B cell tolerance Flashcards
(131 cards)
1
Q
How are peripheral T cell numbers maintained in mature individuals?
A
division of mature T cells outside the central lymmphoid organs
2
Q
Why is positive selection particularly important for a:b T cells?
A
ensures that an individuals T cells will be able to respond to peptides bound to one’s own MHC molecules
3
Q
What is the default fate of developing lymphocytes, in the absence of any signal being received from the receptor?
A
death by apoptosis
4
Q
Which cells in the bone marrow provide the signals for the differentiation of haematopoietic stem cells?
A
specialised nonlymphoid connective tissue stromal cells that are in intimate contact with the developing lymphocytes
5
Q
What are the 2 functions of the stromal cells in the bone marrow?
A
form specific adhesive contacts with the developing lymphocytes by interactions between cell-adhesion molecules and their ligands; provide soluble and membrane cytokines and chemokines that control lymphocyte differentiation and prolfieration
6
Q
What do HSCs first differentiate into?
A
multipotent progenitor cells
7
Q
What is the difference between HSCs and MPCs?
A
aren’t self renewing stem cells
8
Q
What cell surface receptor do MPPs have that binds to stromal cells?
A
FLT3
9
Q
Give examples of transcription factors that MPPs possess that are required for the development of multiple haematopoietic lineages?
A
PU.1 and c-kit
10
Q
What does differentation of the MPPs into the common lymphoid progenitor require?
A
signalling through the FLT3 receptor
11
Q
What 2 subsets of progenitor cell does the MPP produce that gives rise to all lymphocytes?
A
one unnamed- produces the ILC subsets and the common lymphoid progenitor
12
Q
What do B-cell committed CLPs give rise to?
A
pro-B cells
13
Q
Expression of what receptor accompanies the production of lymphocyte progenitors from the multipotent progenitor cell?
A
IL-7 receptor
14
Q
What induces the IL7 receptor expression?
A
FLT3 signalling and PU.1 activity
15
Q
What 2 polypeptides make up the IL-7 receptor?
A
IL-7 receptor alpha chain and the common cytokine receptor y chain
16
Q
What tyrosine kinase do all cytokine receptors with the common cytokine receptor y chain share?
A
Jak3
17
Q
What membrane bound cytokine present on bone marrow stromal cells is required f or the growth of HSCs and earliest B-lineage cells?
A
stem cell factor
18
Q
What receptor does stem cell factor interact with?
A
Kit
19
Q
What chemokine is required fro the early stages of B cell devleopment?
A
CXCL12 (stromal cell-derived factor 1 SDF-1)
20
Q
What is one of the roles of CXCL12?
A
reatin developing B cell precursors in the marrow microenvironment
21
Q
What is hte pro-B cell defined by?
A
induction of the B lineage specific transcription factor E2A
22
Q
What does E2A expression induce?
A
early B cell factor EBF
23
Q
What is the function of E2A and EBF?
A
drive the expression of proteins that determine the pro-B cell state
24
Q
Where do the earliest stem cells reside in the bone marrow?
A
endosteum
25
How do B cells migrate as they develop?
towards the central sinus of the marrow cavity
26
What are the stages of B cell development in order?
early pro-B cell; late pro-B cell; large pre-B cell; small pre-B cell; immature B cell; mature B cell
27
Where does development from an immature to mature B cell occur?
peripheral lymphoid organs
28
How is rearrangement of the heavy-chain locus initiated ?
E2A and EBF induce Rag-1 and Rag-2
29
When does D to J rearrangement occur?
mainly in the early pro-B cell stage
30
What is the function of Pax5?
targets the genes for CD19 and the gene for Iga ; induces expression of B-cell linker protein
31
How is Pax5 induced?
E2A and EBF
32
What indicates that Pax5 is required for commitment of the pro-B cell to the B cell lineage?
without Pax5 cells cannot develop further down the B cell lineage but can be induced to give rise to T cells and the myeloid lineage
33
What is the function of B-cell linker protein?
its a scaffold protein that is required for further devleopment of the pro-B cell and for signalling from the mature B cell antigen receptor
34
When does V-DJ rearrangement occur?
late pro-B cell
35
What defines the large pre-B cell?
expression of the complete immunoglobulin heavy chain
36
How does the large pre-B cell become a small pre-B cell?
by proliferation
37
What is seen in the small pre-B cell?
express the mu heavy chain alone in the cytoplasm as no longer express the surrogate light chains
38
What are the surrogate light chains?
lamda5 and VpreB
39
What happens once a B cell has successfully expressed a light chain gene?
immature B cell
40
What is seen on the surface of a mature B cell?
both mu and delta heavy chain expression
41
What are the earliest B-lineage surface markers?
CD19 and CD45R
42
What surface markers distinguish the pro-B cells?
