ch 8: development of B lymphocytes Flashcards
what are the three subtypes of B cells?
B-1 B cells (CD5 B cells), B-2 B cells (follicular B cells), and marginal-zone B cells
B-1 B cells
occupy and protect body cavities, including the peritoneal and pleural cavities, and their job is primarily to protect gut and lung tissue
B-2 B cells
make up the majority of B cells responsible for surveying and combating infections through activation at secondary lymphoid tissues
marginal zone B cells
reside in the marginal zones of the spleen and primarily protect against bloodborne pathogens.
______ produce high levels of IgM
B-1 B cells
______ produce high levels of IgM/IgG
marginal zone B cells
__________ can bind to carbohydrate antigens
marginal zone B cells
marginal zone B cells are located in the _____ pulp of the spleen
white
HSCs differentiate into
erythroid cells required for the delivery of oxygen to developing tissues
hematopoiesis begins in the _____ of the developing embryo at around 7 days after fertilization in mice and 21 days after fertilization in humans to produce oxygen-carrying erythroid cells
yolk sac
the _________ continues to be the major location of HSC production until the liver takes over at day 13 in mice (day 40 in humans).
placenta
what are pre-B cells?
precursory B cells beginning their development into B cells. by day 17 in mice (day 75 in humans), B cells capable of producing IgM at their cell surface can be detected.
the ___ ______serves as the location for B-cell development while the bone marrow continues to develop
fetal liver
difference between HSCs derived in humans and those derived during fetal development?
HSCs derived from adult bone marrow in mice and humans do not actively proliferate until they receive activation signals. in contrast, HSCs produced during fetal development in the liver must continuously and rapidly divide to produce erythrocytes and populate the immune system.
B cells in mice and humans produced during hematopoiesis in the fetal liver are primarily ___ ___ ____
B-1 B cells
what is the main threat of infection in the developing fetus?
infection via gut or lung entry
key characteristics of B-1 B cells
- B-1 B cells express antibodies that are cross-reactive; many of them recognize carbohydrate antigens shared by multiple microbes
- they do not express terminal deoxynucleotidyl transferase (TdT) at high levels
- their V(D)J recombinase activity only uses a subset of variable V, D, and J gene segments
what potency are HSCs?
multipotent
___ also maintain their chromatin in a state that promotes transcriptional activation by having less-organized nucleosome structure and chromatin packing, as well as through acetylation and methylation of histones, which promotes transcription of genes located close to those modifications.
HSCs
interaction between c-Kit and SCF has two role
(1) keeping HSCs in contact with stromal cells to aid in the delivery of differentiation signals and (2) driving the differentiation of HSCs to the next progenitor, multipotent progenitor cells
what are the two key molecules expressed by multipotent progenitor cells?
CD34 and CXCR4
stromal cells secrete ____ to maintain a population of progenitor cells in the correct location as differentiation continues
CXCL12
the signaling molecule fms-related tyrosine kinase 3 receptor (flt-3) binds to its cell-surface ligand expressed by bone marrow stromal cells and drives signaling that culminates in the expression of what?
the IL-7 receptor in the lymphoid-primed multipotent progenitor cell
cells that remain in ___ _______ continue to elevate expression of the IL-7 receptor, which promotes their further differentiation into common lymphoid progenitor cells
bone marrow
what is the transcription factor that aids self-renewal of hematopoietic stem cells?
E2A
what transcription factors function in activating specific genes responsible for B-cell development?
Ikaros and PU 1
where do B cells begin their development as HSCs?
in the endosteum, located near the surface of the bone
early pro-B cell
- initiate genetic recombination at the immunoglobulin heavy chain loci
- requires recombination that connects a V, D, and J variable gene segment together to create the variable region
- begins with DJ recombination of the heavy chain
pro-B cells
- a V segment must be recombined with the newly formed DJ segment
- developing cells will test the immunoglobulin heavy chain recombination events to determine whether these recombination events were productive or unproductive
pre-B cells
- recombination events occur at the immunoglobulin light chain loci
- V and J variable gene segments of the light chain loci rearrange
- another test determines whether the light chain locus has productively recombined through positive selection
immature B cells
- cells that have productively recombined both their heavy and light chains become immature B cells, which then undergo negative selection within the bone marrow
what is receptor editing?
B cells that react to self-antigen go through a process known as receptor editing in an attempt to further rearrange their light chain and change the immunoglobulin specificity to no longer react with self-antigens
B cells that pass through all the developmental checkpoints migrate from the bone marrow as __________ __ _____ and travel to the spleen.
transitional B cells
T1 transitional B cells are
immature B cells in the spleen which undergo negative selection, a process in which the affinity of the immunoglobulin is tested against self-antigens expressed in the spleen
T2 transitional B cells are
T1 B cells that escape negative selection and receive a survival signal, enabling them to transition into mature B cells, which enter the circulation to aid in humoral immunity
how do B cells differ from T cells in their developmental checkpoints?
T cells can produce two different types of T-cell receptors (αβ and γδ T-cell receptors), while B cells can produce only one functional type of immunoglobulin
what are the two developmental checkpoints for B cells?
test for a functional heavy chain and test for a functional B cell receptor (light chain rearrangement)
when does somatic recombination of the light chain locus occur?
when large pre-B cells undergo several cell divisions and become small pre-B cells
what two genes help rearrange the immunoglobulin heavy chain loci by recombining a D variable segment with a JH variable segment?
RAG1 and RAG2
pro-B cells express what to help test whether rearrangement of the heavy chain produces proper expression and function
a surrogate light chain
the surrogate light chain is composed of what two proteins?
