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41 Cards in this Set
- Front
- Back
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T/F Tolerance can occur naturally.
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true, but can also be induced - not necessarily pre programmed in the genetic code
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What is Tolerance? and how is this produced?
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A state of unresponsiveness for a particular antigen
- LEARNED, very specific and induced by prior exposure to antigen - Includes tolerance to non-self antigen |
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What is self-tolerance?
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Self tolerance – physiological state in which the immune system does not react destructively against self tissue
*one of tolerances most impt actions is: Maintains immune systems ability to NOT attack self tissue |
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What is an example of induced tolerance?
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allergy shots - induced by prior exposure to antigen, predisposing in certain way
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Where may self-tolerance be induced?
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Self-tolerance may be induced in immature self-reactive lymphocytes in generative lymphoid organs (central tolerance), or in mature lymphocytes in peripheral sites (peripheral tolerance)
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Where will central tolerance occur for B cells and T cells?
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B cells in bone marrow,
T cell in thymus |
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Why do we need peripheral tolerance?
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because if some cells escape central tolerance there is the 2nd chance that they can be made self-tolerant
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Immunological tolerance is NOT simply a failure to recognize an antigen - so what is it?
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It IS an active response to a particular epitope and is just as specific as an immune response
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Ex: if you inject a mouse (that is strain A) with Strain B during DEVLOEPMENT, what will the result of a Strain B and C skin graft later on?
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Strain B skin graft will accept - even though the mouse is Strrain A
*Reactivity is prevented by processes that occur during development rather than being genetically pre-programmed. |
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When B or T Cell is exposed to self antigen what are the possible outcomes?
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Anergy (functional unresponsiveness)
Deletion (cell death) B CELL ONLY : Change in specificity (receptor editing) |
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What is a reason why pple develop autoimmunity:
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b/c central tolerance isn't perfect and cells escape and sometime peripheral tolerance just isn't enough to fix it
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The cells are produced in the bone marrow and are negative for all CD4, CD8, etc. once arriving inthe cortex of the thymus what happens?
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They start expressing all of them at LOW levels
Positive selection occurs here - is when: any cell that CAN recognize MHC will be kept. |
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ONce they enter the medulla what happens?
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NEGATIVE SELECTION TAKES PLACE: If low affinity - kept if high affinity (binds self antigen strongly) they are killed
Functional and phenotypic differentiation into CD4+CD8- or CD8+CD4- T cells occurs in the medulla. = mature T cells are released into the circulation. |
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What about the gammadelta cells?
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The γδ TCR-expressing T cells are also derived from bone marrow precursors and mature in the thymus as a separate lineage.
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During maturation in the thymus, most immature T cells that recognize antigens with high avidity are deleted
Some self-reactive CD4+ T cells that see self antigens in the thymus are not deleted but instead... |
differentiate into regulatory T cells
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One subset of T cells is allowed to leave that DOES recognize self antigen - what are they called?
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A regulatory T cells
CD4+ and very specific for self antigen and keep self antigen from being detected by the immune system. |
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What is the choice by lymphocyte activation and tolerance determined by? (beside central tolerance)
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- the properties of the antigens
- state of maturation of the antigen-specific lymphocytes - types of stimuli received when these lymphocytes encounter self antigens (costim. molecules - cytokines and chemokines - , ex: B71&B&2) |
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Where do B cells mature?
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bone marrow; so when B cells leave the bone marrow they are mature unlike T cells (which are also produced in bone marrow)
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Can b Cells be eliminated in the bone marrow?
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can be eliminated in bone marrow if there is a lot of antigen there
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Only B cells experience receptor editing..where does this occur and how?
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you have surface bound to IgM (naive B cell) and if it sees self antigen and binds strongly with antigen = B cell stops growing and has continued like chain rearrangement and low self surface affinity for self antigen - specificity changes - takes up old receptor (that recognized self antigen) and starts expressing new receptor.
If, this receptor still recognizes self antigen - will be deleted, but if it doesn't it will be sent out into periphery |
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What determines the fate of B cells?
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Nature and concentration of the self Ag determine the fate of B cells
- Multivalent Ag (membrane associated proteins) induce B cell death - High concentrations of Ag induce B cell death - Lower concentrations of small, soluble self Ag induce functional anergy - - -RESULTS in: Decreased membrane Ig blocked signal transduction by membrane bound Ig |
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Where does peripheral tolerance take place?
