module 03 section 03 (B-cell development) Flashcards
B cell development has antigen- ____ and ____ phases
independent or dependent
describe (generally) what happens in the antigen-independent phase
a single progenitor cell gives rise to a large number of lymphocytes
what is eliminated during the antigen-independent phase?
cells identified as self-reactive are selectively eliminated
what is the result of the antigen-independent phase?
the generation of immunocompetent, mature B-cells in the bone marrow that can bind to a unique antigen
define “immunocompetent”
denoting a mature lymphocyte that is capable of recognizing a specific antigen and mediating an immune response
what are the two factors that result the ability of a mature B-cell to bind to a unique/specific antigen?
(1) V-(D)-J rearrangement
(2) allelic exclusion
define “V-(D)-J rearrangement”
process that ensures clonally unique Ig variable regions (which specifically bind an antigen), ultimately creating Ig diversity
define “allelic exclusion”
ensures that each B-cell expresses a single antibody on the surface, ensuring specificity
what does the antigen-dependent phase require for initiation? (2)
(1) B-cell activation by antigen binding and (2) co-stimulatory singals from helper T-cells
stimulatory signals from helper T-cells promote:
B-cell differentiation into either memory B-cells or antibody secreting plasma cells
describe (generally) what heppens during the antigen-dependent phase
this phase involves B-cell proliferation, antibody affinity maturation, and antibody class switching
where do the processes of the antigen-dependent stage occur?
all in the germinal centers of secondary lymphoid tissues
what is required by the processes of the antigen-dependent phase?
several surface associated proteins and transcription factors
define “affinity maturation”
the increase in average antibody affinity for an antigen that occurs during the course of an immune response OR in subsuquent exposures to an antigen
what happens to B-cells if there is no antigen activation?
how prevalent is this?
cell death (90% of cases)
the early stages of B-cell development are dependent on which type of cells?
bone marrow stromal cells
what are stromal cells?
CT cells of an organ
list the steps of the early development processes by which pro B-cells become immature B-cells (5)
what is the end result?
(1) lymphoid progenitor cells bind VCAM-1 (on bone marrow stromal cell) via integrin VLA-4 which acts as anchors
(2) VCAM-1 binding promotes the binding of early pro B-cell surface c-Kit receptor (tyr kinase) to SCF on the stromal cell surface
(3) the kinase is activated, VDJ rearrangement of IgM heavy chain occurs
(4) IL-7 is required to drive proliferation and survival of pre B-cell from late pro to pre B-cell
(5) pre B-cells lose their independence on SCF and cease to express c-Kit causing the cell to detach from the bone marrow stromal cell
- end result = immature B-cell
once the pre B-cell becomes an immature B-cell via light chain rearrangement, it may undergo:
further mechanisms, such as receptor editing
what is the first gene rearrangement that occurs during B-cell development? what is the result?
- D-J rearrangement of the heavy IgM
- changes a pro B-cell to an early pro B-cell
mutations to the RAG enzymes or mutions in the heavy J segment leads to:
lack of development of early pro B-cells
what is the second gene rearrangement that occurs during B-cell development? what is the result?
- V-D-J rearrangement
- successful v-d-j rearrangement gives rise to the heavy chain of IgM (expressed on cells surface)
- changes early pro B-cell to pre B-cell
unsuccessful V-D-J rearrangement leads to what?
cell death
in order for heavy chain IgM to be expressed on the cell surface, It has to:
be in association with the surrogate light chain
what prevents the expression of heavy chain IgM on the cells surface?
the gene knockout for the transcription factors lambda 5 or pax 5 or the gene for heavy chain IgM
what type of cell is the IgM heavy chain expressed on?
the pre B-cell expresses the heavy IgM chain associated with the surrogate light chain
the surrogate light chain expressed on the cell’s surface triggers:
rearrangement of the light chain (as kappa or lambda)
-i.e. third rearrangement
what is the third gene rearrangement that occurs during B-cell development? what is the result?
- V-J rearrangement of the light chain
- light chain associates with the heavy chain IgM on the cells surface
- changes pre B-cell to immature B-cell
within the bone marrow, newly developped immature B-cells (with IgM) that recognize self antigens:
may go through a clonal deletion process which leads to the death of self reactive B-cells
can self reactive B-cells be rescued from clonal deletion?
why or why not?
yes - by undergoing further receptor editing of the light chain, so that the heavy chain can associate with a different light chain
-results in an anitbody with different specificity for an antigen
both clonal deletion and receptor editing are types of what?
negative selection
does positive selection occur before or after negative selection?
after
what is the result of positive selection?
- the expression of IgD on the cells surface together with IgM
- which gives rise to the mature B-cell
partial immunoglobulin molecules combine with ___(1)___ in the developing B-cell to direct ___(2)___
(1) invariant chains
(2) gene rearrangement
can Mu heavy chains be expressed on the cell surface on their own?
no
because IgM heavy chain can not be expressed on its own, pre B-cells produce:
a surogate light chain which is composed of 5lambda and VpreB (similar to VL but with extra aa sequences)
explain how Mu chains are expressed on cell surfaces
in an immunoglobulin like complex with a surrogate light chain and signal-tranducting Iga and IgB heterodimers
what does signalling via the Mu:lambda5:VpreB Ig-like molecule trigger?
(1) pre B-cell proliferation and survival
(2) stops further heavy-chain gene rearrangement
(3) induces light chain gene rearrangement
what would happen if there were defects in the surrogate light chain
no B-cells would be produced
what is another term for negative selection?
central tolerance
define “negative selection”
the process of eliminating developing B-cells that recognize self-antigen
what does negative selection ensure?
that the immune system does not attack self peptides
what are the two mechanisms by which negative selection takes place?
clonal deletion and receptor editing
explain clonal deletion
apoptosis of immature B-cells that have expressed receptors that recognize self-antigen before developing into fully immunocomptent mature lymphocytes
what does clonal deletion prevent?
recognition and destruction of self host cells
explain receptor editing
- immature self reactive B-cells with active RAG can be rescued from clonal deletion by editing their light chains (rearrangement)
- rare
rearranged light chains can alter:
the specificity of the antibody by replacing that which offers autoreactivity with one that does not
immature B-cells that have already undergone VDJh rearrangement still express surrogate light chains, true or false? why or why not?
false - instead they express kappa or lambda light chains together with the Mu heavy chains to form IgM
in addition to lambda/kappa light chains and the Mu heavy chain, immautre B-cells will also express:
the Iga-IgB heterdimer
when do immature B-cells become mature B-cells?
when the light chain rearrangement has stopped
every B-cell has the potential to produce 2 different antibodies, what are they?
one from rearrangement of the maternal loci and one from the paternal loci
do antigens have one or two specificities?
one
explain allelic exclusion
- the completion of a successful rearrangement of the first allele results in inactivation of the second allele
- basic concept: one B-cell has on antigenic specificity
what does allelic exclusion ensure?
that functional B-cells never contain more than one VDJ(H) and VJ(L) unit
allelic exclusion suggests that once a productive VDJ(H) rearrangement and a productive VJ(L) rearrangement have occured:
the recombination machinery is turned off so the heavy and light chain genes on the homologous chromosomes are not expressed
the transition from an immature B-cell to a mature B-cell is associated with:
(1) expression of both IgM and IgD on the cell surface
(2) both Ig heavy chains on each cell having the same V region
(3) both Ig heavy chains are associated with the same light chains
do IgM and IgD on a mature B-cell have the same specificity ?
yes
