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78 Cards in this Set
- Front
- Back
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What is tolerance?
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Avoidance of autoimmune self-injury
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What controls tolerance?
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Thymic deletion of autoreactive T/B-cells (most B cells don't have the right T-cells to become activted or are negatively selected)
Peripheral inactivation of autoreactive T-cells Suppression of autoimmune reactions (by T-reg's) |
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Where is tolerance primaruly regulated (at which cells)?
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T-cell level
->since most auto-Ag are Th-cell dependent |
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What is immunological tolerance?
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Absence of autoreactive clones
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Where does central tolerance start?
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Thymus
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How do TCRs recognize MHC?
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Low affinity
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Whhat happens if the TCR recognizes the MHC with high affinity?
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Negative selection (destroys any T cells that have more than low affinity for MHC)
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How many T cells go into the periphery?
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5%
(95% of the cells madein the thymus are negatively selecte against) |
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What happens when the T-cell recognizes MHC with too much affinity?
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Self tolerane .: they are clonally deleted
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What are T cells that are clonally ignorant?
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Below the threshold of affinity and there is no self-tolerance
->these cells are not useful |
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Which T cells can have an autoimmune response?
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The T cells in the zone between igorance and tolerance
->These cells hace the potential to elicit an autoimmune response |
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Where are these clones present?
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Most of them are in circulation
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When can there be an autoimmune response?
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When the clones are activated by an increased number of the peptide
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What does deletion or negative selection require?
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Recognition of MHC plus autologous peptdes with sufficient affinity and density
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When can you get autoimmunity?
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In -cells that are not tolerant to the self-peptide, whch is normally present just below the critical density
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What happens when there is a deviation in the peptide density?
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Can activate mature T-cells and initiate an autoimmune response
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Where does central tolerance/clonal deletion take place?
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Thymus
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What is central deletion?
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High affinity interaction between the peptide complex (MHC) and TCR
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What happens when the MHC and the TCR have the right affinity, but there is weak/no affinity for the peptide?
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Cells aren't positively selected
->These cells are killed by apoptosis |
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When can there be a partial signal?
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The MHC and peptide have moderate affinity
->moderate signal allows ells to be rescued from apoptosis and mature |
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What happens if peptides are recognized too well?
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Clonal deletion because the interaction is too strong
->Active process (unlike negative selection) ->Also get apoptosis (pg 4 of lecture, top slide) |
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What happens in peripheral tolerance?
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Anergy or inactivation
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What is anergy?
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Lack of co-stimulatory signal 2
->Leads to the permanent inactivation of the T-cell ->No immediate cell death, cell is ignored until flushed out naturally |
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What happens if a T-cell only gets a co-stimulatory signal?
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No effect on the T-cel
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What happens if the t-cell only gets a specific signal (no co-stimulatory signal)?
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Anergy
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What is the co-stimulatory signal?
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B7 (on the APC) interacts with the CD28 o the T-cell
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Can anergic T-cells be reactivated?
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No
Peripheral tolerance induces PERMANENT anergy/inacivation |
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What happens when the T-cell is poperly activated?
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T-cell sees the MHC and peptide presented by a proper APC and the T-cell can be activated (get proper MHC and co-stimulatory interaction)
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Is co-stmulatioin necessary on subsequent cells presenting the same marker?
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Has already received the right signals from the APC
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How many cells can the activated T-cell "kill" before dying?
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60-80 target cells
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Where does most B cell tolerance occur?
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Bone marrow
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What happens when polymeric antigens cross-link IgM on the surface of the B-cell?
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Cells are deleted
(These cells didn't express IgD yet) |
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Is it easier to induce tolerance on mature or immature B cells?
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Immature B-cells
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What happens if the B cell recognizes/reacts with self?
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Gets deleted
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What happens to the B cell when the antigen is soluble?
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After migrating to the peripherym the levels of IgM will be lower
-Normal levels of IgD -Cells will be ANERGIC ->they react with antigens, but are never activated |
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What happens when B cells see antigens with low affinity and no cross-linking?
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Get mature B cells that are clonally ignorant (inactive)
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What happens to B cells that have no self reaction?
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Become mature B cells
->these are the B cells that will protect us -> express IgM and IgD on th surface |
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What is required to induce tolerance of B cells?
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Need Ag dose
->low Ag dose needed to induce tolerance until IgD and IgM are present -> Medium Ag dose needed if IgD and IgM is present -> Difficult to eliminate memory B-cells, need high amounts of Ag |
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When are B cells easiest to tolerize?
