Lecture 12+13: B cells Flashcards
what orchestrates the development of lymphocytes
stromal cells and cytokines
what are lymphocytes (B cells, T cells and NK cells) derived from
Hematopoietic stem cells —> multipotent progenitor cells —> common lymphoid progenitor cells —-> lymphocytes
antibody secreting plasma cells…AKA?
effector B cells
adaptive humoral immunity mostly works against ?
extracellular microbes and their products
what are the 2 classes of B cells
B-1 : Primarily mature in fetal liver, can self renew
Follicular B-2 cells: mature in the bone marrow
what is the physical composition of B cells
4 peptide chains joined by disulfide bonds
- 2 identical heavy chains
- 2 identical light chains
– each w/ variable and constant regions
what ligand does the transmembrane region of the B cell interact w/ for signaling
CD79 (Igα + Igβ)
where does B cell development occur
bone marrow
what cells direct the development of B cells in the bone marrow
Stromal cells
the rearrangement of Ig genes starts w/ ?
rearrangement of the heavy chain
early pro-B cell phase starts with what rearrangement
D-J rearrangement of heavy chain
late Pro-B cell development phase continues with what rearrangement
V-DJ
blocking what step in B cell development would prevent further development
large pre B cell
what is allelic exclusion?
ensures B cell expresses only one receptor type
why is it important that B cells don’t make more than one type of BCR
- it would be detrimental to immune response
what is X-linked agammaglobulinemia (XLA)
- mutation in BTK
- characterized by a lack of B cells and serum antibodies
BTK = important kinase in signal transduction from pre-B cell receptor
- BTK mutation cannot transmit the signal for proliferation and differentiation of pre-B cells
- results in apoptosis of the pre-B cell
what does the Lare Pre-B cell step check for
- checks for functional heavy chain
- checks for compatibility w/ surrogate light chain
rearrangements of the light chain starts with …..?
kappa
use of lamba is done to increase the odds of a successful rearrangement
what does combinational diversity depend on
which V, D and J segments are used in the development of the BCR allele
what is junctional diversity
during splicing, has to do with which specific nucleotides are added or deleted
what type of surface receptor do immature B cells make
only IgM
what occurs during receptor editing
- a chance to save the self-reactive B cells
- VJ rearrangements on the light chain can occur
- light chain editing only (kappa followed by lambda)
- new light chain and new IgM made
- once again goes through negative selection process
- heavy chain remains
what occurs after immature B cells make it past negative selection
alternative RNA splicing of the primary RNA transcription occurs in B2 cells
- this produces two different mRNAs
- VDJ region combined w/ mu constant region
- VDJ region combined w/ delta constant region
what allows B2 cells to be able to synthesize both IgM and IgD
alternative RNA splicing
what is the half life of mature B cells
100 days
what are the stages of B cell development?
Progenitor (Pro-B cell)
Precursor (Pre-B cell)
Immature B cell
Mature, naive B cell
in what stage does the initial expression of CD19 and CD20 occur along with initiation of somatic recombination of the heavy chain
pro B cell
in what stage does the initiation of somatic recombination of the light chain occur
Pre-B cell
at what stage of B cell development does negative selection occur
immature B cell
what are the antigen-dependent phases of B cell development
B cell activation
B cell differentiation
what are T-dependent antigens
protein antigens that lead to B cell activation w/ helper T cells
what are T-independent antigens
non-protein antigens that lead to B cell activation w/out helper T cells
where are B1 B cells located
in mucosal tissues and pleural/peritoneal cavities
what type of antigens do B2 B cells mostly respond to
T-dependent antigens
what type of antigens do B1 B cells mostly respond to
T-independent antigens
where do B cells circulate
between blood and lymphoid tissues to find antigens
what attracts follicular B cells to follicles
by B cell-specific chemokines produced by follicular dendritic cells (FDCs)
what happens if follicular B cells don’t get activated in the follicles
they leave following the S1P gradient
how do antigens enter the secondary lymphoid organs from the lymph/blood
by crossing epithelial barriers or by being carried in via DC cells to interact w/ receptors on the follicular B cells
what is the first signal in B2 (follicular) cell activation
follicular B cells are initially activated upon antigen binding to the BCR
for signal transduction, aggregation of receptors is needed to induce proliferation
how can aggregation of receptors occur
- antigen binding and cross linking 2 or more BCRs
- antigen cross-linking a BCR with the CR19/CD21 coreceptor
once follicular B2 cells are activated by the first signal where do they migrate to
the outer edge of the follicle into the T cell zone
B2 cells receive their second signal from what cells
Th cells and Th cell cytokines (CD40, CD40L)
- IL4 induces the proliferation of Th cytokines
If B cells have a strong reaction to self during negative selection, what are the 4 possible fates
- clonal deletion
- receptor editing
- anergy
- immunologic ignorance
what is clonal deletion?
apoptosis of B cells that have a high affinity for self-antigen
what is receptor editing?
further genetic rearrangement to replace BCR with one that doesn’t self-react
what is anergy?
a permanent state of unresponsiveness, eventually leads to death
what is immunological ignorance?
cells have an affinity for self-antigens but don’t respond to them
what percent of immature B cells have some affinity for self
about 75%
- they get sent for receptor editing
during receptor editing, V- J rearrangements occur on what chain
light chain
what stage of B cell development is characterized by the initial expression of CD19 & CD20
Pro-B cell
what stage of B cell development is characterized by the successful recombination and expression of the heavy chain as a Pre-BCR
Pre-B cell
what stage of B cell development is characterized by successful recombination and expression of a membrane-bound BCR complex
Immature B cell
what stage of B cell development does negative selection occur
Immature B cell
Non-protein antigens that lead to B cell activation without helper T cells
T-independent B1-B cells
where does the 2nd signal for B-cell activation come from
the interaction of the B cell with Th cell and Th cell cytokines
what occurs in the germinal center reaction
follicular B cells interact w/ follicular dendritic cells and follicular helper T cells
- class switching from IgM —> another isotope
- affinity maturation = mutations increase binding affinity of antibodies to target
what is extrafollicular focus
A subset of the follicular B cells differentiate rapidly into antibody-producing plasma cells
* Located outside of follicle = extrafollicular focus
* Short-lived plasma cells producing low affinity IgM
after undergoing class switching and affinity maturation in the germinal center reaction, what happens to B cells
they differentiate into effector and memory cells
class switching is directed by?
Tfh interaction via CD40-CD40L
what immunoglobulin does IL-4 induce
IgE
what immunoglobulin does INF-y induce
IgG
what immunoglobulin does TGF-B induce
IgA
what is AID
an enzyme, Activation-induced cytidine deaminase
functions by intentionally introducing mutations that must be repaired
can plasma cells present antigens
no b/c they cannot express MHC class II or co-stimulatory molecules
they are entirely committed to making antibodies
activation of memory B cells is what kind of immune response
secondary
