Immune Regulation Flashcards
Why is IL-2 such a crucial cytokine?
It has autocrine and paracrine function to allow growth and differentiation of itself and the adjacent cells (T and non-T)
What are the three CRUCIAL surface molecules that are uporegulated after T-cell activation?
CD40L- to activate B-cells (give signal 2)
VLA4 - to traffic to the infected tissue
IL-2- to allow differentiation of the T and non-T cells in the area
By what order of magnitude to T cell populations expand upon activation?
1-3 orders of mag
What is a cytokine storm?
large releases of cytokines that overstimulate the innate AND adaptive immune system (IFN and TNF) leading to systemic inflammation
What cell releases IL-12? What type of cell does it usually affect and what is the result?
Macrophages and DCs release it to increase NK cells and to convert T-cells into Th1
What transcription factor has a rapid spike within the first hour or two of the infection to allow proliferation of T-cells?
c-Fos
What occurs during the initial phase of an immune response to influenza?
There is a rapid mobilization and activation of effector T-cells (you will see max level of CD40?, IL-2, IL-2R)
Starting at about 12 hours and peaking at 3 days, what event reaches its maximum level?
DNA synthesis because T-cells are dividing and making copies
Starting at about 4 days post infection, the levels of 3 molecules start to rise. These molecules contract the T-cell response. What are they?
- Fas
- CTLA-4
- PD-1
What is the general role of CTLA4?
It outcompetes with CD28 to bind B7-1/B7-2 (CD80/86) essentially blocking signal 2 for T-cell activation
What is the basic role of Fas?
When Fas on a T-cell encounters fasL there is a potent fas-mediated cell death signal and the cell dies
Why is there a spike in VLA4,5,6 about a week after the infection?
This is the homing molecule of effector and memory T-cells to recirculate them
After a viral infection is contained and the number of infected cells is decreased, there is a _____________________ in the number of influenza specific T-cell numbers.
dramatic reduction
When antigen specific T-cells are reduced after an infection is cleared, do they go back to base level?
No because some will become memory cells. (1 specific T-cell–>1000s–>about 200)
What are the four major mechanisms that account for the decrease in effector T-cells?
- Reduced IL-2
- Upregulated Fas
- Expression of inhibitory molecules (CTLA4)
- differentiation of effector cells to memory cells
What is the effect of removing IL-2 after an infection is cleared?
Many of the effector T-cells starve and go through apoptosis
What is the effect of upregulating Fas, PD-1 and CTLA4 after clearing an infection?
These reduce activation potential of more T-cells
What do CTLA4 and PD-1 elicit in the cell to stop T-cell activation?
They release phosphatases which de-phosphorylate key signalling molecules rendering them inactive
If there is a deficiency in Fas or fasL, what disorder will the patient have? What is it associated with?
They will present with ALPS (autoimmune lymphoproliferative syndrome) and will have a lot of CD4-/CD8- T cells
What T cell does the transcription factor Foxp3 differentiate?
A mutation in Foxp3 would lead to what?
Treg
A mutation would lead to increased levels of autoreactive cells because Treg checks to ensure cells are not autoreactive before they leave the thymus
If the Treg encounters a T-cell that recognizes a self-antigen in the thymus, what does it do?
It inhibits T-cell activation
If the Treg encounters a T-cell that is self-reactive in the LN, what does it do?
It released inhibitory cytokines to inhibit the effector functions of the T-cell
What are the three ways that Treg maintain peripheral tolerance to self-proteins?
- inhibitory cytokines (in periphery)
- inhibiting T-cell activation (thymus)
- dampening inflammation
Tregs are a subset of what type of cell?
CD4+ and is dependent on IL-2 for its survival and development
What disorder is caused by a mutation in Foxp3?
IPEX
What inhibitory cytokines are secreted by Treg?
IL-10 and TGFb
What is an ITIM? What cells would you find these on?
Immune Tyrosine Inhibitory Motifs found in NK cells, T-cells, and B-cells
They are tyrosine phosphorylated after specific receptor cross-linking and then associate with phosphatases that remove phosphates from tyrosine kinase dependent signaling molecules
What are the major phosphatases used to turn off lymphocyte activation signal cascades?
SHP1, SHP2, SHIP
What two surface molecules on the B-cell have ITIMs?
FcgammaRIIb and CD22 (binds SHP-1 and SHIP)
For intense inflammatory responses, what dose of IVIG is appropriate?
1-2g/kg
How does IVIG sialylated alpha2-6 suppress the immune system?
It upregulates inhibitory Fc receptors on macrophages and monocytes
What does a mutation in fas/fasl result in?
What is the disorder called?
What will the patient present with?
lymphoproliferative diorder in which the cells are activated and expand without control.
ALPS (lots of DN cells)
They present with splenomegaly (because of the excess of lymphocytes in the spleen)
APECED results from a mutation in what?
AIRE which presents self-tissue from other parts of the body to T-cells in the thymus to ensure they are not autoreactive
What problem is associated with IPEX? It is a mutation in what TF?
immune system that destroys itself because it lacks Treg
