Self Tolerance

Question 1

Central and peripheral tolerance

Answer 1

Question 2

Possibilities for T cells and B cells which fail the negative selection step

Answer 2

Immature self-reactive T cells may develop into regulatory T cells to inforce self-tolerance.

Immature self-reactive B cells have the opportunity to rearrange their antigen receptor and “try again” at being self-tolerant. This is called receptor editing.

Otherwise, the cells apoptose.

Question 3

Main mechanism of central tolerance

Answer 3

clonal deletion

Question 4

Mechanisms of peripheral tolerance

Answer 4

Deletion

Suppression

Anergy

Question 5

Only a ___ may display intolerance to a non-protein self antigen.

Answer 5

Only a B cell may display intolerance to a non-protein self antigen.

Question 6

Central tolerance in T cell selection

Answer 6

Question 7

Antigen presentation in the context of negative T cell selection

Answer 7

Question 8

Tissue specific antigens or Tissue resident antigens (TRAs)

Answer 8

Not widely expressed and usually appear only within a specific tissue. The immune system relies upon AIRE and peripheral tolerance to avoid reactivity to these antigens.

Question 9

AIRE

Answer 9

Question 10

T_reg surface markers

Answer 10

Question 11

CD25

Answer 11

The IL-2 receptor

Question 12

T_regs are dependent upon ___ for growth and for long-term survival.

Answer 12

T_regs are dependent upon IL-2 for growth and for long-term survival.

Question 13

____ leads to activation of the T_reg phenotype.

Answer 13

Demethylation of the FOXP3 locus leads to activation of the T_reg​ phenotype.

Question 14

T_regs. Where do they come from?

Answer 14

Question 15

The majority of T_regs within an individual are ____ in origin.

Answer 15

The majority of T_regs within an individual are thymic in origin.

Question 16

Peripheral T_reg development depends upon ___ and ___.

Answer 16

Peripheral T_reg development depends upon TGF-β and IL-2.

Question 17

T_regs. What do they do?

Answer 17

Question 18

T_reg-derived effector cytokines

Answer 18

Question 19

Peripheral Tolerance diagram

Answer 19

Question 20

T cell anergy mechanisms

Answer 20

Question 21

Mechanism of T cell exhaustion

Answer 21

upregulation of PD-1 during states of chronic activation

Question 22

CTLA-4 not only binds to B7, but. . .

Answer 22

. . .pulls it out of the APC membrane and degrades it in a phagolysosome.

Question 23

FAS

Answer 23

May be upregulated on T cells during chronic activation. Binds to FAS-L.

Contains a cytoplasmic death domain which directly activates caspase 8.

Question 24

Deletion may occur upon antigen recognition in the absence of a second signal due to. . .

Answer 24

up-regulation of pro-apoptotic genes and down-regulation of anti-apoptotic genes.

Question 25

In receptor editing, . . .

Answer 25

. . . B cells re-express RAG-1/2 to mediate their additional ground of light-chain rearrangement.

Question 26

Central tolerance in B cells

Answer 26

Question 27

Peripheral B cell tolerance

Answer 27

Question 28

Ig heavy chain locus

Answer 28

Question 29

The TCR α chain and Ig light chain do not contain ____.

Answer 29

The TCR α chain and Ig light chain do not contain D segments (VDJ).

Question 30

Order of VDJ recombination

Answer 30

D to J, then V to DJ.

Question 31

The VDJ and C regions of an antibody are combined in. . .

Answer 31

. . . RNA splicing.

Question 32

Junctional diversity in VDJ recombination

Answer 32

When DNA is being recombined to make a random V region, the DNA is cut between V, D, and J. Before it is re-ligated, a few random nucleotides are added inbetween the V, D, and J regions. These are the N nucleotides.

P nucleotides are non-random and are simply the new complementary nucleotides added to fill in the sticky ends left by the restriction enzyme cut. This creates blunt ends on the 5’ and 3’ ends of the VD and DJ junction, which are where the N nucleotides are inserted.

Question 33

Junctional diversity diagram

Answer 33

Question 34

Enzymes responsible for junctional divserity

Answer 34

Artemis makes the cut

Tdt adds the nucleotides

Question 35

More than 25% of all B cells that produce Ig with lambda light chains are derived from an immature B cell precursor that has undergone receptor editing. If you analyzed the Ig light chain loci in this B cell, what would you find?

Answer 35

During B cell development, the first light chain locus to rearrange is the chromosome 2 kappa chain locus, first on one chromosome, and if that fails, then on the other chromosome, and if that fails, then one of the lambda light chain loci on chromosome 22 undergoes rearrangement, and if that fails the other chromosome 22 lambda locus will rearrange.

So, think: κ1 → κ2 → λ1 → λ2 → apoptosis

Question 36

CD25 is expressed on. . .

Answer 36

T regs always

activated T cells transiently

Question 37

A “normal” amount of blood T regs

Answer 37

~5%

Question 38

Parasthesias

Answer 38

Burning/chilling/tingling of skin. Due to interactions with cutaneous neurons. Lots of possibilities, but one is hypocalcemia via hypoparathyroidism.

Question 39

Mucocutaneous candidiasis is VERY common in chronic autoimmunity. Why?

Answer 39

Because anti-IL-17 and anti-IL-22 antibodies develop frequently in cases of chronic autoimmunity, and so the Th17 response is impaired, predisposing to fungal and bacterial infections.

Question 40

Hemophagocytic lymphohistiocytosis

Answer 40

Question 41

Titer

Answer 41

of 2-fold dilutions before undetectable.

Question 42

CD40-CD40L is involved in both. . .

Answer 42

B cell and Mphage activation → two phenotypes in X-linked Hyper IgM syndrome depending on where in the pathway the mutation is