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spleen, LN, lymphoid organs in peripheral sites
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what is peripehral tolerance?
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deletion or anergy of mature B/T lymphocytes that recognize self antigen in peripheral tissues - is the mechanism by which mature T/b cells that recognize self antigens in peripheral tissues become incapable of responding to these antigens
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What are Mechanisms of Peripheral Tolerance
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clonal deletion, or apoptosis (programmed cell death - not necrosis)
Clonal Anergy (recogn. antigen and CHOOSE to do nothing - this can be reversed) Suppression: regulatory T cells, inhibition of cellular activity or interactions with cellular products or cells * not specific * Ignorance:co-existence of self-reactive clones and antigen; cells do not respond to antigen |
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What Factors determining which mechanism(s) are operative: in peripheral tolerance?
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* - Concentration of self antigen in generative lymphoid organs =
-- If large amount of antigen = deletion apoptosis will be active -- If small amount present of antigen = clonal anergy -- moderate amount of antigen = suppression - Affinity of antigen receptor for antigen - Nature of antigen (multivalent, lipid) - Concentration and availability of co-stimulatory molecules (B71/B72...) |
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Peripheral tolerance in B cells- Not all potentially reactive cells are eliminated or inactivated and enter peripheral circulation. what are the 3 main mechanisms of peripheral tolerance?
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anergy
follicular exculsion apoptosis |
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What do B cells require in order to have functional response?
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REQUIRE helper T cells
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How do T cells Affect the outcome of B cell Activation in the Periphery?
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Two signal hypothesis:
Signal 1 - generated through the Ig Receptor (MHC and TCR) SIgnal 2 - CD40(B)/CD40 ligand(T) |
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What happens if the signals aren't there for the B cell?
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B cell = anergy
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Anergic cells show a block in ___________
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Anergic cells show a block in TCR-induced signal transduction
- Lack of costimulation by B7/B72 - costimulation by inhibitory receptors - e.g. CTLA-4 |
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CTLA-4 competes with what co stims? how?
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with CD28 for B71 and B72
-binds with higher affinity than CD28 |
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What are the two ways that T cell can become anergic to a self antigeN
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- lack of costim from B7/B72 (on the APC)
- expression of CTLA4 - inhibitory |
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Peripheral Tolerance: apoptosis is when Self-reactive cells may be ‘deleted’ from the repertoire.
What are the ways in which the cells can be deleted or apoptosis induced? |
-- Activation in the absence of IL-2 (necessary in proliferation) can lead to death
-- Persistent Ag - continual stimulation "too much of a good thing" -- Activation-induced cell death - other signals can be sent out by immune system that tells cell it needs to die. |
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HOw does peripheral tolerance: suppression work?
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normal response is still going on
but, another active response may alos be going on - suppressor T cell (regulatory CD4+) generated - either they themselves (suppressors) or cytokines that cell is making is inhibiting T cell activation or T cell function. |
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Peripheral Tolerance: ignorance can be aka:
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Self-reactive T cells may ‘ignore’ self antigens (passive).
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How does ignorance happen
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- Antigen is expressed in a privileged site/sequestered.
-- T cells cannot get to the antigen across an endothelial barrier -- Perhaps the antigen is not expressed in the context of MHC molecules. |
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Tolerance can actually be induced, but how?
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- Foreign antigens may be administered in ways that preferentially induce tolerance rather than immune responses
-- protein antigens administered subcutaneously or intradermally with adjuvants favor immunity -- high doses of antigens administered systemically without adjuvants tend to induce tolerance -- vaccine actually induce immunity not tolerance* |
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Tolerance and immunity are the same, true?
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NO, FALSE!
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Doe oral administartion favor tolerance?
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yes Oral administration of Ag favors tolerance induction
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Why is oral admin. favored and what are the effects?
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- state of immune hyporesponsiveness follows oral administration of an antigen
- Responsible for maintenance of homeostasis -- No immune response to food antigens A (in general) - Human disease trials utilizing fed proteins to abrogate autoimmune disease -- lack of toxicity, ease of administration over time, and antigen-specific mechanism of action |
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What does a low dose vs. high dose of drug admin. = ?
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Low dose = induction of Th2, active suppression
High dose = deletion or anergy of Th1 and Th2 cells, clonal deletion or anergy both =oral tolerance induction |
