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34 Cards in this Set

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  • Back
Which process in the generation of immune tolerance is more stringent?
Positive selection in the thymus is more stringent. You much recognize MHC-self. Negative selection is less stringent
If you don't have negative selection in the thymus what occurs?
What does the AIRE protein do?
AIRE controls expression of self antigens on thymic medullary epithelial cells.
What occurs with a defeciency in AIRE?
APECED, a rare autosomal, single gene disease. Patients develop diabetes due to lack of neg. selection against insulin-specific T-cells in medulla. Also develop autoimmune thyroid disease.
What are the two signals needed in activation of T-cell?
Antigen-specific cascade (signal 1) which is the binding of the TCR with antigen presented on MHC. Signal two is binding of T cell with co-stimulatory molecules principally B7-CD28, CD40-CD40L
After which signal are cytokines released from the T-cell?
After signal 2. Need to fully activate T-cell via upregulation of CD40 and CD28 on T-cell and CD40L and B7 on APC. This leads to threshold being met
What is anergy?
If a T-cell receives signal 1, but either no or reduced signal 2 then there is reduced tyrosine kinase phosphorylation, decreased Ca2+ influx, no activation of MAP kinases or NF-kappa Beta.
What is T-cell ignorance?
T-cell receives signal 2 but no signal 1.
How does T-cell inactivation occur?
CTLA-4 which is a homolog of CD28 competes for B7 on APC. This is a high affinity interaction that transduces a negative signal to the T-cell. No need to know what the antigen is to turn off T-cell.
What therapy has incorporated the idea of T-cell inactivaton?
Abaracept which is soluble CTLA-4 Ig has been approved for use in RA
How does clonal deletion occur?
Death by neglect or Activation Induced Cell Death
Death by neglect
At the end of an immune response. The elimination of antigen/signals causes the release of cytochrome c from mitochondria leading to the activation of caspase 9 causing cell death by neglect.
Activation Induced Cell Death
Persistance of antigen signal causes a Fas/FasL interaction. this causes activation of caspase-8 and Activation Induced Cell Death
Autoimmune Lymphoproliferative Syndrome
Genetic Fas deficiency, causes splenomegaly, lymphadenopathy, autoimmune hemologic disease, auto antibodies, increased circulating DN T-cells, not much inflammation, lymphomas later on possible
What do Tregs do?
Tregs preferentially suppress weakly activated T cells (autoreactive) over T cells in a strongly inflammatory environment.
What are the mechanisms of Tregs?
1. directly contacting cells (APCs, Tcells, Bcells)
2. secreteing suppressor cytokines (IL-10, TGF-B)
3. Killing other cells
nTregs function
(CD4+, CD25+)Suppress inflammatory responses in the periphery in a contact dependent manner, however induction of response in antigen-dependent. Constitutively express CTLA4
What are the costimulatory molecules, cytokines, or proteins necessary for nTreg development, survival and function
development - CD40 and CD28
survival - CD28 and IL-2
function - foxP3 (master transcriptional regulator)
CTLA-4 defeciency causes what condition?
Cause and outcome associated with IPEX
X-linked FoxP3 deficiency leads to immune dysregulation, polyendocrinopathy, bowel problems. Patients die young
With low amounts of nTregs what diseases occur?
endocrine diseases such as diabetes, thyroid diseases, Addison's disease
Over expression of FoxP3 leads to..
more rejection episodes, but also more likely to correct acute rejection
(CD4+,CD25-) arise in periphery in response to antigen. function more or less the same as nTregs
Treg with suppresion via IL-10 and TGF-B secretion. Development dependent on Ag exposure in presence of IL-10 in the periphery. Produces high IL-10 and no IL-4, some IL-5 and TGF-B
What disease in associated with IL-10 gene polymorphisms?
Lupus and other autoimmune conditions
Tr1 regulatory T-cells help regulate what diseases?
Diabetes, Colitis, Allergy
TGF-B secreting regulatory T-cell.
Where are Tregs especially important?
Important in the gut because the largest interface where the body encounters antigen, bacterial and dietary antigens
What diseases are caused by a loss of tolerance in the gut?
celiac disease loss of tolerance to dietary antigen
inflammatory bowel disease (Chron's) loss of bacterial tolerance
Most important cytokines in immune tolerance
IL2, IL10, TGF-B
IL-2 deficiency
lymphoproliferation and inflammation with reduction in nTregs
IL-2 receptor polymorphism associated with what disease
autoimmune susceptibility gene. gain of function mutation leading to more tyrosine phosphatase less TCR signaling, less IL-2 production --> susceptible to multiple autoimmune diseases and RA, but not Lupus
promotes generation of aTregs
in presence of IL-6-->production of inflammatory TH17 cells
in abscence of IL-6--> aTreg