autoimmunity is the phenomenon of the immune system attacking host cells, including immune system cells. it arises either from "spontaneous" factors, or from infection, or from various environmental triggers. autoimmunity can be viewed in the same framework as the four types of hypersensitivity in that the mechanisms are the same. the exception is type I hypersensitivity, which involves a class switch to IgE- this mechanism is not seen in autoimmunity. type II autoimmunity involves a class switch to IgG, which binds to different self-antigens.
the first example of type II autoimmunity is autoimmune hemolytic anemia, in which b cells specific for red blood cells start proliferating and producing antibodies, which bind to red blood cells. in this case, the b cells can proliferate using a "antibody crosslinking" mechanism, bypassing the need for IFN-gamma. the antibodies opsinize red blood cells and leave them primed for phagocytosis and destruction by macrophages and natural killer cells. myesthenia gravis is another example of type II autoimmunity, in which antibodies bind to acetylcholine receptors at the neuromuscular junction and thus prevent neural conduction. grave's disease is the third example, where antibody binds to thyroid stimulating hormone receptors, this time stimulating the receptor, resulting in hyperthyroidism.
type III autoimmunity involves a class switch to IgA. this often induces formation of antibody/antigen complexes which block blood vessels or nephritic tubules and cause macrophages to come and secrete reactive oxygen species and damage surrounding tissue. lupus is an example of type III autoimmunity- where the self antigens are all contained within the nucleus of cells: histones, nucleosomes, spliceosomes, transcription factors. these self antigens are thus attacked only in places of high cell turnover or division; such as the skin and joints.
type IV autoimmunity involves a t cell mediated response against self antigens. the first main example is type I diabetes, where pancreatic beta cells are attacked by CD8 t cells specific for insulin, which are activated by dendritic cells which express co-stimulatory molecules by means of a simulaneous infection (or other "spontaneous" means). in multiple sclerosis, the self antigen is the myelin basic protein which coats neurons-- in this case CD4 t cells are activated to produce antibody which opsinize the myelin sheath and cause macrophages to attack. at this point the myelin sheath can be regenerated from oligodendrocytes, but eventually CD8 t cells are activated to attack the oligodendrocytes as well. finally, rheumatoid arthritis is an autoimmune disease in which the antigen is not clearly defined; either collagen or heat shock proteins, which end up with macrophages being recruited to joints and causing damage by reactive oxygen species, etc. rheumatoid factor is also present in the disease, which acts as an antibody to antibodies and can form antibody complexes which can exacerbate disease by damage by macrophages.
questions
1. what is autoimmunity?
2. how does autoimmunity arise?
3. what are some factors involved in development of autoimmune disease?
4. what percentage of monozygotic twins and dizygotic twins show autoimmune disease concordance?
5. what disease occurs when an autoimmune response to myelin basic protein is mounted?
6. what disease occurs when an autoimmune response to insulin is mounted?
7. what is type I hypersensitivity and how is it related to autoimmunity?
8. what is type II hypersensitivity and how is it related to autoimmunity?
9. what are the two ways in which IgM normally class switches to IgG?
10. describe the mechanism of autoimmune hemolytic anemia.
11. describe the mechanism of myesthenia gravis.
12. describe the mechanism of grave's disease.
13. how would one test for the presence of an autoimmune disease in which host cells are being killed (as in question 10)?
14. how would one test for the presence of an autoimmune disease in which host cell receptors are being blocked? (question 11)?
15. how would one test for the presence of an autoimmune disease in which host cell receptors are being overstimulated (as in question 12)?
16. what is the class switching that occurs in type III autoimmunity?
17. how is damage caused by self-specific IgA in type III autoimmunity?
18. what are the self antigens in lupus?
19. why does lupus cause joint pain and skin problems?
20. what is the difference in the autoimmune response to apoptosis vs. necrosis?
21. what is type IV autoimmunity? what are some examples?
22. why does type I diabetes result in hyperglycemia?
23. what is the hereditary component to type I diabetes?
24. which immune system cells "escape tolerance" in type I diabetes?
25. describe the mechanism of autoimmunity in type I diabetes.
26. how are CD8 t cells activated in type I diabetes?
27. what is glutamine acid decarboxylase and how is it related to type I diabetes?
28. what is MS?
29. what is the relative prevalance of MS in males compared to females?
30. what is the average age of onset in MS?
31. what are some epidemiological trends of MS?
32. what is the mechanism to the autoimmune response in MS?
33. what is the role of oligodendricytes in MS?
34. what is rheumatoid arthritis?
35. what is the relative prevalance of rheumatoid arhritis in women vs. men? why?
36. what is the self antigen in rheumatoid arthritis?
37. what are heat shock proteins and what do they do?
38. what are gamma delta t cells and how might they be involved in rheumatoid arthritis?
39. how are joints damaged in rheumatoid arthiritis?
