about 12-20 weeks old and get diabetic, hyperglycemia all the time these mice are not treated with insulin and not all islets killed but high blood sugar levels. We think human Type 1 diabetes same process (T cells mediate islet destruction)
XIV. Autoimmune Thyroiditis [S15]
a. Has two forms Lymphocytic thyroiditis-chronic inflammatory lesion that ends up destroying the thyroid, difference is that thyroid follicles can regenerate and replace the function making thyroglobulin
b. Beta cells are the opposite, if they are gone=no insulin (can occur ~ 6months)
c. Thyroid gland can regenerate, so takes a long time to deplete them all to get hypothyroidism (20 years, 10 years)
d. Sometimes people get Specific Ab to TSH receptor, which is a molecule on follicle cells that makes them respond and that controls level of growth and activity of thyroid follicular cells. When you get this Ab, turn to be hyperthyroid. Normal mechanism TSH receptor stimulates thyroid hormone production. Unlike normal system that has a control-Here, excess thyroid hormone feedbacks to drive thyroid to excess. Therapy is to surgically remove thyroid.
XV. Graves’ Disease [S16]
a. Sometimes people have extraoccular eye muscle associated with Graves’ disease.
b. If you get rid of Ag can cure disease (take out thyroid, give radioactive iodine)
c. Can’t just cut out the brain in MS—but both autoimmune
XVI. [S17]
a. photomicrograph of thyroid gland with active follicular epithelium, involutions, inflammatory infiltrate inside
XVII. [S18]
a. Hashimoto’s disease don’t really see follicular hyperplasia
b. Struggling Follicular cells killed by inflammatory infiltrate, sometimes get germinal centers
c. All lymphocytes, looks like a lymph node, some efforts at regeneration, can result in complete destruction of all thyroid cells
XVIII. [S19]
XIX. [S20]
a. surgical specimen shows little lymph nodes in thyroid gland completely replacing follicle areas remaining red meaty tissue has thyroid follicular cells still there
XX. Myasthenia Gravis [S21]
a. Neurologic disease in which there is muscle weakness, blurred vision is a symptom
b. Have to be extremely controlled nerves to muscles, can’t coordinate two eyes
c. Also get slurring of speech because tongue is also amazingly connected to your brain
d. Both require tight muscular control, don’t get muscle weakness in big muscles like hips, delicate muscles first to go
XXI. Myasthenia Gravis [S22]
a. Caused by Antibody developing to ACH receptor, causes it to be internalized and digested, a little bit of receptor is put back on cell surface but have only about 10% receptors put back on and the NMJ is not working correctly. Not complete connection between nervous impulse and muscle.
XXII. Inflammatory Bowel Disease [S23]
a. comes in two types-Crohn’s (regional enteritis)=trans mural inflammation of any part of GI tract, tends to focus in ileum but can go in colon or esophageal lesions
b. there are so called skip lesions-inflammation in one part of SI and another part of colon but in between can have no tissue damage at all, similar to MS lesions popping up at different places and resolve
c. in Crohn’s there are lesions that go through to muscle, mucosa, and serosa. You can get erosion and fistulas that can cause problems like a fistula between intestine and bladder can occur, spillage can occur.
d. inflammation causes bloody diarrhea, lose weight etc
e. animal models of Crohn’s=IL-10 is a cytokine that inhibits MQ activation
f. counter regulatory molecule to gamma interferon, if IL-10 is knocked out, get IBS so suggests that normally its an inhibited immune response because of normal intestinal contents
g. Ulcerative colitis is a little different-inflammation restricted to mucosa (the superficial layer=usually in colon but involves contiguous areas of the colon, essentially one big ulcer that grows and is all connected
XXIII. [S24]
a. this is an Ulcer in crohn’s disease in a small bowel section
XXIV. [S25]
i. epithelium is completely eroded, fibrin clots, cells, fluids
ii. involves inflammation in muscle layer and serosa leads to fistula formation-treatment is to cut out those sections of the intestine, can give immunosuppressive drugs but doesn’t prevent new lesions
XXV. [S26]
giant cells form from lesions
XXVI. [S27]
a. linear ulcers-bear claw lesions, all parts of ulcer are topographically connected to one another
XXVII. [S28]
a. pseudopolyps-when it gets really severe
b. bumps are remaining normal intestines, shiny flat stuff is ulcer bed with fibrin coating but bacteria and intestinal contents are leaking into tissue and a lot of inflammation associated with big ulcer
c. no Ag has been identified in either of these diseases but it has been suggested that it could be luminal bacteria, makes an ulcer a little better but no Antibiotic treatment for Crohn’s (autoimmune)