B cell development (complete) Flashcards
does blood cell development begin in the bone marrow right at fertilization
no, it blood cell development is mostly in the liver and moves to the bone marrow after the bone marrow is formed
What is the main difference between the B-cells generated in the fetal liver and those generated in adult bone marrow
B-cells from the fetal liver are primarily B-1 cells, those in the adult bone marrow are B-2 Cells
What are some of the characteristics of B-1 cells
- they come from the fetal liver
- their antibodies bind to carbohydrate antigens
- the antibodies have minimal receptor diversity
- they are primarily located in body cavities
- they are self-renewing, even outside of marrow/liver
what determines the stages of hematopoeisis
cell-surface markers
transcription factor expression
Ig gene rearragnements
What are the different stages of B-cell development
- Pre-pro
- early pro
- late pro
- Large pre
- small Pre
- Immature B
- Mature B
When B-cells are at the immature stage, they are tested against self antigens, what are the three possible outcomes of that testing?
- Clonal deletion of strongly autoreactive cells
- Receptor editing
- Anergy
What type of selection is used in B-cell development to make sure the B-cells function correctly
Negative
what is the process of negative selection of B-cells
they are tested against self-antigens, if they bind very tightly to self antigens they will undergo clonal deletion. if they bind less tightly but sill bind to self antigens, they will either have their receptors edited or enter a state of anergy (can’t bind anything anymore)
even after the B-cells have undergone negative selection in the bone marrow, they aren’t fully matured. What are the subsets of B-cells at this point
T-1 and T-2 (B cells)
T-1 when the leave the bone marrow and enter the spleeen
T-2 cells in the spleen
what happens after B-cells have gone from being T-1 to T-2 cells
the T-2 cells will differentiate into:
- Mature, primary B-2 cells
- Follicular (B-2) cells
- Marginal zone B cells
what happens to the B-1 cells in your body as you go from being a fetus to being a full blown adult
they remain in specific body cavities (B-2 cells aren’t there) and continually regenerate.
how long do mature primary B-cells live in the periphery
4.5 months
what is the primary function of mature primary B-cells
respond to antigens with T-cells by making antibodies
what do mature B-cells have in abundence on their surfaces
IgM/IgD
Where do you find marginal zone cells, and what do they do
they are found in the white pulp of the spleen
- they are specialized to recognize Blood borne Antigens
- recognize protein and carb antigens
- have low IgD and Fc
how are B and T cell development similar
- rearragnement of gene sequences
- screening processes to avoid self-reactivity
- production of small subsets with discrete functions
- production of larger “general purpose” subunits
How are B and T cell development different
- location of maturation and screening
2. screening processes used
what does the clonal selection hypothesis state (of B cells)
- that each B cell has one surface Ig receptor
- the binding of the specific antigen causes the B cell to clone itself so that there are many cells with the same receptor
What are two different ways in which B-cells can respond to Ags
- T-dependent response (generated by protein Ag)
2. T-independent response (generated by multivalent/polymerized Ag)
what are the two types of T-dependent responses
- TI-1 Ag binds to the B cell through PRRs and mlgs
2. TI-2 Ag cross link large numbers of BCRs
What does the binding of TI-2 Ag with the cross linking of BCRs cause the B cell to do
- induces activation and proliferation
- Ag is internalized and processed (presented by MHC class 2)
- interaction with T-helper cells provides conditions for differentiation and memory cell production
what is the structure of BCR
a membrane bound Ig and a heterodimer (Iga and IgB)
two light chains and two heavy chains
how do B-cells create an almost infinite amount of Igs
they use groups of parts of genes
what are the different gene segments that are used in the creation of Igs in B-cells
V - variable
D - diversity
J - joining
C - constant
which gene segments are used in the formation of the light chain of BCRs
V, J, and C gene segments
which gene segments are used in the formation of the heavy chain of BCRs
V, D, J, and C gene segments
what does an Ig protein consist of
two identical heavy chains and two identical light chains
what are the two types of light chains
kappa or lamda
what gene segments are involved in kappa light chains
V, J, and C
in mice there are 18 V families, 4 functional J families, and one C
