Breakout (L7) Flashcards
Only cells with antigen-specific receptors can be tolerant. This limits the effects of tolerance to ___ and ___ cells
B and T cells
___: Tolerance that occurs early in lymphocyte development
Central Tolerance
Where does central tolerance occur for B cells? for T cells?
B cells - bone marrow
T cells - thymus
_____: allows for regulation of “escapees” of central tolerance
Peripheral Tolerance
What can occur if a cell escapes from both central and peripheral tolerance?
Auto-immune responses
Once a B cell starts to express ___ on the surface of the bone marrow, the immature B cell undergoes selection for self-reactivity
IgM
If the immature B cell expresses a self-reactive IgM on the surface of the cell, central B cell tolerance is induced by one which two mechanisms?
1) Clonal Anergy
2) Clonal Deletion
Clonal anergy typically occurs with ___ antigens
Clonal deletion typically occurs with a ___ or ___ antigens ; it involves arrested development followed by apoptosis
Clonal anergy = soluble antigens
Clonal deletion = particulate; cell-associated antigens
Once in the peripheral lymphatics, self-reactive B cells that escaped central tolerance receive _______ through the B cell receptor on cell surface
constant, low level stimulation
What helps maintain B cell in anergic/unresponsive state?
Chronic stimulation of BCR in absence of secondary signals
All the peripheral B cells require stimulation through a receptor for the cytokine ___ for survival
BAFF
Why do anergic B cells have a significantly short half life in the periphery?
Anergic B cells do not compete well with non-anergic mature B cells for the limited amount of BAFF in lymphatic system
Scientists have discovered that, in tolerizing signals that induce anergy, the ITAM motifs are ____
hypo-phosphorylated
In tolerizing signals that induce anergy, ITAM motifs are hypo-phosphorylated. This lack of complete ITAM phosphorylation results in altered signal, which leads to activation of ___ and ___, but not ___
NFAT; AP-1
NOT NF-kB
What is a major factor that renders the immature B cell as anergized and not activated?
Absence of NF-kB activation in immature B cells
Under pathological conditions, when a self-reactive, immature B cell is exposed to a membrane bound self-antigen for which they are specific, the ITAM motif becomes ______
hyper-phosphorylated
What are the effects of hyper-phosphorylation of ITAM motif in self-reactive, immature B cells exposed to membrane-bound antigen that they’re specific for?
1) Induction of BCR signal transduction cascade
2) Inappropriate activation of ERK1/2
The activation of ERK1/2 in the immature B cell results in the _____ and the _____
1) induction of apoptosis cascade
2) deletion of self-reactive B cell
During central T cell tolerance, T cell clones whose TCR strongly recognizes self-peptides present in MHC molecules undergo ___
apoptosis
Peptides presented in MHC molecules in the thymus are almost always what kind of peptides?
Self peptides
Where does peripheral tolerance of T cells occur?
Peripheral tissues (spleen and lymph nodes)
Primary stimulation of T cells (MHC/peptide-TCR) without secondary stimulation (B7-CD28) can result in functional inactivation of the T cell called ____
clonal anergy
What is required in peripheral T cell tolerance to stabilize IL-2 mRNA and stop it from being degraded?
B7-CD28 interaction
What renders a T cell anergic?
1_
True or False: Once T cells become anergic, they cannot be activated even if they encounter their specific foreign peptide/MHC molecule
True
(this is thought to be MAIN mechanism for induction of unresponsiveness to antigens in the periphery)
Repeated stimulation of activated T cells can cause T cells to die via _____
apoptosis (clonal deletion)
True or False: T cell tolerance is usually less rapid and prolonged compared to B cell tolerance
False - T cell tolerance is usually more rapid and prolonged compared to B cell tolerance
What subpopulation of T cells can inhibit activation of T cells by self peptide/MHC
Regulatory T cells
___: a protein initially found to be expressed in the thymus and shown to be responsible for increasing the expression of tissue-specific antigens in the thymus
AIRE
Where is AIRE expressed in high levels? low levels?
high levels: mTECS (Medullary thymic epithelial cells) of thymus
low levels: dendritic cells (thymus)
What three mechanisms does AIRE use to increase the expression of tissue-specific antigens?
1) works with chromatin-remodeling proteins to modify large parts of the chromosome, leading to increase in accessibility to TF
2) Directly increases transcription of genes by acting as a TF
3) Interacts w protein compexes on “stalled” tissue-specific promoters to induce RNAPII to complete transcription of tissue-specific gene
Tissue specific proteins that are expressed in the mTEC’s can be expressed on the ____ to induce deletion of developing T cells that are exposed to self antigen
HLA-Class 1
When mTECS secrete tissue specific proteins, these proteins are taken up by ____ cells
local thymic dendritic cells
- dendritic cells endocytose proteins and present them in HLA Class II, leading to deletion of developing T cells that are specific for self antigen in context of HLA class II
AIRE expression in the thymus leads to expression of self-antigens that are found ___ in the body and leads to deletion of these ____ T cells
thymus; self-reactive
Autoimmune Poly-endocrinopathy-candidiasis ectodermal dystrophy (APECED) is related to mutations in ___
AIRE
Three symptoms of APECED?
1) chronic mucocutaneous candidias
2) hypoparathyroidism
3) adrenal insufficiency
