Immunological Tolerance - Powell Flashcards
What is the difference between peripheral and central tolerance?
Central Tolerance = occurs in generative lymphoid organs involving immature self reactive lymphocytes recognizing self antigen.
Peripheral Tolerance = in peripheral sites involving mature self- reactive lymphocytes encountering self antigen.
How is tolerance achieved?
Tolerance can be natural or induced
- Natural = self tolerance or oral tolerance.
- Induced = graft rejection, prevent allergies, or autoimmunity.
What is Tolerance?
a state of unresponsiveness for particular antigen
What is self tolerance?
Immune system does not react destructively against self tissue. IMPORTANT
What is Anergy?
Programmed “ignorance” to ignore certain cells…
Tolerance is an active response that is just as specific as an immune response, True or false?
True
The most important aspect of tolerance is ______.
Self tolerance
Central Tolerance in B cells occurs in the ______.
Bone Marrow
____ & ____ of the self Ag determine the fate of B cells in Central tolerance.
Nature & Concentration
- High concentration of and Multivalent Ag induce Cell death
- Low concentrations of small, soluble Ag induce functional Anergy
What is Peripheral Tolerance?
Is the mechanism by which mature T cells that recognize self antigens in peripheral tissues become incapable of responding to this antigens.
What are the 4 mechanisms of Peripheral Tolerance?
- Clonal deletion/apoptosis
- Clonal Anergy
- Supression
- Ignorance
What is Clonal deletion/apoptosis?
Actual elimination from the cellular repertoire by activation induced cell death.
What is Clonal Anergy?
Mature cell is present but its functionally inactivated (but can be reversed)
What is Suppression?
inhibition of cellular activity through interaction with other cells.
What is Ignorance?
Co-existing of self reactive clones and antigen; do not respond to antigen.
In regards in peripheral tolerance, What factors determine which mechanisms are operative?
- Concentration of Self antigen in generative lymphoid organs.
- Affinity of antigen receptor fro antigen.
- Nature of antigen.
- Concentration and availability of con-stimulatory molecules.
True or False? In peripheral tolerance in B cells, all potentially reactive cells are eliminated or inactivated and enter peripheral circulation.
False, not all potentially reactive cells are eliminated or inactivated.
How do T cells Affect the outcome of B cell activation in the periphery?
TWO SINGAL HYPOTHESIS
Signal 1 = Generated through the Ag receptor.
Signal 2 = mediated by CD40 and CD40L
What is B cell Receptor editing? (Central tolerance)
Is the attempt to modify receptor on B cell to be more “friendly”. If he cannot be reformed he undergoes apoptosis.
*receptor editing in B cells (Central tolerance) is a one shot deal.
How does peripheral tolerance: Anergy work?
Anorexic cells show a block in TCR-induced signal transduction.
- Lack of costimulation by B7/B72
- costimulation by inhibitory receptors
In Peripheral Tolerance (Anergy) , CTLA-4 does what?
- Competes with CD28 fro B71 and B72
- Keeps T cells in check
Mice lacking CTLA-4 will develop what?
- uncontrolled lymphocyte activation
- Massively enlarged lymph nodes and spleen
- Fatal multiorgan lymphocytic inflitrates
How does Peripheral tolerance: Apoptosis work?
Self reactive cells may be deleted from the repertoire.
- Activation in the absence of IL-2 can lead to death.
- Persistent Ag
- Activation-induced cell death
How does Peripheral tolerance: Suppression work?
T cell mediated suppression
- Supressive T cells inhibit T cell activation, T cell proliferation or T cell differentiation
The state of tolerance may be maintained by _______.
Immune regulation
_____ inhibits T cell proliferation. (Suppression)
TGF-beta
_______ & ______ inhibit macrophage activation. (Suppression)
IL-10 & TGF-beta
_______ inhibits actions of IFN-gamma. (suppression)
IL-4
How does Peripheral tolerance: Ignorance occur?
- 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.
* Ignorance is not typical a method the immune system uses.
Protein antigens administered subcutaneously or intradermally with adjuvants favor ________.
Immunity
High doses of antigens administered systemically without adjuvants tend to induce ______.
Tolerance
Oral administration of Ag favors ________ induction.
Tolerance
A state of ________ follows oral administration of antigen.
hypo-responsiveness