what genes segments are involved in lamda light chains
V, J and C but the J is paired with a particular C
in humans 40% of light chains are lamda type
30 Vs and 7 JC pairs (4 are functional)
in heavy chains how many of each gene segments are there
38 V’s
30 + D’s
6 J’s
8 C’s
what proteins are used in V(D)J recombination
RSSs
RAG1
RAG2
What does RSS do in V(D)J recombination
recombination signal sequences that flank each antibody gene segment, forms a complex with RAG1 to cleave the DNA
What does RAG1 do in V(D)J recombination
forms a complex with RSS and cleaves the DNA
what does RAG2 do in V(D)J recombination
binds to RSS/RAG1 complex and stabilizes it
What happens if you have no RAG1 and RAG2
you have no acquired immune system
What type of Ig is more common in T-1 B cells, and which is more common in T-2 type B cells
T-1 type have high IgM
T-2 type have high IgD
which of the gene segments codes for IgM and IgD
C
C-d = IgD
C-M = IgM
what is the process of V(D)J recombination
- Heavy Chains are recombined first
- once it is formed transcription is shut down until it binds to a SLC (surrogate light chain)
- machinery starts up and the light chain recombination occurs
what ensures that each B-cell will synthesize only one heavy and one light chain
Allelic exclusion (the part of the allele that isn’t matched up is cut out)
what are the steps (attempts) to create a heavy chain
- combine J-D regions (throw away the stuff in the middle
- move the V region next to the J-D region (throw away stuff in the middle)
(you get two tries at combining the V to the J-D region to make a good heavy chain (because of the two alleles) if that doesn’t work then the cell will die)
what are the steps (attempts) to create a light chain
after the heavy chain has been made
- you get two tries to combine the V-J portions for the kappa type
- if neither of those work you get two tries to combine the V-J portions for the lambda type
if none of those work the cell will die (two tries at each type because of the two alleles for each type)
what happens after the V-D-J segment of heavy chains has been made
then the C regions is joined on and the space between is removed. ( if its C-M then you get IgM, if its C-D then you get IgD)
this is mRNA splicing
mRNA splicing controls whether the Ig will be IgM or IgD, but what else does it control
if the Ig will be secreted or membrane bound
secreted Ig gene location is found prior to the membrane Ig gene
what happens when a BCR binds an Ag
the Ag is internalized and processed in the exogenous pathway (with class 2 MHC)
what happens to the B cell once it has bound Ag and becomes activated
it expresses CCR7, which helps it migrate to T-cell rich areas of secondary lymphoid structures. then they move through the T-cells until they find their specific match
what causes B cells with CCR7 to migrate to high T-cell locations
the CCL19 and CCL21 secreted by stromal cells in T-cell rich areas of secondary lymphoid structures
what happens to activated B cells that have found their matching T-cell.
they down regulate the CCR7 and move to follicles
What causes B-cells to migrate to lymph nodes, and what causes B-cells and T-cells to migrate together
CXCR5 on B cells is attracted to CXCL13 from the lymph node
CCR7 on activated B cells is attracted to CCL21 and CCL19 in the T-zone
Activated Tcells express CXCR5, which brings them close too
what happens to activated B-cells that can’t find their matching T-cell
they enter a state of anergy
What do plasma cells do
produce tons of Ig (secreted Ig)
Ag activated B cells have two fates which are
- become germinal center B-cells
2. promote plasma cell outcome
what is in the dark zone of germinal centers
proliferating B-cells
what is in the light zone of germinal centers
B cells with FDC
what is somatic hypermutation/affinity selection
mutations in the Ig light and heavy chain
what is AID when talking somatic hypermutation
activation induced cytidine deaminase, which is one way that somatic hypermutation occurs
when does CSR occur and what is it
it occurs within the Germinal center after Ag contact
it is when an Ig goes from one class (IgM) to another (IgE)
what determines which class an Ig will switch to in CSR
the cytokine signal
IL4 = IgE/IgG4
What signal must be received for a B cell to undergo class switch recombination
CD40
what happens to most B-cells when their antigen is gone
apoptotic clearance (they undergo apoptosis)
how does affinity of Memory B cells compare to that of Plasma cells
they are generated later so they have a higher affinity
how does a secondary response compare to an initial response of B cells
it is ten times more long lived
what promotes plasma cell differentiation
IL-6
