Jitt # 6 Reading Chp. 15 315-319

Question 1

Immunological Tolerance

Answer 1

Defined as an unresponsiveness to an antigen that is induced by previous exposure to that antigen

Question 2

Self-tolerance

Answer 2

tolerance to self antigens

Question 3

autoimmunity/autoimmune disease

Answer 3

Immune reactions against self antigens that result in diseases

Question 4

In healthy individuals, why aren’t self antigens recognized by lymphocytes?

Answer 4

Lymphocytes that recognize self antigens early in development are killed or inactivated or the specificity of these lymphocytes is changed

Question 5

Central Tolerance

Answer 5

Maturation that occurs in the bone marrow and thymus for B cells and T cells respectively. Maturation occurs to ensure that maturing lymphocytes do not react to self. It is important to note that there are not many (if any) non-self antigens in central lymphoid organs. Peripheral lymphoid organs house non-self antigens.

Question 6

Peripheral Tolerance

Answer 6

Is induced when mature lymphocytes recognize self antigens and die by apoptosis, or become incapable of activation by re-exposure to that antigen.

Question 7

Treg

Answer 7

Regulatory T Cells, actively suppress self antigen-specific lymphocytes. Suppression occurs in secondary lymphoid organs and in nonlymphoid tissues; Arise from CD4+ lineage

Question 8

How does the anatomy effect immunological response?

Answer 8

Some barriers, testes and eyes, do not interact with lymphoid receptors. Some other areas of the body do not as well, but it is not well understood.

Question 9

Why is it important to understand tolerance in the context of CD4+ T cells?

Answer 9

Because not only are CD4+ important in cell mediated immunity, but they also activate humoral facets of immunity.

Question 10

Deletion/Negative selection

Answer 10

The process by which T cell receptors who recognize antigens with high avidity are deleted.

Question 11

Where does negative selection for T cells occur?

Answer 11

Occurs in double positive T cells in the thymic cortex and newly generated single-positive T cells in the medulla.

Question 12

Antigens in the thymus

Answer 12

Antigens in the thymus are typically only those present in certain peripheral tissues. Important for ensuring non-reactivity to self

Question 13

AIRE

Answer 13

Autoimmune regulator protein; Protein that is responsible for the presentation of peripheral tissue antigens. Secreted by thymic medullary epithelial cells; important in the process of negative selection

Question 14

APS1

Answer 14

Autoimmune polyendocrine syndrome I; multiorgan autoimmune disease caused by a mutation in the genes encoding for AIRE; Characterized by injury to the endocrine organs parathyroids, adrenals and pancreatic islets.

Question 15

What happens to some self reactive CD4+ cells that recognize self antigens in the thymus?

Answer 15

They differentiate into regulatory T cells specific for these antigens; they leave the thymus and inhibit against self reactive antigens in the periphery.

Question 16

What are the three mechanisms of peripheral tolerance?

Answer 16

Anergy, suppression by regulatory T cells and deletion

Question 17

Anergy

Answer 17

Functional unresponsiveness; Mature CD4+ T Cells that are exposed to an antigen in the absence of co-stimulation or innate immunity may make the cells incapable of responding to that antigen; prolonged signal 1 ( antigen recognition) without costimulator confers anergy.

Question 18

What are the three costimulators?

Answer 18

B7-1, B7-2, CD28

Question 19

Ubiquination and TCR in self-tolerance

Answer 19

Receptors that recognize self-antigens are ubiquinated and thus targeted for degradation by proteasomes or lysosomes; Cbl-b ubiquitin ligase important in T cells.

Question 20

DiGeorge Syndrome

Answer 20

Congenital absence a thymus. Results in low numbers of mature T cells in the circulation and peripheral lymphoid tissues.

Question 21

Thymocytes

Answer 21

Developing T Cells in the Thymus

Question 22

Which type of T cells mature into CD4+ or CD8+ in the thymus?

Answer 22

alpha/beta T cells

Question 23

What functions do DCs and epithelial cells play in Thymocyte maturation?

Answer 23

epithelial cells and DCs express MHCI/II in the thymus. Important for Thymocyte maturation.

Question 24

What function do thymic stromal cells, along with epithelial cells play in lymphocyte maturation?

