Microc - Cal Williams

Front 1

Main mechanism for central Tcell tolerance:

Back 1

Negative selection in thymus

Front 2

5 mechanisms for peripheral Tcell tolerance:

Back 2

CIRIA
-Clonal deletion
-Inhibition
-Regulatory Tcells
-Ignorance
-Anergy

Front 3

What achieves clonal deletion?

Back 3

Fas/FasL killing

Front 4

What chieves Inhibition?

Back 4

CTLA4/B7 interaction

Front 5

What achieves regulatory Tcells?

Back 5

Tregs

Front 6

What is the basis for ignorance?

Back 6

Anatomical barriers

Front 7

What achieves anergy?

Back 7

Lack of the costimulatory molecule B7

Front 8

What are the special APCs in the thymus that present self peptides to naieve double positive Tcells?

Back 8

Medullary epithelial cells

Front 9

What does the fact that MHC Class II expression is highest in the medulla of the thymus tell us?

Back 9

That the medulla is where negative selection occurs.

Front 10

Where does positive selection occur?

Back 10

In the cortex.

Front 11

What is the highest level of maturity that most thymocytes reach in the thymus?

Back 11

Double positive, expressing the complete TCR.

Front 12

What % of double positive thymocytes fail positive selection? (bind too weakly)

Back 12

80%

Front 13

Of the 20% of thymocytes that succeed positive selection, What percent of those survive negative selection?

Back 13

5%

Front 14

So what % of thymocytes actually mature and get into the peripheral circulation?

Back 14

Only 5%

Front 15

What is a common manifestation of failure of self-tolerance?

Back 15

Arthritis

Front 16

What is Velocardiofacial syndrome?

Back 16

DiGeorge's syndrome

Front 17

What chromosomal deletion is associated with DiGeorge syndrome?

Back 17

22q11

Front 18

What are the symptoms of DiGeorge syndrome?

Back 18

-Hypoplastic thymus
-Hypoplastic parathyroids
-Heart defects
-Cleft palate
-Neuropsychiatric problems

Front 19

What problems are seen with the thymus in DiGeorge's syndrome?

Back 19

-Unable to positively select enough T lymphs (lymphopenia)
-Unable to achieve successful negative selection (autoimmune)

Front 20

What do aire Gene mutations result in?

Back 20

APECED

Front 21

What does Aire encode?

Back 21

A transcription factor expressed at high levels in the thymus.

Front 22

What type of inheritance is seen with aire Gene mutation caused disease?

Back 22

Autosomal recessive

Front 23

How many different mutations in the aire gene have been described?

Back 23

Over 40

Front 24

What specific cells express the aire protein?

Back 24

Thymic medullary epithelial cells

Front 25

What does aire protein expression allow thymic medullary epithelial cells to do?

Back 25

Express tissue-specific proteins for the intestines, liver, brain, eye, and pancreas.

Front 26

What are 2 ways that anergy is induced in peripheral tolerance?

Back 26

1. Lack of B7
2. Presence of CTLA-4

Front 27

What makes Tcells express CTLA-4?

Back 27

Low levels of B7

Front 28

What makes Tcells NOT express CTLA-4?

Back 28

High levels of B7

Front 29

What are 2 mechanisms of cell deletion in peripheral tolerance?

Back 29

1. Death receptors
2. Apoptotic proteins

Front 30

What induces death receptor expression on Tcells?

Back 30

Repeated stimulation by self antigen

Front 31

What are the death receptors on Tcells?

Back 31

Fas and FasL

Front 32

What is the result of Fas/FasL binding?

Back 32

Apoptosis

Front 33

What is ALPS?

Back 33

Autoimmune
LymphoProliferative
Syndrome

Front 34

What is the mode of inheritance for ALPS?

Back 34

Autosomal dominant

Front 35

What are the characteristic findings of ALPS?

Back 35

-Splenomegaly
-Lymphadenopathy (nonmalignant)
-Autoimmunity against RBCs
-Thrombocytopenia
-Hemolytic anemia

Front 36

What is the HALLMARK of ALPS?

Back 36

Large numbers of double negative Tcells in the peripheral blood.

Front 37

What is the source of the double negative Tcells in the peripheral circulation in ALPS?

Back 37

They are mature, AGED cells that escaped apoptosis

Front 38

What are the important cytokines secreted by Tregs?

Back 38

-Il-10
-TGF-beta

Front 39

What are the effects of IL-10?

Back 39

-Inhibits APC functions (decreased IL-12, B7)
-Inhibits macrophage activation

Front 40

What are the effects of TGFbeta?

Back 40

-Inhibits Tcell activation
-Inhibits macrophage activation

Front 41

What gene is ESSENTIAL for Treg development in the thymus?

Back 41

foxp3

Front 42

What do Tregs develop from?

Back 42

A double positive Tcell

Front 43

What happens if the foxp3 gene is absent?

Back 43

That is INCOMPATIBLE WITH LIFE!

Front 44

What is the disease associated with mutated foxp3?

Back 44

IPEX

Front 45

What is IPEX?

Back 45

Immune dysregulation
Polyendocrinopathy
Enteropathy

Front 46

What are the symptoms of IPEX?

Back 46

-Diabetes
-Bowel inflammation
-Diarrhea
-Wasting

Front 47

What is the CD marker for BCells that is present throughout their lifespan?

Back 47

CD19

Front 48

What is the CD marker present on Bcells at the beginning of their life, in pro-B cells?

Back 48

CD34

Front 49

What are 2 characteristic markers of immature B cells?

Back 49

IgM and CD19

Front 50

What are the characteristic markers on mature B cells?

Back 50

IgM, IgD, and CD19

Front 51

What is the mechanism of central tolerance for B cells? Where?

Back 51

Negative selection - in the bone marrow

Front 52

What are the 2 ways that Bcells that fail negative selection are taken care of?

Back 52

-Apoptosis
-Receptor editing

Front 53

If a Bcell doesn't get self antigen presented to it during maturation in the bone marrow, what will it do?

Back 53

Go to peripheral lymphoid follicles

Front 54

How do mature Bcells achieve self tolerance in peripheral lymphoid organs?

Back 54

By seeing Self antigen presented without the help of T cells, which causes anergy.

Front 55

What will happen to Mature B cells that do see self antigen in peripheral lymphoid follicles, and are partially activatd by Tcells?

Back 55

They will be excluded from the follicles and undergo apoptosis.