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When they're immature: only have IgM
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What happens to the B cell when they leave the spleen/lymphoid?
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Can't really ecome activated because they're aren't any specific Th-cells (only make IgM/D in responses to T-cell independent Ag)
->Difficult to anergize/delete these cells |
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Why are memory B cells so difficult to eliminate?
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IgG receptors have a very high affinity for Ag and activated B-cells are hard to kill/anergize
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Why might low affinity BCRs not mature?
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Might not be able to bind enough Ag to cross-link Ig-receptors
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What happen if there is no T cell help?
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Can;t get isotype switching, maturation or immune memory
->.: B-cells that could e problematic won't cause a problem |
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When can these cells become problematic?
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Under lab conditions/rare conditions of cytokine release
-> IgM can cause some minor pathology by activating complement. But no memory .: individual goes back to normal |
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When can high affinity B cells undergo apoptosis?
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When activated by Ag in the absence of stromal or cytokine signals
--> activation induced cell death (Clonal exhaustion) |
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What happens when antigen is present in early development of immature B and T cells?
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Cell with idiotpic receptors that react strongly with the Ag are deleted
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Can immune cells still be susceptible to tolerance induction in offspring?
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Yes, in some species whose offspring are born at a very early stage of development
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Describe the experiment by Burnett and Medawar.
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Transferred cells from one animal to another to see if it would learn to tolerize
-> Took newborn mice (physically/immunologically immature) ->Inject mice A with bone marrow cells from mouse B -> Gave mouse A a skin graft from mous B (control: gave mouse A skin graft from mouse C) Results: Graft from mouse B survives, graft from mouse C is rejected |
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What did this experiment show?
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After embryonic development, an organism can learn to tolerate antigens
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What requires more antigen for their induction of tolerance: T cells or B cells?
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B cells require more Ag for their inuctions of tolerance
->Low doses of Ag only induce T cells -> Large doses of Ag induce both B and T cells |
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How is tolerance maintained?
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By continuous exposure to the inducing agent
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What happens when the inducing Ag is lost?
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The one marrow and thymus can make new B and T cells without clonal deletion
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Describe Mitchison's experiment.
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-Took gps of mice and gave them varying amounts of Ag
-In very low doses of Ag: not enough to produce a visible immune response -Moderate amts of Ag: presentation by APCs and a decent response is mounted -As the amt of Ag is increased, the response stopped until a point when the response DEC (this is exhausting of the system and leads to tolerant cells) -The gps of mice were taken and re-challenged with the optimal dose -> Those who had already seen a high dose had LESS memory, since both the B and T cells had been tolerized and potentially reactive cells are somehow deleted -> Those who had seen low ose of Ag had less memory and tolerance to the Ag (B cells were normal, but T cells were tolerized). T cells only need nanogram lvls to be tolerized |
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How is tolerance lost?
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As the tolerance inducing agent is lost
-> New immunocompetent cells come from the bone marrow |
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What happens about 10-20 days after the exposure?
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The animals become non-reactive
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What happens when the protein is degraded from circulation?
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The tolerance is lost in reverse order of tolerance induction.
-> Mature B cells take about 2 months to lose their tolerance -> T cells take 150+ days to lose their tolerance |
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Can the immune system be reprogrammed?
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Yes
In the case of autoimmune diseases, it is possible to eradicate the immune system and repopulate it with better bone marrow cells |
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What is the response to Ag when there are normal B and T cells?
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Normal Ab response
CMI response |
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What is the response to Ag when there are normal B and tolerantT cells?
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Only IgM Ab
NO CMI response |
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What is the response to Ag when there are normal T cells and tolerant B cells?
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No Ab
Normal CMI |
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What is the response to Ag when there are tolerantl B and T cells?
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No Ab response
No CMI response |
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Therefore what type of response do normal T cells produce?
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CMI response
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What type of response do normal B cells produce?
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Ab, but require normal T cells to do this
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What does immunization via mucosal tissue (nasal or gut) do?
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Favors induction of tolerance
-> focuses on allergies and IgE |
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What does the activation of Th2 lead to?
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Production of IgA
->this can block the activation of Th1 cells or activate T reg cells -This process appears to temporairily reduce the severity of some autoimmune diseases |
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What happens to the levels of reacting CD4 cells after tolerance is induced by injection of Ag-specific T-cells?
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The number of reacting CD4 cells are relatively low when he Ag enters
(in the control, ge moderate response to Ag) |
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Can Th cells transiently suppress the opposite arm of the immune respnse (immune deviation)?
