Lecture 19: Immunologic Tolerance and Autoimmunity

Question 1

Central tolerance is induced in ____, and where

Answer 1

Immature self reactive lymphocytes in the primary lymphoid organs

Question 2

Peripheral tolerance is induced in ___ and where

Answer 2

Mature self reactive lymphocytes in peripheral sites

Question 3

Outcomes of immature lymphocytes in generative lymphoid organs that react with self Ag

Answer 3

Deleted
Change BCR specificity
Develop into Treg cells

Question 4

Outcomes of mature lymphocytes self reactive lymphocytes in peripheral tissues

Answer 4

Inactivated (anergy)
Apoptosis
Suppressed by Treg cells

Question 5

Which thymocytes are positively selected

Answer 5

Only those that are activated by MHC self peptide complexes below a certain threshold (affinity cant be too high, but it there has to be some affinity)

Question 6

What happens to B cells with no/weak/strong recognition of self Ag

Answer 6

None- survive
Weak- May lead to anergy
Strong- Apoptosis or receptor editing

Question 7

Kappa/lambda light chain ratio in peripheral B cells is

Answer 7

3:2

Question 8

Treg cells effect on T cells and B cells

Answer 8

May inhibit T cell activation by APC and differentiation

May prevent T cells from helping B cells produce Abs

Question 9

FoxP3 expression can be induced in naïve CD4 T cells by

Answer 9

Ag recognition in the presence of TGF-b, if IL-6 is NOT present

Question 10

Ag recognition in the presence of TGF-b and IL-6 does what

Answer 10

Prevents FoxP3 expression and induces expression of retinoic acid receptor (RAR) and then RORyt, causing Th17 cell differentiation

Question 11

Development and survival of Treg cells requires

Answer 11

IL-2 and FoxP3

Question 12

CD22 is a BCR inhibitory receptor phosphorylated by Lyn and recruits SHP-1 tyrosine phosphatase, attenuating (weakening) BCR signaling- defects in this cascade can cause what, and why

Answer 12

Autoimmunity, because BCR is not inhibited and may allow reaction to self Ag

Question 13

Peripheral B cell tolerance depends on

Answer 13

The balance of BCR signaling and BAFF signaling

Question 14

Which cells would be effected most if IL-2 was depleted and what may occur

Answer 14

Treg cells, autoimmunity

Question 15

What causes IPEX syndrome

Answer 15

FoxP3 deficiency- impaired production of Treg cells

Question 16

What is the effect of complement deficiency of C1q and C4

Answer 16

Decreased clearance of immune complexes and impaired tolerance of B cells

Question 17

What causes Autoimmune polyendocrine syndrome (APS) and what mechanism fails

Answer 17

Defects in AIRE gene- failure of central tolerance

Question 18

What is the function of medullary thymic epithelial cells, and what role does AIRE play

Answer 18

They have a key function as APCs
They express a large number of self Ags that are presented to developing T cells
Mutations in AIRE is associated with decreased expression of self Ag in thymus- leading to more self reactive T-cells being able to leave undetected

Question 19

Natural Treg cells are positively selected where via ___ TCR interactions with self Ags

Answer 19

In the thymus via strong TCR interactions

Question 20

Treg cells express ___ and ___ and are ___/___ positive

Answer 20

Express FoxP3 and CTLA-4

CD4+ CD25+

Question 21

CD25 is actually what

Answer 21

IL-2 receptor Alpha chain

Question 22

TGF-b promotes Th17 differentiation in cooperation with what cytokines

Answer 22

IL-1 and IL-6

Question 23

TGF-b inhibits development of what and activation of what

Answer 23

Differentiation of Th1/Th2 and activation of M1 macrophages

Question 24

TGF-b stimulates production of what

Answer 24

IgA, by inducing B cells to switch to that isotype

Question 25

What is typically the first step in autoimmunity development (besides the genetic susceptibility)

Answer 25

Inflammation or an initial innate immune response

Question 26

What genes are most strongly associated with autoimmunity

Answer 26

MHC

Question 27

Molecular mimicry

Answer 27

Method of microbial Ag initiating autoimmune disorder
Rheumatic fever is triggered by streptococcal infection and mediated by cross reactivity between streptococcal Ags and cardiac myosin

Question 28

Polyclonal (bystander) activation

Answer 28

Method of microbial Ag initiation autoimmune disorder
-Can cause polyclonal activation of autoreactive lymphocytes due to massive activation of naïve cells and release of cytokines

Question 29

Release of previously sequestered Ag

Answer 29

Microbes that kill cells can cause inflammation, the release of sequestered Ags (Ags that are not presented well in the primary lymphoid organs) causing autoimmunity

Question 30

Autoimmune disease are more common in women because

Answer 30

Estrogens exacerbate SLE (systemic lupus erythematosus) by altering the B cell repertoire in the absence of inflammation

Question 31

How can drugs alter immune repertoire

Answer 31

Penicillins and cephalosporins can bind to RBC membrane and generate neoantigen that elicits an Auto-Ag causing hemolytic anemia

Question 32

Blockade of TNF-a and autoimmunity

Answer 32

TNF-a has inhibitory effects on activated T cells

It induces autoimmunity