40. what is it that recruits macrophages and neutrophils to the joint areas?
41. what is rheumatoid factor? how does it exacerbate disease?
answers
1. an immune response to self-tissue.
2. either by spontaneous/unknown causes, or in response to extreme childhood stress or trauma, or by infection.
3. environmental (including nutrition), hereditary, the tissues involved, the mechanism of the autoimmune response.
4. mono: 20%, di: 5%
5. multiple sclerosis.
6. diabetes.
7. an allergic response which involves a class switch to IgE. this type of mechanism is not found in autoimmunity.
8. a cytotoxic/antibody dependent response which involves a class switch to IgG. this type of mechanism is the main response used against self tissues in autoimmunity.
9. via IFN-gamma or CD40/CD40L.
10. b cells which are specific to host blood cells are not destroyed during development as they should be and begin proliferating and class switching to IgG (subverting the normal mechanism in question 9 by "cross linking antibodies"). IgG binds to red blood cells and are either opsinized by macrophages or destroyed by NK cells.
11. b cells secrete antibodies which are specific for the host's nicotinic acetylcholine receptors- which blocks acetyl choline binding and results in muscle weakness.
12. b cells secrete antibodies which are specific for thyroid stimulating hormone receptors- which stimulate the receptors, resulting in hyperthyroidism and a downregulation of the TSH receptors on the affected cells.
13. in the case of autoimmune hemolytic anemia, one could look for an abnormally low red blood cell count or an abnormally high b/t cell count in a blood sample.
14. one could test for elevated amounts of the ligand which can no longer bind to the receptor.
15. one could test for elevated levels of the product of the stimulation of the particular host cell, or test for presence of phosphorylated proteins (indicating that the receptor has been bound to and endocytosed).
16. a class switching of IgG or IgM to IgA.
17. IgA can form large complexes with self antigen in vessels or nephritic tubules and block them. additionally, macrophages will bind to the antibodies using Fc receptors and produce reactive oxygen species, which will damage nearby tissues.
18. histone, nucleosome, spliceosome, transcription factors: Ro, La.
19. the self antigens are contained in the nucleus of cells; thus they are primarily exposed to the autoimmune response at places of high apoptosis and necrosis, which would expose nuclear contents during degradation. the joints and skin are two such places.
20. apoptosis is considered "silent" compared to necrosis because only necrosis initiates the inflammatory response.
21. t-cell mediated autoimmunity: multiple sclerosis, type I diabetes, rheumatoid arthritis.
22. because the insulin producing beta-islet cells in the pancreas are destroyed and thus cells can not take in glucose from the blood.
23. the passing down of HLA molecules which are predisposed for diabetes: HLA DR3, DR4, DQ, DQB1*0302.
24. CD8 t cells, CD4 t cells, b cells.
25. a dendritic cell phagocytoses and presents insulin on its surface in both MHC classes. normally, this does not provoke a response from the immune system; however, if this occurs simultaneously with an infection, co-stimulatory molecules will be expressed and t cells specific to insulin will be stimulated to destroy pancreatic beta cells.
26. APC's will stimulate CD4 t cells, which will differentiate into Th1 cells, which will produce IFN-gamma, which will activate CD8 t cells.
27. another antigen that can invoke a similar autoimmune response against the pancreas.
28. an autoimmune disorder which results in multiple sites of demyelination in the brain, spinal cord without axonal degeneration.
29. 7:1 more common in females.
30. 25-35
31. high prevalence in far northern and far southern locales: might be vitamin D related. also very dependent on residence during the first 15 years of life. higher prevalance in high socioeconomic groups and among caucasians.
32. dendritic cells ingest and present myelin basic protein in both MHC classes, causing CD4 t cells to differentiate into Th1 cells, which secrete IFN-gamma, which cause a class switch in MBP specific b cells to produce IgG. IgG binds to myelin and opsinizes, priming myelin for opsinization by macrophages (by way of Fc receptors).
33. oligodendrocytes produce MBP and as such can counter the effects of MS-- until the CD8 t cells are stimulated to attack the oligodendrocytes.
34. an autoimmune disease that leads to destruction of cartilage, bone, and joint deformities.
35. 3:1 prevalence in women as compared to men-- estrogen triggers higher TNF-production via macrophages.
36. unknown; possibly collagen, or heat shock
37. bind to denatured proteins and prevent them from being degraded; activated by excess heat or cold.
38. a special type of t cell that makes high levels of IFN-gamma, causing a class switch to IgG, and also is involved in the production of RF factor.
39. by macrophages which produce reactive oxygen species, IL-1, TNF-alpha.
40. Th17 cells, cytokines such as IL-1, TNF-alpha, IL-6, IL-17.
41. antibody for antibodies which can bind to all antibodies within one isotype. they exacerbate disease when forming antibody "complexes", the accumulation of antibody and RF factor, which blocks vessels and causes macrophages to come and produce ROS, etc.
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