Immunology 11

Front 1

Which process in the generation of immune tolerance is more stringent?

Back 1

Positive selection in the thymus is more stringent. You much recognize MHC-self. Negative selection is less stringent

Front 2

If you don't have negative selection in the thymus what occurs?

Back 2

autoimmunity

Front 3

What does the AIRE protein do?

Back 3

AIRE controls expression of self antigens on thymic medullary epithelial cells.

Front 4

What occurs with a defeciency in AIRE?

Back 4

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.

Front 5

What are the two signals needed in activation of T-cell?

Back 5

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

Front 6

After which signal are cytokines released from the T-cell?

Back 6

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

Front 7

What is anergy?

Back 7

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.

Front 8

What is T-cell ignorance?

Back 8

T-cell receives signal 2 but no signal 1.

Front 9

How does T-cell inactivation occur?

Back 9

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.

Front 10

What therapy has incorporated the idea of T-cell inactivaton?

Back 10

Abaracept which is soluble CTLA-4 Ig has been approved for use in RA

Front 11

How does clonal deletion occur?

Back 11

Death by neglect or Activation Induced Cell Death

Front 12

Death by neglect

Back 12

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.

Front 13

Activation Induced Cell Death

Back 13

Persistance of antigen signal causes a Fas/FasL interaction. this causes activation of caspase-8 and Activation Induced Cell Death

Front 14

Autoimmune Lymphoproliferative Syndrome

Back 14

Genetic Fas deficiency, causes splenomegaly, lymphadenopathy, autoimmune hemologic disease, auto antibodies, increased circulating DN T-cells, not much inflammation, lymphomas later on possible

Front 15

What do Tregs do?

Back 15

Tregs preferentially suppress weakly activated T cells (autoreactive) over T cells in a strongly inflammatory environment.

Front 16

What are the mechanisms of Tregs?

Back 16

1. directly contacting cells (APCs, Tcells, Bcells)
2. secreteing suppressor cytokines (IL-10, TGF-B)
3. Killing other cells

Front 17

nTregs function

Back 17

(CD4+, CD25+)Suppress inflammatory responses in the periphery in a contact dependent manner, however induction of response in antigen-dependent. Constitutively express CTLA4

Front 18

What are the costimulatory molecules, cytokines, or proteins necessary for nTreg development, survival and function

Back 18

development - CD40 and CD28
survival - CD28 and IL-2
function - foxP3 (master transcriptional regulator)

Front 19

CTLA-4 defeciency causes what condition?

Back 19

autoimmunity.

Front 20

Cause and outcome associated with IPEX

Back 20

X-linked FoxP3 deficiency leads to immune dysregulation, polyendocrinopathy, bowel problems. Patients die young

Front 21

With low amounts of nTregs what diseases occur?

Back 21

endocrine diseases such as diabetes, thyroid diseases, Addison's disease

Front 22

Over expression of FoxP3 leads to..

Back 22

more rejection episodes, but also more likely to correct acute rejection

Front 23

aTreg

Back 23

(CD4+,CD25-) arise in periphery in response to antigen. function more or less the same as nTregs

Front 24

Tr1

Back 24

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

Front 25

What disease in associated with IL-10 gene polymorphisms?

Back 25

Lupus and other autoimmune conditions

Front 26

Tr1 regulatory T-cells help regulate what diseases?

Back 26

Diabetes, Colitis, Allergy

Front 27

Th3

Back 27

TGF-B secreting regulatory T-cell.

Front 28

Where are Tregs especially important?

Back 28

Important in the gut because the largest interface where the body encounters antigen, bacterial and dietary antigens

Front 29

What diseases are caused by a loss of tolerance in the gut?

Back 29

celiac disease loss of tolerance to dietary antigen
inflammatory bowel disease (Chron's) loss of bacterial tolerance

Front 30

Most important cytokines in immune tolerance

Back 30

IL2, IL10, TGF-B

Front 31

IL-2 deficiency

Back 31

lymphoproliferation and inflammation with reduction in nTregs

Front 32

IL-2 receptor polymorphism associated with what disease

Back 32

diabetes

Front 33

PTPN22

Back 33

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

Front 34

TGF-B1

Back 34

promotes generation of aTregs
in presence of IL-6-->production of inflammatory TH17 cells
in abscence of IL-6--> aTreg