B cell development / differentiation upon activation (Exam III) Flashcards
1
Q
B cell development / differentiation
A
T cell dependent interactions
2
Q
What phases of B cell development are in the BM?
A
Repertoire assembly
Negative selection
3
Q
What phases of B cell development are in the secondary lymphoid organs and circulation?
A
Positive selection
Searching for infection
Finding infections
Attacking infection
4
Q
List the B cell development order
A
Repertoire assembly
Negative Selection
Positive selection
Searching for infection
Finding Infection
Attacking infection
5
Q
Repertoire assembly
A
Generation of clonally expressed B cell receptors in the bone marrow
6
Q
Negative selection
A
Alteration, elimination or inactivation of B cells receptors that bind to components of the human body
7
Q
positive selection
A
promotion of a fraction of immature B cells to become mature B cells in the secondary lymphoid tissues
8
Q
searching for infection
A
recirculation of mature B cells between lymph, blood, and secondary lymphoid tissues
9
Q
finding infection
A
Activation and clonal expansion of B cells by pathogen derived antigens in secondary lymphoid tissues
10
Q
attacking infection
A
Differentiation to antibody-secreting plasma cells and memory B cells in secondary lymphoid tissue
11
Q
Pro B cell stages
A
- Early Pro B cell
- Heavy chain rearrangement
12
Q
Pre B cell stages
A
- Check point
- Light chain rearrangement
- Second checkpoint
13
Q
Immature B cell phase
A
- Immature B cell
14
Q
Early pro B cell
A
commits to B cell lineage
15
Q
Heavy chain rearrangement
A
Generates heavy chain gene diversity in pro-B cell population
16
Q
First checkpoint (development of B cell)
A
Selects for functional heavy chains
17
Q
Light chain rearrangement
A
Generates light chain gene diversity in pre- cell population
18
Q
Second checkpoint (B cell development)
A
Selects for functional light chains
19
Q
Immature B cell stage
A
Makes functional IgM
20
Q
Pre-B cell receptor testing, would be considered to be in what phase of B cell activation?
A
First checkpoint
21
Q
Second checkpoint
A
functional rearrangement of light chains
22
Q
what which point is BTK required?
A
first checkpoint - testing of Pre - B cell receptor
23
Q
Pre B cell receptor (intracellular expression)
A
- Signals from a properly assembled Pre B cell receptor, induces allelic exclusion at other heavy chain locus
- surrgoate light chain takes place of rearranged light chain
- allows for testing of the heavy chain
24
Q
surrogate light chain composition (PRE-B cell receptor
A
- VpreB
- Labmbda 5
25
B cell receptor surface expression
Fully formed B cell receptor has both heavy and light chains
26
early pro B cell survival
H - chain rearrangement
- D-J rearrangement on both chromocomes
(if positive, moves on to *late* pro B cell phase)
27
Late pro B cell
Heavy chain rearrangement
- V-DJ rearrangement on first chromosome (if positive, signaled to survive and become Pre B cell)
- if ^ didn't work, V-DJ rearrangement on second chromsome (if positive, signaled to survive and become Pre B cell)
- If neither worked, signaled to die by apoptosis: 50% of cells
28
Pre B cell light chain rearrangement order
1. Rearrange K on first chromosome
2. Rearrange K on second chromosome
3. Rearrange Lambda on first chromosome
4. Rearrange Lambda on second chromosome
If any of these worked, cell becomes immature B cells. If not - Apoptosis
29
As many as _ successive attempts can be made at successful rearrangement of the _ chain
5; kappa
between its V-J
30
Immature B cell selection:
Immature B cell undergoes Negative selection.
**Still bone marrow **
**Receptor editing** allows the immature B cell more chances to make a non-autoreactive BCR (**editing only in light chain**)
*Immature B cell continues to rearrange light chain genes*
**Immature B cell makes a new light chain and thus an IgM with a different specificity **
- if the new receptor is NOT self-reactive, the B cell leaves the bone marrow.
1. this cell moves into the blood and expresses IgM and IgD, and can search for antigens for activation.
- if the new receptor is self reative, light chain genes continue rearranging.
1. successive new receptors are self reactive. no further rearrangement are possible and the immature B cell undergoes apoptosis
31
Maturation of B cells
- Immature B cells leave the bone marrow and enter circulation, secondary lymphoid organs, and lymph
- to survive and mature, immature *B cells must enter lymphoid follicles *
- Interaction with Follicular dendritic cells (FD) provides the required maturation and survival signals - **positive selection**
- competition with other B cells is the limiting factor for space in the follicle
32
B cell interaction with Follicular dendritic cells
provides the required maturation and survival signals - **positive selection.**
33
B cell precursors rearrange its immunoglobin genes
Generation of B cells receptors in the bone marrow
34
immature B cell bound to self cell surface antigen is removed from the repertoire
negative selection in the bone marrow
35
mature B cell bound to foreign antigen is activated
migration of B cells to peripheral lymphoid organs and activation (for positive selection)
36
Activated B cells give rise to plasma cells and memory cells
antibody secretion and memory cells in bone marrow and lymphoid tissue
37
Plasma cell - IgM
antibody secretion
38
IgG Expressing B cell
Isotype switching
39
High affinity Ig-Expressing B cell
Affinity Maturation
+
Memory B cell
40
from naive to activated to differentitated
1. Antigen recognition
- naive (IgM, IgD) B cell + antigen
2. Helpter T cells, other stimuli
- Activated B cells
3. B cell and proliferation and differentiation
**- proliferation
1. antibody secretion
2. isotype switching (AID)
3. affinity maturation (AID)
4. memory B cell
41
Memory B cell vs B plasma cell
Plasma cell - secretes antibodies off the surface
memory cell - antibody remains on the surface of the cell
42
how does antigen get noticed by B cells
- Antigen arrives from tissues via affarent lymphatics into lymphoid organs (follicle)
1. small antigens delivered to follicles via conduits
- May be picked up by (conventional) denritic cells in medulla and migrate to lymphoid organs (follicle)
- Larger antigen taken up by macrophages in subscapular sinus and denritic cells in medulla and travel to follicle
43
follicular dendritic cells display
intact antigens on their cell surface so that B cells receptors can bind to them and become activated
44
enigmatic dendritic cells
storage vessels for antigens.