Answer 24

They secrete chemokines and cytokines that are important for lymphocyte development. IL-7 is a growth factor. CCL21 and CCL19 are both recognized by CCR7 and mediate the movement of thymocytes through the thymus.

Question 25

Pro T Cell Stage

Answer 25

(CD8-, CD4-); Rag 1/2 first expressed here; Db to Jb rearrangement; Vb to DJb rearrangement to transition to Pre-T stage

Question 26

Pre T Cell Stage

Answer 26

Officially a Pre T Cell after Vb to DJb rearrangement; and expression of Pre-TCR.

Question 27

Pre TCR

Answer 27

Made up of TCR beta chain, invariant Pre T-alpha chain, CD3 and zeta proteins; mediates the selection of a correctly rearranged TCR B chain; Pre TCR mediates survival of T cell and contributes to proliferation; also contributes to the initiation of alpha chain rearrangement and the transition of double negative to double positive stage of thymocyte development; also has signals that limit other B chain to rearrange (allelic exclusion) along with the production of the Pre TCR b protein

Question 28

Double Positive Thymocyte stage

Answer 28

Occurs after Pre TCR stage. CD4+ and CD8+; CCR7 chemokine receptor activation (aids in the migration of thymocytes from the cortex to the medulla); Chemokines secreted by stromal cells; rearrangement of TCR alpha chain and gene expression; TCRab heterodimer expressed (caused by after TCR a expression); now available for positive selection.

Question 29

Late Pre T Stage

Answer 29

2nd wave of Rag genes expressed; TCRa rearrangement; Rag1/2 turned off by TCRab heterodimer during positive selection;

Question 30

TCR a rearrangement

Answer 30

Occurs in late Pre-T cell phase. Only V to J rearrangement; no allelic exclusion for alpha chain. May express two alpha chains; failure to rearrange alpha chain leads to no positive selection; results in deletion of TCR delta locus (cell no longer capable of being gamma delta T cell)

Question 31

Single Positive Thymocytes

Answer 31

Have either CD4+ (produce CD40 ligand) or CD8+(produce cytotoxic compounds)

Question 32

Positive TCR Selection

Answer 32

Occurs when a thymocytes TCR binds to self-peptide & self MHC with low avidity. Selects for its survival; non-recognition leads to apoptosis; MHCI/II-CD4+/CD8+ designation made here.

Question 33

Negative selection

Answer 33

The process by which thymocytes whose TCRs bind strongly to self peptide antigens in association with self MHC molecules are deleted. Eliminates autoreactive T cells.

Question 34

Which type of cells are involved in positive selection? Negative Selection?

Answer 34

Cortical epithelial cells (positive selection); DCs and medullary epithelial cells (negative selection)

Question 35

What is the role of CCR7 in thymocyte maturation?

Answer 35

CCR7 is a receptor for CCL21 and CCL19 (chemokines) which mediate the migration of double positive T Cells to the thymic medulla.

Question 36

Bim

Answer 36

Pro-apoptotic protein; TCR signaling causes induction of protein

Question 37

Pro-T Cell

Answer 37

Tdt expressed, Rag1/2 expressed in late pro- T; No TCR expression; DNA unrecombined; Cell surface markers c-kit, CD44+/CD25+; (No response to antigen)

Question 38

Pre- T Cell

Answer 38

Recombined B chain gene; VDJ rearrangement; B chain mRNA; Pre - T receptor (B chain/ pre-T alpha); cell surface markers CD44-;CD25+; c-kit. (no response to antigen)

Question 39

Double Positive T-Cell

Answer 39

Recombined B, a genes; [V(D) J-C]; B and A chain mRNA; membrane AB TCR; Cell surface marker CD4+, CD8+, TCR/CD3’˚; Response to antigen (positive and negative selection)

Question 40

Single Positive (Immature T-Cell)

Answer 40

Recombined B, a genes; [V(D) J-C]; B and A chain mRNA; membrane AB TCR; Cell surface marker (CD4+/CD8-) or (CD4-/CD8+) TCR/CD3hi;

Question 41

Naive mature T Cell

Answer 41

Recombined B, a genes; [V(D) J-C]; B and A chain mRNA; membrane AB TCR; Cell surface marker (CD4+/CD8-) or (CD4-/CD8+) TCR/CD3hi; Response to antigen: proliferation and activation in the periphery

Question 42

Nude Mouse

Answer 42

A mouse that does not have a thymus.