B Cells 9

Question 1

what is the purpose of tolerance?

Answer 1

prevents immune system from destroying host tissue

Question 2

why do we need tolerance?

Answer 2

many random rearrangements used to create B and T cell receptors could be SELF-REACTIVE, so tolerance prevents them from circulating in bloodstream

Question 3

where does T cell development occur?

Answer 3

initially develop in the bone marrow, then mature in thymus

Question 4

what are developing T cells called?

Answer 4

thymocytes

Question 5

how do T cells mature?

Answer 5

by a rigorous selection process

Question 6

what are the 2 regions of the thymus?

Answer 6

1. cortex
2. medulla

Question 7

what are the 4 cell types in the thymus?

Answer 7

1. cortical epithelial cells
2. medullary epithelial cells
3. thymocytes
4. macrophages

Question 8

which regions of the thymus are thymocytes and macrophages in?

Answer 8

both cortex and medulla

Question 9

what type of cells are T cell precursors when they enter the thymus?

Answer 9

Double Negative cells –> don’t express CD4 or CD8

Question 10

describe how CD4 and CD8 receptor expression changes during development in the thymus and which regions of the thymus each step occurs in

Answer 10

1. double negative –> cortex
2. double positive (both CD4 and CD8) –> cortex
3. single positive (1 of CD4 or CD8) –> medulla
4. then leaves for circulation

Question 11

which part of the thymus do T cell precursors enter?

Answer 11

cortex

Question 12

what do T cells develop during development?

Answer 12

develop MHC restriction and undergo a process for self-tolerance

Question 13

what is positive selection?

Answer 13

selects FOR thymocytes with receptors that can bind self-MHC molecules, resulting in MHC restriction

Question 14

what is negative selection?

Answer 14

selects AGAINST thymocytes with high-affinity receptors for self-MHC/self-peptide complexes, resulting in self-tolerance

Question 15

describe the process of positive selection and 3 possibilities

Answer 15

1. cortical epithelial cells express high levels of MHC I and II
2. double positive T cells browse peptide MHC on the surface of these cells

(1) if TCRs can’t bind –> die by neglect
(2) if TCRs bind too strongly –> cells die bc too reactive to a self-peptide
(3) if TCRs bind low-just right –> positive selection to single positive stage

Question 16

what happens to the T cells that die due to improper binding?

Answer 16

macrophages in cortex clean up debris

Question 17

what percent of T cells will die bc they can’t bind?

Answer 17

90-96%

Question 18

what allows a double positive T cell to become a single positive T cell?

Answer 18

if TCR binds low to just right

Question 19

what type of single positive T cell occurs when a T cell binds MHC II with its CD4?

Answer 19

Becomes single positive CD4+ T cell

Question 20

what type of single positive T cell occurs when a T cell binds MHC I with its CD8?

Answer 20

Becomes single positive CD8+ T cell

Question 21

why is negative selection necessary?

Answer 21

ensures self-tolerance

Question 22

how does negative tolerance occur?

Answer 22

medullary epithelial cells express TF called AUTOIMMUNE REGULATOR (AIRE) which induces expression of many tissue-specific proteins in thymic epithelial cells which can be processed and presented on MHC I or II

then single positive T cells will browse self p:MHC on the surface of thymic epithelial cells

Question 23

where does positive tolerance occur?

Answer 23

in cortex

Question 24

where does negative tolerance occur?

Answer 24

in medulla

Question 25

what is another name for negative selection?

Answer 25

central tolerance

Question 26

what happens if single positive T cells don't bind self-p:MHC?

Answer 26

cell survives --> not self-reactive

Question 27

what happens if single positive T cells do bind self-p:MHC? 3 possibilities

Answer 27

1. usually clonal deletion --> self-reactive T cells die 2. clonal anergy --> self-reactive T cells inactivated 3. clonal editing --> another chance at rearranging genes to make non-self reactive TCR

Question 28

what is peripheral tolerance?

Answer 28

when self-reactive T cells escape negative selection in thymus

Question 29

how does peripheral tolerance occur?

Answer 29

anergy occurs when there is strong self-antigen signaling thru TCR in absence of costimulation, maintained by T_Reg

Question 30

why is only negative selection required for B cells?

Answer 30

no need for MHC restriction

Question 31

where does B cell development occur?

Answer 31

mainly in bone marrow, completed in periphery (including spleen)

Question 32

where does negative selection of B cells occur?

Answer 32

bone marrow

Question 33

describe the 3 possible outcomes of negative selection of B cells

Answer 33

BCRs are tested against self-antigens 1. clonal deletion of strongly autoreactive cells thru apoptosis 2. receptor editing --> reactivate recombination machinery 3. anergy

Question 34

what self-peptides are used for negative selection of B cells?

Answer 34

there is no AIRE-equivalent --> use self-Ag that are soluble proteins in circulation or presented on stromal cells, i.e. anything that is nearby

Question 35

any potentially self-reactive B cell that's been activated requires .....

Answer 35

any potentially self-reactive B cell that's been activated requires the activation from a T cell

Question 36

during negative selection, where does receptor editing of potentially autoreactive receptors occur?

Answer 36

light chains

Question 37

why do we need receptor editing? what 2 types of editing can be used?

Answer 37

a functional Ab may bind to self antigens --> must turn on recombination machinery as a "last-ditch effort" to salvage the rearrangement or inactivate the self-reactivity can implement COMBINATORIAL and JUNCTIONAL diversity

Question 38

what happens when B cells leave the bone marrow?

Answer 38

they are still immature --> go to the spleen for further maturation

Question 39

what happens when B cells leave the spleen?

Answer 39

they are mature and migrate to the lymphoid follicles - express high levels of IgM/IgD on surface - negative selection --> peripheral tolerance - recirculate btwn blood and lymphoid organs

Question 40

what is the half-life of mature B cells in periphery?

Answer 40

4.5 months

Question 41

what are the 3 results of central tolerance

Answer 41

1. clonal deletion 2. receptor editing 3. clonal anergy

Question 42

what are the 3 results of peripheral tolerance?

Answer 42

1. anergy 2. deletion 3. immune regulation

Question 43

what are the 2 results of defects in tolerance?

Answer 43

1. organ-specific autoimmunity 2. systemic autoimmunity

Question 44

what is organ-specific autoimmunity?

Answer 44

predominant injury of an organ or tissue

Question 45

what is systemic autoimmunity?

Answer 45

injury of many different tissues

Question 46

what are the 2 mechanisms of autoimmunity?

Answer 46

1. cell-mediated autoimmunity 2. Ab-mediated autoimmunity

Question 47

what is cell-mediated autoimmunity (4)

Answer 47

1. mostly T cell mediated 2. transferable by T cell transfer 3. sensitive to thymectomy 4. MS, T1D

Question 48

what is Ab-mediated autoimmunity? (3)

Answer 48

1. mostly Ab-mediated 2. transferable by serum 3. lupus