Ready for B cell stimulation.
45
follicular dendritic cells express:
2 types of different complement receptors that bind to intact antigens or pathogens that are coated with complement opsinins.
- CR1
- CR2
46
two types of antigens activate B cells
- T dependent antigens - Require T cell help for production of antibodies
- T independent antigens - no requirement for T cell help
47
antigen binding site of the BCR
consists of the heavy and light chain in the variable region
48
BCR signaling requires the assistance of
the signaling machine IgA+IgB
49
B cells become activated when their receptors are cross linked by antigens
antigen binding site binds with high affinity to a given antigen. if that antigen is repeated on the surface of the bacteria/pathogen, then the erceptors of the B cells may express cross linkage.
Cross linkage - the receptors are brought together, so that the signal can be amplified by the fact that many B cell receptors are being triggered at the same time.
50
Clustering of antigen receptors allows receptor associated kinases to phosphorylate the ITAMS
Syk binds to doubly phospjorylated ITAMs and is activated on binding
51
Much like T cell activation, B cell activation requires cross linking (clustering) and association with signaling with signaling adapters
The signaling cascade is initiated from the ITAM domains in IgA, and IgB
52
b cell receptors perform crosslinkage through antigens which leads to
change in gene expression in nucleus
53
BTK
necessary for activation of the signaling cascade
54
downstream of the signaling cascade, these trancsription factors are activated
- NFAT
- NFkB
- AP-1
move to the nucleus where they initiate changes in gene expressions
55
the signaling thorugh of BCR through IgA and IgA requires
BTK
56
BCR triggering is greatly enhanced by
- B cell co-receptor
- CD40/CD40 ligand
57
B cell co-receptor
- CDR19/CR2/CD81 (complex)
- increase BCR signal by up to 10,000 fold
- work best with **complement** labeled antigens bringing together complement receptors and BCR
58
CD40/CD40 lignad
Interaction with T cells
- essential for **T cell help**
- required for isotype switching and affinity maturation
59
B- Cell complex (CR2, CD19, CD81)
if an antigen is bound by complement, it will bind to CR2 and then reqruit the rest of the complex to enhance signaling
B cell activation
Any complement labeled item (pathogen or protein) can bind to B cell receptor
60
CD40: CD40L
B cells need two signals for full activation by T dependent antigens
61
???????
B cell receptor binds an antigen. leads to signal 1 indicating B cell receotri had bound annd recognized the antigen its specific for.
Taken up bymediated endocytosis. antigen presented as MHCII
62
T dependent antigens
require T cell help for production of antibodies
- typically protein antigens
63
T independent antigens
TI - 1
- a combination of BCR and TLR signals activate B cell
TI-2
- Repetitive carbohydrate antigens present at high density on a pathogen surface, leads to extensive BCR cross linking
64
TI - antigens require contribution from TLR signaling
- B cell receptor
- TLR4
65
TI- 2 antigens
All about cross-linking
High density on pathogen surface
- recruit B cell receptors together
- Many repeated antigens close together
66
what antibody isotype can be generated from T independent reactions?
IgM only
67
Differentation of activated B cells in secondayr lymphoid organs
- upon antigen encounter in lymphoid organs, B cells are detained in the T cel areas where they recieve signals to proliferate and differentiate
- some become **plasma cells** and migrate to medullary cords or to the bone marrow
- plasma cells have no cell surface immunoglobin or MHC class II, no furhter division, specialized for antibody secretion
68
plasma cells are devoted to
antibody production
69
Germinal centers
- Other activated B cells migrate to a nearby follicle which becomes a secondary follicle, containing a germinal center
- these sites, are where somatic hypermutation, affinity maturation and isotype switching occurs
- memory B cells are maintained and circulate through the body, ready to rapidly respond upon re-exposure to pathogen.
70
true / false
Plasma cells undergo affinity maturation?
False
71
B cells are prolferating and getting T cell help in this location
Germinal center.
1. activation of B cells and migration into germinal center
2. B cell proliferation
3. Somatic mutation and affinity maturation; isotype switchong
4. exit of high affinity antibody secreting cells and B cells
72
Somatic hypermutation
AID makes point mutations in the variable region, leading to high affinity binding to the antigen
