Lecture 19

Question 1

Define central tolerance

Answer 1

Ensures that mature lymphocytes are NOT REACTIVE to self antigens in primary lymphoid organs

Question 2

Define peripheral tolerance

Answer 2

Needed to prevent activation of these potentially dangerous lymphocytes in the tissues (peripheral sites)

Question 3

What are the fates of lymphocytes that recognize self antigens in both central and peripheral tolerance?

Answer 3

Central: deleted (apoptosis), change BCR (B cells only), develop into Treg cells

Peripheral: inactivated (anergy), deleted (apoptosis), suppressed by the Treg cells

Question 4

What happens when there is TCR signaling in immature T cells in the thymus?

Answer 4

Mitochondrial pathway of apoptosis is triggered; negative selection

Question 5

What kind of cell does this describe? CD4+, CD25+, CTLA4+

Answer 5

Treg cells that express FOXP3 transcription factor

Question 6

What is the process of receptor editing in B cells?

Answer 6

Rearrangement and replacement of the IgL-chain (lamda) genes; occurs until non-self-recognizing receptors are produced or the cell dies; this process changes the specificity of their BCRs when immature B cells recognize self Ags

Question 7

What is the result of weak recognition of self Ags by B cells in the bone marrow?

Answer 7

Anergy (functional inactivation); these cells have a reduced lifespan and fail to enter the follicle, but are allowed to migrate into peripheral compartment

Question 8

What are the 2 pathways for apoptosis of self-reactive lymphocytes? What initiates each pathway?

Answer 8

Mitochondrial (intrinsic) Pathway: initiated by cell injury, deficiency of growth factors/survival signals, DNA damage, and protein misfolding

Death Receptor (extrinsic) Pathway: Fas receptor/Fas ligand, TNF receptor/TNF

Question 9

What are the ways Treg cells can mediate peripheral resistance?

Answer 9

May inhibit T cell activation by APCs, inhibit T cell differentiation into CTLs, prevent T cells from providing help to B cells in the production of Abs

Question 10

Where can FOXP3+ Treg cells be generated from?

Answer 10

Thymus from immature lymphocytes and peripheral T cells (induced Treg cells; iTreg cells)

Question 11

How are iTreg cells generated?

Answer 11

FOXP3 expression is induced by TGF-beta in naive CD4+ cells; Ag recognition in the presence of TGF-beta induces FOXP3 if IL-6 is NOT present; Ag recognition in the presence of both TGF-beta and IL-6 prevents FOXP3 expression and instead induces the expression of the retinoic acid receptor (RAR), related orphan nuclear receptor ROR-gamma-t expression, and Th17 differentiation

Question 12

Discuss the CD22 inhibitory receptor in B cells

Answer 12

It is phosphorylated by Lyn and recruits SHP-1 tyrosine phosphatase, attenuating BCR signaling; defects in Lyn tyrosine kinase, SHP-1 tyrosine phosphatase, and CD22 receptor leads to autoimmunity

Question 13

If you have high expression of BAFF and low BCR signaling, what happens to the B cell in peripheral tolerance?

Answer 13

B cell matures; low BAFF and high BCR signaling results in apoptosis

Question 14

What does a AIRE deficiency cause?

Answer 14

Autoimmune Polyendocrine Syndrome; failure of central tolerance; decreased expression of self-Ags by medullary thymic epithelial cells (function as APCs in thymus) needed for selection of T cells

Question 15

What does a FOXP3 deficiency cause?

Answer 15

IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) Syndrome; impaired production of Treg cells

Question 16

What does complement deficiency of C1q and C4 cause?

Answer 16

Decreased clearance and impaired tolerance induction by apoptotic cells

Question 17

What do CTLA-4 polymorphisms cause?

Answer 17

Altered immune signaling, failure of anergy in CD4+ T cells; polymorphisms associated with several autoimmune diseases such as type 1 diabetes and Grave’s disease

Question 18

What deficiencies are associated with breaking central tolerance?

Answer 18

AIRE

Question 19

What deficiencies are associated with breaking peripheral tolerance?

Answer 19

C1q, C4, CTLA-4, Fas/FasL, FOXP3, IL-2/IL-2R alpha/beta, SHP-1

Question 20

What does Fas/FasL deficiency cause?

Answer 20

Defective deletion of anergic self-reactive B cells, reduced deletion of mature CD4+ T cells; autoimmune lympho-proliferative syndrome (ALPS)

Question 21

What does IL-2/IL-2R alpha/beta deficiency cause?

Answer 21

Defective development, survival or function of Treg cells

Question 22

What does SHP-1 deficiency cause?

Answer 22

Failure of negative regulation of B cells

Question 23

What could blocking of signaling in the TCR complex be the cause of?

Answer 23

Recruitment of phosphatases to TCR complex, activation of ubiquitin ligases that degrade signaling proteins, engagement of inhibitory receptors CTLA-4

Question 24

When T cells recognize self Ags, what is responsible for terminating the T cell responses?

Answer 24

Inhibitory receptors of the CD28 family; main one is CTLA-4

Question 25

What is the cell-intrinsic mode of CTLA-4 action?

Answer 25

Engagement of CTLA-4 on a T cell may deliver inhibitory signals that terminate further activation of that cell

Question 26

What is the cell-extrinsic mode of CTLA-4 action?

Answer 26

CTLA-4 on Treg cells or responding T cells bind to B7 molecules on APCs or makes unavailable to CD28 and blocking T cell activation

Question 27

What is the function of immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO)?

Answer 27

Suppresses T-cell responses and promotes immune tolerance by mechanisms of tryptophan starvation

Question 28

What is the function of TGF-beta?

Answer 28

Inhibits proliferation and effector functions of T cells, inhibits activation of M1 macrophages, stimulates production of IgA, promotes tissue repair by stimulating collagen synthesis after immune/inflammatory responses

Question 29

What is the first step in the development of autoimmunity?

Answer 29

Inflammation or an initial innate immune response

Question 30

What are ways microbial Ags can initiate autoimmune disorder?

Answer 30

Molecular mimicry, polyclonal (bystander) activation, release of previously sequestered Ags

Specific examples on slide 49

Question 31

T/F: Autoimmune diseases are much more common in men than in women

Answer 31

False; much more common in women than men