Download B-Cell Development, Activation, and Differentiation and more Study notes Immunology in PDF only on Docsity!
B-Cell Development, Activation,
and Differentiation
Sarah Holstein, MD, PhD
Nov 13, 2014
Lymphoid tissues
• Primary
– Bone marrow
– Thymus
• Secondary
– Lymph nodes
– Spleen
– Tonsils
– Lymphoid tissue within GI and respiratory tracts
Overview of B cell development
- Early B cell development constitutes the steps that lead to B cell commitment and expression of surface immunoglobulin, production of mature B cells
- Mature B cells leave the bone marrow and migrate to secondary lymphoid tissues
- B cells then interact with exogenous antigen and/or T helper cells = antigen- dependent phase
Overview of B cells
Role of bone marrow stromal cells
• At various points
in development,
progenitor and
precursor B cells
interact with
specific stromal
cell populations
secreting specific
cytokines
HSCs
multipotential
- Give rise to all blood cells
- Depending on stimuli
received, different
transcription factors can
drive HSCs down different
developmental pathways
all important transcription
factors for B cell fate
(receptor for stem cell
factor)
LMPPs (lymphocyte primed
multilineage progenitors)
flt-3 ligand on BMSCs), leading to IL-7 receptor synthesis
loss of MPP to develop into red blood cells or megakaryocytes, but still can differentiate into myeloid or lymphoid
ELPs (early lymphoid progenitors)
• Express RAG1/
(recombination
activating genes)
• Some migrate to
thymus, remainder
stay in the marrow as
B cell progenitors
Immunoglobulin gene rearrangements
and B cell development
- During early stages of B cell development, functional
rearrangements of the heavy chain gene locus (IgH)
allows for assembly of the pre-B cell receptor
complex cessation of IgH rearrangements (allelic
exclusion) light chain rearrangements (kappa,
then lambda)
- Production of complete Ig (2 heavy chains, 2 light
chains) allows for assembly of mature B cell receptor
on the cell surface signals cessation of light chain
gene rearrangement mature B cell stage
Pre-Pro B cells
• Express CD45R, a B-cell lineage-specific
marker
• Increase expression of EBF-
• EBF-1 and E2A bind the Ig gene, promoting
accessibility of D-JH locus, preparing for the 1 st
step in Ig gene recombination
• EBF-1 also important for expression of other B
cell proteins, including CD79α/β and genes
encoding the pre-B cell receptor
Pre B cells
- Ig heavy chain genes complete V-D-J recombination
- Allows surface expression of Ig heavy chain and surrogate light chains complex = pre-B cell receptor
- CD79a and CD79b (Ig-α and Ig-β)
- associate non-covalently with surface Ig
- signal transducing components of the pre-B cell receptor
- also components of the Ig receptors on the surface of mature B cells
- Signaling through the pre-B cell receptor induces a few rounds of proliferation; at the end of this the pre-B cell receptor is lost from the surface late pre B cell stage
- If pre B cell receptor cannot be displayed on cell surface because of nonproductive VHDJH gene rearrangement, then B cell development stops and the cell undergoes apoptosis (1st^ checkpoint)
- Pre-B cell receptor signaling causes transient decrease in RAG1/2 and loss of Tdt
- Ensures that as soon as one heavy chain gene has been rearranged, no further recombination is possible (allelic exclusion)
- Light chain rearrangement is initiated following re-expression of RAG1/
- Once light chain rearrangement has been successfully completed, the intact IgM receptor can be expressed - If light chain rearrangement does not occur successfully, then the 2nd^ checkpoint occurs
Immature B cells
- Have functional IgM but no other Ig expression
- Express B220, CD25, IL-7R, CD
- Once there is a functional BCR on the membrane, it has to be tested for its ability to bind self-antigens to ensure that few auto-reactive B cells are released
- Three fates if autoreactive
- Clonal deletion via BCR-mediated apoptosis
- Reactivation of RAG to initiate process of light chain receptor editing
- Survive and escape the BM but become anergic
- B cell loss prior to leaving the BM = central tolerance
- Export to spleen where further development occurs
- Very susceptible to tolerance induction
T1 and T2 transitional B cells
- T1: mIgMhi^ , mIgD -/lo, CD21-, CD23-, CD24+, CD93+
- T2: higher levels of mIgD, CD21+, BAFF-R
- T1 T2 mature B cells
- Most T1 transitional B cells differentiate to T2 within the spleen but ~25% of T emerge directly from the BM
- T2 cells capable of recirculating among the blood, lymph nodes, spleen
- T2 cells can enter B cell follicles
T1 and T2 transitional B cells
eliminated by apoptosis in
response to strong antigenic
signal (peripheral tolerance)
- 55-75% of immature B cells lost this way
- T2 cells become resistant to antigen-induced apoptosis
- Increased Bcl-X1 expression
- BAFF receptor expression
first detected in T1 B cells,
increases thereafter
- Promotes survival of transitional B cells