CD43; Kit and IL-7R
43
What surface marker does the late pro-B cell start to express?
CD24
44
What surface markers is a pre-B cell distinguished by?
enzyme BP-1, Kit is no longer expressed
45
When does V to DJ rearrangement occur on both chromosomes?
if V to DJ rearrangement does not produce a functional H chain on the first chromsome
46
What makes up the pre-B cell receptor?
H chain with VpreB and lambda5
47
What associates with the pre-B cell receptor?
Iga and Igb
48
What does association of the pre-B cell receptor with the Iga and Igb chains do?
tells the cell to stop H rearrangement and undergo proliferation
49
Which type of light chain rearrangement occurs first?
kappa light chain
50
What is the difference between D to J rearrangement and DJ to V rearrangemetn?
D to J occurs on both chromosomes whereas DJ to V rearrangement occurs first on only one
51
When is TdT expressed in B cell development?
pro-B cell stage
52
Why are there less N-nucleotides seen in light cahins?
expression of TdT declines at the pre-B cell stage
53
What is the checkpoint that mediates the transition betwen the pro-B cell and pre-B cell?
formation of the pre-B cell receptor and signalling through it
54
How are the signals required for transition through the chekpoint created by the pre-B cell receptor?
form dimers or oligomers that generate signals
55
What downstream signalling molecules are required for signalling through the pre-B cell receptor?
BLNK and Btk
56
What allows the pro-B cell to become sensitive to IL-7?
signallling generated by the pre-B cell receptor stops further rearrangement of the heavy chain locus---sensitivity induces prolfieration
57
How does the pre-B cell receptor prevent a B cell from producing 2 receptors of different antigen specificites?
enforces allelic exclusion
58
How does the pre-B cell receptor enforce allelic exclusion?
reduces the expression of Rag1 and Rag2; causes Rag2 to be targeted for degradation; reduces access of the heavy chain locus to the recombinase machinery
59
How are many cells with different antigen specificites created from one pre-B cell?
after proliferation, all the cells undergo light chain rearrangements
60
How can several attempts at recombination of a light chain gene be made on one chromosome?
repeated rearrangements of unused V and J segments can occur
61
How is the k:l ratio in mature lymphocyte populations useful in clinical diagnostics?
an aberrant ratio indicates the dominance of once clone and the presence of a lymphoproliferative disorder
62
What is release of immature B cells from the bone marrow dependent on?
expression of S1PR1
63
How do B cells leave the marrow?
through sinusoids
64
What happens if the BCR encounters a strongly cross-linking antigen in the bone marrow?
development is arrested
65
What are the 4 possible fates of a self-reactive BCR?
receptor editing; cell death by apoptosis restuling in clonal deletion; anergy; immmunological ignorance
66
What determines the fate of a self-reactive BCR?
the interaction of the BCR with the self-antigen
67
What causes a B cell to undergo receptor editing?
if recognises a multivalent self antigen
68
What happens in receptor editing?
replacement of the light chain until a nonself reactive receptor is produced or there are no additional light chain V and J segments avaialable
69
What happens to immature B cells that encounter more weakly cross-linking self antigens of low valence such as small soluble proteins?
anergy
70
Where are anergic B cells detained?
T cell areas of peripheral lymphoid tissues and cannot access lymphoid follicles
71
Why should immunologically ignorant B cells be considered inert?
they can be activated when there is lots of inflammation or when self-antigen reaches high concentration
72
What would happen is the elimination of self-reactive cells was too efficient?
receptor repertoire might become too limited
73
Why are not all autoreactive B cells purged in the bone marrow?
only lyphocytes specific for autoantigens that are expressed in or can reach the bone marrow are affected
74
Why do B cells only become fully mature in the periphery?
provides an opportunity for immature B cells to encounter peripheral self antigen and undergo tolerance
75
How does the expression of sIgM and sIgD change between immature and mature B cells ?
immature have more sIgM than sIgD whereas for mature it is the opposite
76
Which cells produce BAFF most abundantly?
follicular Dcs
77
What are follicular DCs?
non-haematopoieitc cells resident in B cell follicles specialised to capture antigens for recognition by B cell receptors
78
What are the 3 receptors for BAFF?
BAFF-R; BCMA; TACI
79
What is the difference between BAFF-R and BMCA/TACI?
BMCA and TACI also respond to APRIL
80
What is important about APRIL?
IgA production
81
What 2 transitional stages do immature B cells in the spleen proceed through?
T1 and T2
82
What are T1 and T2 defined by>
the absence/presence of CD21
83
What happens to mice lacking BAFF?
cannot acquire CD21 and progress to T2
84
What is required to promote the final stages of B cell maturation in the periphery?
weak BCR signals and BAFF
85
What disease is linked to overexpression of BAFF?
