Who tend to be immunologically immature?
Children and elderly
What is avidity?
The total sum of strong or weak interactions between lymphocytes and antigens
When are both co-receptors CD4 and CD8 expressed on T-cells?
After a complete TCR is expressed on the T-cell between checkpoint 2 and 3
Where does positive selection occur for T cells?
what is positive selection consist of?
Cells that express both CD4 and CD8 are allowed to survive. Weak recognition of Class I or Class II MHC leads to survival. Also, after positive selection, the T-cells only express one class of MHC molecule (they go from double positive to single positive)
Where does negative selection occur?
What does negative selection consist of?
Any cell that recognizes self antigens with high avidity, either class I or class II MHC, will be killed through apoptosis Any cell that doesn't recognize self antigen at all will also be killed through apoptosis (death by neglect)
What do defects in negative selection lead to?
What is the AIRE gene?
AIRE is a transcription factor that drives the expression of numerous tissue-specific self peptides of peripheral organs.
What does a loss of AIRE result in?
auto-immune disease because of making a lot of auto-antibodies to organ specific antigens They also make autoantibodies to IL-17, which is important in controlling fungal infections
What is a T regulatory cell? Markers? Purpose?
Markers: CD4, CD25, Foxp3 Purpose: key regulatory molecules for peripheral tolerance
What are the mechaisms of peripheral tollerence? (3)
Anergy, suppression and deletion
How is ANERGY used in peripheral T cell tolerance (2 mechanisms)
T cell binds with MHC/self antigen: BUT 1) APC doesn't express B7 (because there was no inflammatory event) so T cell becomes anergic or 2) T cell expresses inhibitory co-receptor CTLA4/ITIM (caused by Treg), which binds to B7 and causes T cell to become anergic
Why would an APC not express B7?
If there was no inflammatory event, then the APC would not have gotten signals to express B7
How is SUPPRESSION used in Peripheral T cell tolerance? (2 mechanisms)
Contact Dependent: Tregs bind to mature T cells and induce them to express CTLA-4, and thus inhibit activation Contact Independent: Treg secrete high levels of TGF-beta and IL-10 that inhibit T cell activation
How does CTLA-4-Ig biologic immunotherapy work?
Fuse the extracellular domain of CTLA-4 with a modified Fc molecule. The CTLA-4 will essentially be placed on the T-cell of your choice and will inhibit that T cell by binding to CD80 of the APC and prevent 2nd signal (CD28 with B7)
What is Immune dysregulation, polyendocrinopathy, linked syndrom (IPEX)? Cause? Who does it affect? Symptoms?
Cause: mutation in Foxp3 and loss of T regulatory cells Affects: boys in infancy Symptoms: broad regional hyper-inflammatory response in the mucosa
How is DELETION used in peripheral T cell Tolerance?
Because of REPEATED stimulation by an antigen (likely for self peptides because they'll be a lot of them) pro-apoptotic factors are induced and T cell is killed. There is an extrinsic as well as an intrinisic mechanism for apoptosis.
What is Fas and FasL?
These are key apoptosis mechanisms used in the immune system. Used in extrinsic mechanism for T cell deletion.
What are the mechanisms of Central B cell tolerance? What does High and Low avidity with antigens lead to? (3)
Strong avidity leads to: Receptor editing (rearrangement of Ig L chains Deletion (negative selection by apoptosis) Low Avidity leads to: anergy
Where does Receptor editing take place?
Ig light chain of antibodies
Peripheral B cell tolerance: Where? Differences from naive B cells? (4)
Where: germinal centers Differences: short lifespan, defects in BCR signaling, defects in germinal centers, low parafollicular cortex migration
What is autoimmunity? What causes it? (2)
an immune response against self antigens, a failure of tolerance Cause: 1) inheritance of susceptibility genes which contribute to failure of self tolerance 2) environmental triggers may activate self reaactive lymphocites
A confluence of what three factor would most likely lead to autoimmune diseases?
1) Genetic susceptibility 2) Environmental triggers 3) uncontrolled immune response
While there are many potential causes of autoimmune problems, which gene was stressed in lecture as a common gene implicated in autoimmune diseases?
The gene encoding MHC
How can the environment trigger an autoimmune response? (2)
1) A microbe induces a costimulatory molecule to be expressed, thus a self-reactive T cell that otherwise would have been killed, is instead activated 2) molecular mimicry --> microbial peptide is similat to self peptide