Tolerance and Autoimmunity Flashcards
What is self tolerance?
Immune system is unresponsive to self cell components
What is the different in tolerance between T and B cells?
T cells tolerize earlier, to a higher threshold of activation, and last longer than B cells.
Where does central tolerance occur? What are the mechanisms?
In primary lymphoid organs, during the selection process of immune cells.
Clonal deletion, clonal anergy, and receptor editing in B cells (light chain)
What is clonal anergy? How can this be reversed?
When cells are unresponsive but not deleted. Can be reversed via IL-2, which upregulates CD28
What are the mechanisms of peripheral tolerance? Where does it happen?
Taking place in secondary lymphoid organs
- Clonal deletion
- Clonal anergy
How does clonal deletion occur?
3 ways:
- Activation-induced cell death
- Superantigens (1/2 are very similar)
- Apoptosis via Fas-FasL interaction
How do cells become anergized?
Cells receive TCR stimulation without costimulation via CD28/B7
What cytokines do Th1 cells produce?
IFNgamma and TNF alpha
IFNy inhibits Th2 functions
What cytokines do Th2 cells produce?
IL-4, IL-13 (induce b cells), IL-5 (eosinophils), IL-10 (anti-inflammatory)
IL-4 is antiinflammatory and inhibits Th1
What is the function of Treg cells and what cytokines do they produce?
Suppress activation of immune response via production of TGFb and/or IL-10
What are natural Tregs?
Cells generated in thymus based on intermediate affinity for self-MHC. Upregulate the Foxp3 transcription factor, and highly express CD4 and CD25 (beta chain of IL-2 receptor)
What is an induced Treg? How are they made?
An antigen-specific Treg produced in the periphery.
How is a FoxP3+ induced Treg made?
They are originally CD25-, but are induced by TGFb in the absence of IL6 (would make Th17), and begin secreting TGFb
What is a Th3 cell?
A FoxP3- Treg found mostly in the mucosal immune system. They produce IL-4 and IL-10(like Th2), but also make TGFb.
Thus, not all Treg cells utilize one particular marker.
How are immune-priviledged sites generally treated? Use testes as an example?
The tissues are tolerized.
Testes stromal cells express FasL, and can apoptose any immune cells entering the tissue.
How does maternal placenta not interact with fetus?
They are tolerant to eachother, since paternal MHC could cross-react
Give one example of autoimmunity being a good thing for RBC clearance?
IgG autoantibodies can bind senescent cell antigen and clear aged RBCs.
During what regenerative process has T cell autoimmunity been shown to play a role?
Neural regeneration following injury
What is an autoimmune disease?
Pathologic condition resulting from failure of tolerance mechanism to self antigens.
Can result from a defect in innate OR adaptive immunity
What types of immune responses are associated with organ specific vs systemic?
Organ specific: cellular
Systemic: humoral
What are two classes of genes which can affect one’s genetic predisposition to autoimmune disease?
- MHC association - can be a predictive marker for relative risk
- Non-MHC genes - including AIRE and FasL
What are some environmental factors influencing autoimmune disease development?
Geography - MS disease risk decreased towards equator
Infection
Anatomical injury - immune-privileged sites lose tolerance due to trauma
Hormonal - females more susceptible
Exposure to drugs, radiation, and toxins - i.e. SLE and UV light
How does molecular mimicry play into infection causing autoimmune disease?
If the antigen used to clear the infection looks alot like a self antigen, T cell tolerance might be lost and the immune system could begin attacking self.
I.e. Coxackie virus B4 and IDDM
What are two ways in which immune mechanisms can fail to cause autoimmune disease?
- Complement over-activation can cause cellular damage due to inflammation
- Treg cells fail to regulate disease manifestation
What is the autoimmune disease with highest prevalence?
Graves’ disease, followed closely by rheumatoid arthritis