Cellular Basis for Immunological Tolerance

Question 1

What is the result of loss of tolerance to self-antigens?

Answer 1

Autoimmune diseases

Question 2

What is a major problem concerning chronic infections and tolerance?

Answer 2

Chronic infections can lead to immunological tolerance against the infections agents and therefore recurring infections

Question 3

Where is central tolerance developed?

Answer 3

In the thymus: T-cells that react too strongly to self-antigens are eliminated

Question 4

.How do regulatory T cells play a role in peripheral tolerance?

Answer 4

Regulatory T cells are professional T cells that are designed to impose suppression on other T cells and accessory cells

Question 5

What are myeloid derived suppressor cells (MDSCs)

Answer 5

MDSCs are a group of myeloid cells that become potent immunoregulatory cells when exposed to inflammatory cytokines such as IFN-gamma and kill activated T cells to prevent further stimulation

Question 6

What happens to T cells that are inappropriately or insufficiently stimulated?

Answer 6

They become anergic

Question 7

How does AIRE aid the the process of central tolerance?

Answer 7

AIRE gene enables thymic stromal cells to express non-thymic genes. It allows for the presentation of self antigen to developing thymocytes. T cells that react too strongly die via apoptosis

Question 8

Where are regulatory T cells generated in the thymus?

Answer 8

Hassall’s corpuscle

Question 9

Where is AIRE expressed?

Answer 9

Primarily in the medulla of the thymus

Question 10

Where are nTregs generated?

Answer 10

nTregs are generated in the thymus and impose suppression of other immune cells (mainly T cells).

Since they are generated in the thymus, their antigen diversity is limited to mostly “self-antigens”

Question 11

What sorts of environmental factors manipulate iTregs?

Answer 11

food, commensal organisms, pathogens and tumors

Question 12

What two cytokines drive the differentiation of naive T cells into iTregs?

Answer 12

TGFbeta and IL2

Question 13

Presence of what cytokines inhbit the induction of iTregs?

Answer 13

inflammatory cytokines, primarily IL6

Question 14

Which vitamins serve as co-factors for the induction of iTregs

Answer 14

Vitamin A and D

Question 15

What are Tr1 cells?

Answer 15

Tr1 cells produce the immunosuppressive cytokine IL-10

Question 16

Which two cytokines induce the differentiation of Tr1 cells?

Answer 16

TGFbeta and IL-27. High levels of IL-10 are also sufficient to produce Tr1 cells.

They are NOT Foxp3

Question 17

WHat is IPEX?

Answer 17

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX): syndrome characterized by systemic autoimmunity, typically beginning in the first year of life. IPEX is cased by loss of dysfunction of FOXp3.

Question 18

What happens to T cells that are presented antigens in the absence of the crucial “second signal” - stimulation from CD28 (ligand is CD80/CD86).

Answer 18

They become anergic

Question 19

What is the purpose of CTLA-4?

Answer 19

CTLA-4 is expressed by T cells after activation and competes with CD28 for binding to B7 (and has a higher affinity for B7 than CD28).

In the natural sequence of antigen action of T cells, there is progressive increasing production of CTLA-4 as a regulatory mechanism to prevent runaway T cell proliferation

Question 20

What happens to people with deficient CTLA-4?

Answer 20

They die in utero, due to lethal autoimmune diseases

Question 21

How do clinicians try to suppress graft vs host disease after bone marrow transplants?

Answer 21

Though inhibition of co-stimulation done by using CTLA-4 in a “trans” manner to block T cell activation from the outside.

This is accomplished through the use of man-made biologic modified CTLA-4-Ig, which is now also tested in clinical trials to treat autoimmune disorders