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Lecture 30- Autoimmune Disease.docx

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McGill University
PHGY 313
Russell Jones

Lecture 30- Autoimmune Disease - 05/04/2013 Announcements: Office hthrs will be held in McIntyre 703 on the following days:  Friday April 12 1:00-2:00  Monday April 15 1:00-2:00  Immunological Tolerance: A state of functional unresponsiveness for a particular antigen  Breaking tolerance: a process where the immune system is made response to an antigen.  Breaking tolerance to a self antigen can cause autoimmunity  Tolerance is an active process that needs to be maintained with various mechanisms 1. A primary mechanism of central tolerance deletes T and B cells before they are allowed to mature if they recognize higher than a certain threshold affinity  B cells: recognize intact self antigen in the bone marrow  T cells: recognize self MHC and peptide in the thymus 2. Peripheral tolerance is a precaution that inactivates self reactive lymphocytes that escaped the primary lymphoid organs. 3. Lymphocytes are also naturally removed at the end of their life span by apoptosis. This removes some autoreactive clones.  We will focus on the following 4 types of tolerance: 1. Central: killing of lymphocytes in the primary lymphoid organ 2. Peripheral: inactivation because lymphocytes receive signal 1 without signal 2 3. Regulatory cells: Tregs are dynamic molecules that suppress immune cells 4. Clonal deletion: Killing of lymphocytes after they've been activated 1. Central Tolerance  When T cells are in the double positive stage, they are tested by thymocytes to ensure they recognize self-MHC and that they are not autoreactive  We have around 400 alleles of MHC. The thymic epithelium and peripheral cells express multiple variants of MHC. For a T cell to be selected, it needs moderate affinity to its own allele while not reacting to other MHCs  Positive selection: When T cells recognize self MHC and self-peptide and are allowed to mature  Negative selection: 2 situations o When T cells bind to strongly to self MHC complex  deletion o When T cells don't bind to self MHC complex at all  death by neglect  Important question: how come we don't make autoreactive T cells against proteins in specialized tissue such as the retina and pancreas? o Answer: There is a specialized mechanism in the thymic epithelium to express protein from all tissues. A transcription factor called AIRE is able to turn on peripheral genes from distant tissues. Thus, AIRE present developing thymocytes with peripheral gene products inducing negative selection. o AIRE defect: Not good. You would develop many autoreactive T cells and get multi organ systemic autoimmunity. There's no good way to combat this. A bone marrow transplant wouldn't save you even though you got a new line of T cells, because the deficiency is in the thymic epithelium not the T cells themselves. 2. Peripheral Tolerance  Recall that for a T cell to be activated, 2 signals need to occur: one from the MHC complex and one from the co-stimulator. If a T cell receives the specific signal or the costimulatory signal alone, the cell either becomes anergic or nothing happens (respectively).  Anergy: renders the T cell unable to stimulate its own proliferation by not being able to make IL-2. Figure 1: Effects of receiving different combinations of signal 1 and 2. 3. Regulatory T cells  Small population of CD4 T cells suppress all lymphocytes, and sometimes even non lymphoid cells.  They're antigen specific, and are suppressive when their TCR is activated by a peptide MHC complex. This suppression is dominant o Secrete IL-10 and TGF-B as immunosuppressive  Majority of Tregs are CD4+CD25+ and express Foxp3, a transcription factor that represses genes. Once they are activated, antigen is no longer needed and they will suppress the cells they are in contact with.  Treg1 and Th3 cells are found in the intestine (secrete IL-10 and TGF-B, respectively) but both are minor cells.  The above are natural Treg cells, meaning they are made to be immunosuppressive. However regular T cells c
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