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yes
-> Th1: when activatd, produce cytokines to develop CMI (produce a lot of IFN-gamma, which inhibits Th2 cells while promoting more Th1 cells) -> Th: when activate, produce IL-10, which produces humoral immunity and suppresses Th1 |
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Which arm does the immune system focus on (which Th arm)?
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Focuses on the arm of the immune system that will bye ost beneficial and not allowing them to both be active
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How is tolerance adaptable?
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State of tolerance is not fixed
B cells express autoreactive receptors that aren't normally activated by Ag because specific Th-cells are absent Transient autoimmune Ab responses occur, but usually only make IgM Persistent autoimmune pathology is rare (IgM Ab disappear quickly and pathology is usually not fatal) Somatic mutations to autologous ptns don't appear to cause autoimmunity (if genes that code for ptns undergo pt mutations, very rarely causes autoimmunity) -Cancers apparently induce a form of anergy, tlerance or evasion of immunity |
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How can tolerance be broken?
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-Activation of autoimmunity
-Direct activation of autoreactive B-cells (generates autoreactive B-cells and Ab, not usually a major problem if the Ab remains IgM) -Thymic escape of forbidden T-cell clones (defect of some kind: henetic or transient ass't with trauma/infection). Peripheral mechanisms are uually enough to stop any serious consequences - T-cell activation by cross reactive Ag seen during infection due to molecular mimicry or expression of similar epitopes: occurs relatively often. In infection of bacteria that has epitopes that cross-react, you can decelop autoimmune diseases that are on-going (only reactive upon reinfection by the bacteria that caused it) -Cytokine disregulation that activates latent autoreactive B and/or Th cells: disrupts the balance btw the 2 arms of the immune system -Failure of normal negative fdbk or regulation of immune reactivity: messes up T-reg cells, which can change the likelihood of deveoping autoimmune disorders |
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What is required to break B cell Tolerance?
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Th2 cells
-Cross reactive help from T-cells activated by foreign antigen |
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What are teh 2 types of diabetes?
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Type 1: Body is insulin resistant and pancreas is less able to produce insulin to mobilize sugars
Type 2: Juvenile diabetes (insulin dependent): can be due to unknown virus that targets cells that produce insulin. Immune system kills virus and also the cells that produce insulin |
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Describe the experiment that models the diabetes theory (experiment that showed that exogenous events can induce endogenous autoimmune reactions)
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-Created transgenic mic
->Inserted an insulin promoter coupled to a nucleoptn (NP) of a virus (the virus used was very fatal to mice, caused meningitis) -> When mice grew up, they expressed the NP ptn only in the pancreas because they're under control of the insulin promoter -Some mice were then infected with the virus ->virus propagates in the cells and activates an immune response ->the response generates T-cyt cells that find every infected cell and eradicates the virus -> the beta-cells in the Islets of Langerhans also express the NP ptn and, even though they are not infected, they're killed .: the mouse becomes diabetic This is a cross-reactive response: when Th-1 response is activated, the animal becomes diseased |
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How does the local production of Th1 cytokines induce autoimmune CMI?
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Disregulation of cytokins ass't with Th1 response:
-used insulin promoter linked to IFN-gamma which helps activate Th1 cells and macrophages -Whe this is expressed in the pancreasm there is a production on IFN-gamma and Th1 cell, recognizing MHC-2 on APCs and other "specialized" cells -Non-professional APCs that have IFN-gamma induced MHC-2 on their surface can now present MHC-Ag to the Th1 cells (these cells lack to co-stim signal 2, but IFN-y acts as a costimulator)) -The Th1 cells produced will make IL-2, which activates T-cyt, which then come and kill the beta cells in the islets of Langerhans |
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What does local IFN-y release induce?
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Local inflammatory responses that induce Th1 activation (helps T-cyt with CMI)
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What happens under chronic inflammation?
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Can develop autoimmune reactivity
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Summary of tolerance.
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Can affect both T and B cells
Promarily imposed at the Th cell level Central deletion of high affinity clones Peripheral anergy of autoreactive cells Maintained by the presence of autoantigens Autoimmunity may arise if the lack of Th-cell is bypassed: -by cross-reative exogenous Ag -By exogenous molecular mimics or homologues -by non-specific cytokine disregulation |
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Are our auto-Abs the cause or the outcome of autoimmunity?
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Unknown cuz clinical treatments treat the symptoms, not the cause
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