VpreB and λ5, where VpreB mimics the variable region of the light chain and λ5 mimics the constant region
what is the pre-B cell receptor?
the receptor that contains the rearranged heavy chain, the surrogate light chain, and the signaling molecules Iga and Igb
the pre-B cell receptor is tested for its ability to bind to antigen
FALSE, it is tested for productive rearrangement of the immunoglobulin receptor complex
developing B cells engage in allelic exclusion after passing which check point
the immunoglobulin heavy chain rearrangement checkpoint
what occurs during B cell allelic exclusion?
- RAG1 and RAG2 are shut down
- developing B cell proliferates
- chromatin at heavy chain is inactivated preventing further rearrangement
what would happen if allelic exclusion did not occur in a developing B cell?
If allelic exclusion does not occur, somatic recombination of the heavy chain loci continues and could result in the B cell producing more than one heavy chain. each heavy chain would drive different antigen specificity, and the ensuing polyspecificity of the B cell would dampen the humoral adaptive immune response.
what are large pre-B cells?
pre-B cells that have not reactivated rearrangement for the light chain
what are small pre-B cells?
pre-B cells that are rearranging the light chain through upregulation of TdT and V(D)J recombinase
somatic recombination of the light chain begins at a random κ or λ light chain locus
TRUE
what is the result if rearrangement is unproductive at the four light chain loci?
the cell undergoes apoptosis
why would you predict that most pre-B cells are likely to move through the light chain checkpoint and develop into immature B cells?
because there are 4 distinct opportunities for productive rearrangement during light chain recombination
after testing for a functional B-cell receptor (with productive rearrangement of the heavy and light chains), immature B cells undergo what process to remove self-reactive cells?
negative selection
what is clonal deletion?
the process by which immature B cells with self-reactive antigen can be removed from the B-cell population through an immunoglobulin-mediated activation of apoptosis within the cell
the negative selection of self-reactive B cells in the bone marrow leads to peripheral tolerance
FALSE, this negative selection leads to central tolerance
what is receptor editing?
when a self-reactive immature B cell in the bone marrow is capable of reactivating somatic recombination at the immunoglobulin light chain locus in an attempt to alter the antigen specificity
when all receptor editing possibilities are exhausted, the developing B cell will die through apoptosis
FALSE, the B cell will die through clonal deletion
anergy is an arrested state developing B cells can be placed in when they become unresponsive to antigen
TRUE
what are some defining features of anergy?
- anergic B cells can still express immunoglobulin at their cell surface
- anergic B cells tend to express more IgD rather than the IgM
- anergic B cells are incapable of responding to antigen and live for 2 to 10 days
negative selection of B cells is ____ stringent than that of T cells, likely due to B-cell activation being dependent on help from T cell
LESS
circulation of self-reactive B cells is ____ tolerated as long as negative selection of T cells in the thymus is maintained at a stringent level
MORE
there is no AIRE activity in the bone marrow
TRUE, therefore developing B cells are not exposed to endocrine-specific proteins
what can induce a state of unresponsiveness or anergy, preventing a B cell from responding to the antigen it recognizes?
recognition of a soluble monovalent self-antigen
approximately ___ % of immature B cells exit the bone marrow primed to develop into mature B cells in the B-cell follicle of secondary lymphoid tissues such as lymph nodes. however, the other ___ % must travel to the spleen, where they will complete their development into mature B cells
25%, 75%
what are T1 transitional B cells characterized by?
- high level of IgM
- low level of IgD
- cell surface markers CD24 and CD39
- expression of BAFF-R
T1 cells undergo a round of negative selection to promote ________ tolerance
peripheral
approximately ___% to ___% of immature B cells that develop into T1 transitional B cells die through this mechanism of peripheral tolerance
55%, 75%
what are T2 transitional B cells characterized by?
- higher IgM expression
- express higher level of BAFF-R
- cell surface markers CD21 and CD23
T2 cells within the spleen undergo positive selection in which signaling through the immunoglobulin stimulates survival signals via an increase in what two molecules?
intracellular calcium and diacylglycerol
what happens when B cells transition from T1 to T2 stage?
- initiation of alternative splicing of immunoglobulins
- increase in BAFF-R
- increase in IgD
what happens to the T2 cells transitional B cells if they do not receive the BAFF signal?
they die by neglect
why are mature B cells that exit the spleen called naive B cells?
they have yet to encounter antigen that their immunoglobulin recognizes
upon entry into the secondary lymphoid tissue, the B cell migrates to a __________ ______________ ___________, where it scans for the presence of antigen that its immunoglobulin is designed to recognize
primary lymphoid follicle
what is true about the movement of B cells into and out of a lymph node?
- B cells activated T cells activated by APCs migrate to follicle of B cell zone
- mature B cells in circulation enter secondary lymphoid tissues and enter primary lymphoid follicle
- B cells that are not activated reenter circulation
what are the main features of B-1 B cell development?
- lack diversity due to limited V(D)J recombination and TdT activity
- they commonly express immunoglobulins with antigen specificity toward common microbial carbohydrates
- signals that drive negative selection of T-1 transitional B-2 cells are required for positive selection of B-1 B cells
- B-1 B cell development occurs independently of the action of BAFF
- B-1 B cells seem to regenerate in the periphery of the organism
- B-1 B cells are present much earlier in the development of an organism
what are the main features of marginal zone B cell development?
- high level of IgM
- low level of IgD
- high CD21 but low CD23
- express membrane-bound adhesion molecules and receptors of phospholipids that allow them to adhere to other cells
- can express immunoglobulins that recognize proteins or carbohydrates
- specialized in recognizing antigens of bloodborne pathogens
- require signaling through BAFF-R
- require Notch signaling to differentiate