Sjogrens
86
How can marginal B cells be identified?
very high levels of CD21 expression
87
What is a major determinant of whether a B cell will be follicluar or marginal zone?
the specificity of the BCR
88
What is the function of marginal zone B cells?
poised to make rapid responses to antigens or pathogens filtered from the blood- early line of defense for blood borne pathogens
89
What is expressed by fDCs to attract B cells to the follicles?
CXCL13 (binds to CXCR5)
90
What happens to mice lacking Syk and what does this indicate about its function in maturation?
have immature B cells but not mature B cells therefore a Syk-transduced signal from the BCR must be required for full B cell maturation
91
What indicates that continuous BCR expression is required for B cell survival?
clonal deletion of BCRs in mature B cells results in loss of all mature B cells
92
What part of the immune system are B-1 B cells part of
innate immune system
93
Where are B-1 B cells found in high numbers?
peritoneal and pleural cavities
94
What is the function of B1 B cells?
major source of natural antibodies- those constitutively produced circulating antibodies secreted prior to infection
95
What do most antibodies made by B-1 B cells recognsie?
capsular polysaccharide
96
What is one important feature of B-1 B cells?
can produce IgM antibodies wihtou help from T cells; although response can be enhacned by cooperation
97
What are most B-1 B cells derived from?
progenitor cells found in the fetal liver
98
How are B-1 cells renewed?
self-renewal
99
What is the difference between the dependence on other signals in B-1 cells and B-2 cells ?
B-1 cells do not need BAFF or IL-7
100
What is a difference between immune tolerance and immunosuppression?
immune tolerance is antigen specific whereas immunosuppression is non-ag specific
101
What is immunosuppression?
when an appropriate immune response does not happen resulting in harm to the organsim- infection or tumour
102
What is the deletion in scurfy mice?
deletion in the forkhead domain of FOXP3
103
How long does it take scurfy mice to die?
3-5 weeks
104
What does FOXP3 stand for?
forkhead box protein 3 gene
105
What is the only treatment for IPEX
bone marrow transplantation
106
What is CLP Pax5 expressing cell?
committed B cell precursor
107
Which B cells undergo VJ joining of the light chain locus?
small pre-B cells
108
When do B cells start to express CD45?
early pro-B cell
109
What cytokine is required for a cell to become a large pre-B cell?
IL7
110
When do B cells start to express CD19?
late pro-B cell
111
What are marginal zone B cells?
non-class switched memory B cells that populate the marginal zone which can differentiate into short lived IgM secreting plasma cells
112
What happens once a B cell has encountered an antigen?
naive B cells move from the mantle zone to primary follicle to start a germinal reaction
113
What is the name for B cells in the dark zone?
centroblast
114
What are the B cells in the light zone called?
centrocyte
115
What are the features of plasma cells?
don't express CD19; CD20; CD40; MHC-II or sIg, can no longer receive T cell help and are incapable of cell division
116
What happens to B cells that encounter self antigens in peripheral lymphoid tissue?
anergy if mature or Fas mediated apoptosis if transitional
117
What are the features of anergic B cells?
downregulate Cd21; express high levels of inhibitory receptors; downregulate lymph node homing CCR7 so leave follicle and die
118
What first identified the regultory potential of B cells?
transfer of splenocytes lacking B cells failed to prevent T cell induced delayed-type skin hypersensitivity, but if give splenocytes from a mouse already exposed to the antigen, don;t develop
119
Prpduction of what cytokine is linked to the regulatory function of B cells?
IL-10
120
What is the mouse model for Bregs?
no Breg deficient mouse model analogous to Scurfy
121
What is the phenotype for Bregs?
no single conclusive phenotype and no transcription factor analogous to FOXP3 foudn
122
What are other potential mechanisms by which B cells induce toelrance?
TGFb; IL-12; IL4; FasL expression
123
How can Breg function be induced?
with CD40L and CPG and IL-1b and IL-6
124
What do the factors that induce Breg function suggest about when they arise?
that they arise in the inflammatory site
125
What is the function of Breg?
suppress activated T cells and monocytes proliferation/cytokine secretion; induce Treg differentation
126
What are Tr1 cells?
IL-10+ regulatory T cells
127
How do Bregs carry out their functions?
IL-10 dependent; cellular contact is required
128
What diseases have been linked to decreased numbers and function of Bregs?
MS; ITP; SLe; RA
129
What are the risks with the therapeutic potential of immune regulation?
non-specific immune suppression- infection; tumours; autoimmunity; conversion to pathogenic cells
130
What diseases have ongoing trials into the use of Tregs as therapeticsc?
GvHD; transplantation and some autoimmune disorders
131
Why is it difficult to identify Bregs for studying them?
in order to stain for IL-10 you have to kill the cell
