6. Immunological Tolerance and Autoimmunity Flashcards
What two fates awaits T Cells that are self reactive in the generative (central) lymphoid organ (thymus in this case)?
Apoptosis or they become Treg Cells
What two fates await any self reactive lymphocyte in the peripheral tissues?
Anergy
Apoptosis
What apoptotic pathway occurs in immature T Cells that respond to self antigens presented in the Thymus?
Mitochondrial apoptotic pathway.
What type of cells express FOXP3?
Tregs
What is caused by antigen stimulation without adequate costimulation?
Anergy
What is the given example of “checkpoint blockade” cancer therapy?
Treatment of patients with anti-CTLA4 and anti-PD1 that block the receptors that would lead to anergy when T Cells respond to the cancer cells.
What receptor that is essential for survival of all T Cells is expressed in large amounts in Tregs?
CD25 (IL-2α Receptor)
What type of cell is allowed to survive after displaying high affinity to self antigens in the Thymus?
FOXP3+ T Cells (which then become Tregs)
What mechanism protects Treg cells from being apoptosed in the Thymus?
They produce anti-apoptotic molecules
What do Tregs do when they are activated by their antigen in the peripheral tissues?
They inhibit nearby T and B Cells to ensure they don’t respond to that antigen.
Where are induced Tregs formed?
Outside the Thymus, in the peripheral tissues
What cell type shares a close developmental relationship with iTregs?
Th17 cells
When would TGF-β induce FOXP3 expression, and when would it not?
TGF-β would induce FOXP3 expression when IL-6 is not present. If IL-6 is present, TGF-β and IL-6 work together to form Tregs.
What is the function of retinoic acid in T Cell differentiation?
Inhibits production of Th17 cells, and stimulates de novo generation of FOXP3+ Tregs from Naive CD4+ CD25- T Cells
What are the main cytokines produced by Tregs?
IL-4, IL-10, TGF-β
What cell membrane proteins are downregulated in APCs after Tregs inactivate them?
What ILs are up/downregulated?
CD40
CD80/CD86 (B7-1, B7-2)
IL-12 downregulated
IL-10 upregulated
What is the function of IDO?
Degrades tryptophan and inactivates dendritic cells
What happens to a B Cell in the bone marrow if it has high avidity for self antigens?
What if it has low avidity for self antigens?
High avidity = apoptosis OR receptor editing
Low avidity = anergy
What is the function of CD32?
It is an inhibitory receptor phosphorylated by Lyn, which attenuates BCR signaling. Prevents autoimmunity
What happens when AIRE goes bad?
Decreased expression of self-antigens (tissue restricted antigens / TRAs) in the Thymus
What kind of tolerance (central or peripheral) would a mutation in AIRE cause a deficiency in?
Central tolerance
How does CTLA-4 on a Treg cell decrease the activity of other T Cells?
It binds to B7 on dendritic cells and outcompetes the T Cells for their costimulator.
What happens when CTLA-4 doesn’t work?
Uncontrolled proliferation of T Cells
What gene polymorphisms are associated most strongly with autoimmunity?
MHC genes
Self reactive TCRs is not enough to trigger pathogenesis of T Cell autoimmunity. What other factor is also necessary?
Why is this necessary?
“Environmental Factors”
Such as infection, tissue injury, etc. Something to mobilize T Cells to the region.
Because the T Cells require activation by dendritic cells, and dendritic cells are only active as a response to environmental factors. If there are no environmental factors, the dendritic cells won’t produce CD80/86 and the self T Cell will become anergic.
What is the cause of Rheumatic Fever?
Streptococcal infection leads to cross reactivity between anti streptococcal antibodies and cardiac myosin. :(
What is the cause of Multiple Sclerosis?
T Cells react with Epstein-Barr, Influenza A, and Papilomavirus
What are the three general methods that microbial antigens can use to induce autoimmunity?
Molecular mimicry
Polyclonal (bystander) activation
Release of previously sequestered ags.
What exacerbates Systemic Lupus Erythematosus in mouse models?
(… and hopefully in humans as well, otherwise…)
Estrogens
What two drugs can bind to RBCs and create a “neoantigen” that leads to hemolytic anemia?
Penicillins and Cephalosporins
What kind of drugs can induce Multiple Sclerosis and Systemic Lupus Erythematosus in certain persons?
TNF-γ blockers.
