BIOL 435 Ch. 9 (B-Cell Development) Flashcards
B-cell development begins in
- the bone marrow
- is completed in the periphery
- mature in the spleen
immature B-cell
-exposed to self-antigens
>not until complete B-cell
*negative selection
-if good=leave bone marrow into blood to the spleen to mature
stromal cells
- provides support and growth factors to developing cells
- interact with B-cells during development in bone marrow
- provide guidance to cause a B-cell, T-cell or other cells
pre-B-cell receptor
- after VDJ rearrangement
- mainly intracellular, a few on membrane
- proliferation
mature B-cells encounter antignes in
-secondary lymphoid organs
bone marrow structure
- dynamic and complex
- stem cells
- stromal cells
- results in generation of a common lymphoid precursor (CLP)
stem cells
-differentiate into many cell types
stem cell factor (SCF)
-causes HSC to become a CLP
CLP
-common lymphoid precursor
-be T or B cell
-if interacts with CXCL12
>pre pro B-cell to pro-B cell
pro-B cell
-interact with IL-7 and become a pre-B cell
>pre-B cell will become an immature B-cell
S1P
- sphingosine 1-phosphate
- signal from the blood
- interacts with immature B-cell, and tells it to leave the bone marrow and enter the blood
bone marrow stromal cell-derived proteins
-indue early HSCs to beceom increasingly commited to the lymphoid lineage
sequentially activated transcription regulators
- drive differentiation
1. SCF
2. CXCL12
3. IL-7
IL-7
- survival
- proliferation
- transcription of B-cell associated genes (recombination)
- B-cell commitment
- inhibits other signals
later stages of B-cell development
- result in commitment to the B-cell phenotypes
* 2 checkpoints
1st checkpoint
-between late pro-B and large pre-B
*when have expression of a functional pre-B-cell receptor
>H chain and SLC
-can try again if doesn’t work
2nd checkpoint
- between small pre-B and immature B
- need a functional membrane bound IgM
- most get there and pass it
immature B-cells in bone marrow
-exquistely sensitive to tolerance induction
>eliminate self-reactive cells
-surface receptors are tested against self-antigens
3 outcomes when surface receptors are tested
- Clonal deletion
- Receptor editing
- Anergy
clonal deletion
- of strongly autoreactive cells by apoptosis
- occur within bone marrow: central tolerance
receptor editing
- reactivation of light-chain recombination machinery
- may be primary mechanism
- occurs within bone marrow: central tolerance
anergy
- induction of nonresponsiveness to further stimuli
- no proliferation or activation
- mechanism of self-tolerance outside the bone marrow
deleted in bone marrow
-many, but NOT all self-reactive B-cells
transitional cells
-functionally immature B-cells exported from the bone marrow
>enter perioarteriolar lymphoid sheath (PALS)
transitional cells
-functionally immature B-cells exported from the bone marrow
2 subsets of transitional cells
- T1
- T2
* important
T1 and T2
-differ in gene expression as they progress through the spleen for further maturation into conventional, B2 cells
T2 subset becomes
- Follicular B-cells (migrate to lymph nodes and circulation)
- Small % become marginal zone (MZ) B-cells
>important for blood borne pathogens (remains in the spleen)
categories of B-cells
- B-1 B cells (not from HSC)
- B-2 B cells
>T1
>T2 (*3. MZ B-cell)
>T3
T1 subset
-is still undergoing screening
>negative selection possible (BCR+Ag dependent)
*surviving transition to T2 stage
postive selection of T2
-survival signals (ex. BAFF)
-T2 up regulates BAFFR and bind BAFF
*competition=limited number of BAFF
>many B-cells die
BAFF
-B-cell activating factor belonging to the TNF family
-tonic signal (all the time)
-if binds to BAFFR on T2=survival signals
>MATURE B-cell
BAFF made by
- macrophages and dendritic cells
- more made during an infection to get more mature B-cells
mature, primary B-2 B-cells
- migrate to lymphoid follicles
- express high levels of IgM/IgD on their surface
- recirculate between blood and lymphoid organs
- help respond to Ag with T-cell help
- 4.5months half-life in periphery
help respond to Ag with T-cell help
-by producing Ab
>isotype switching after Ag activation
T3 B-cells
- self reactive
- may have been rendered anergic by contact with soluble self-Ag but not yet elminated
- respond to Ag but don’t divid, differentiate or secrete Ab->may die
T3 B-cells maybe
-indicates another mechanism for peripheral tolerance
>induced after B-cells have matured and left the bone marrow/spleen microenvironments
B-1 B-cells
-derived from a seperate developmental lineage (not HSC)
>earlier in development
-populate different anatomical niches than B-2 cells
-constantly regenerated outside the bone marrow
-30-50% of B-cells in pleural and peritoneal cavities of mice
-relatively limited receptor repertoire
-undergo apoptosis unless they interact with self Ag
Tdt B-1 B-cells
-minimally expressed in the precursor of B-1alpha cells
>non-templated nucleotide diversity is more limited so little N region addition in Ab produced
B1 B-cell receptors
-tend to bind microbial CHO Ags and lipids
>bind with relatively low affinity
>much more similar to PRRs of innate
-act as a bridge between innate and adaptive
B-1 B cells natural Ab
-secret them >most IgM >IgG or IgA -can secret them without binding an Ag >constantly secreting *are the first line of defense
marginal zone cells
- found in white pulp outer regions of the spleen
- specialized for blood-borne Ag recognition
- low levels of IgD and Fc receptor
- derived from T2 cells with strong self-Ag signalling through BCR
blood-borne Ag recognition
-recognize protein and CHO Ags (similar to B-1 cells)
>some may be able to do so without T-cell help
