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35 Cards in this Set

  • Front
  • Back
two major phases of B cell development
1) Ag-independent phase
-takes place in bone marrow (fetal liver or spleen)
- involves Ig gene rearrangement

2) Ag-dependent phase
-takes place in peripheral lymphoid organ
-upon recognition of Ag, B cell:
-becomes memory cell or plasma cell
-class switches
Three steps of B cell development
1. Ig gene rearrangement
= Ag specific B cells
(Ag independent phase)

2. movement to periphery
-contact Ag, then
-90% B cells die: self-reactive cells apoptose(clonal deletion)
3. along with T cell help, B cells will develop into plasma cells or memory cells
-class switching
(Ag dependent phase)
sequential pathway of B cell development
Stem cell
Pro-B cell
Pre-B cell
Immature B cell
Mature B cell
B cell development :
Stem Cell to Pro B-cell
1) stem cell + cytokines (GF) = B cell

2) IgH chain made first D-J then V-DJ
-Ab interaction with BM stromal cells

3. Pro-B cell expression
-RAG1/2 expression
-Tdt expression
-Iga/Igb espression
B cell development :
Pre B-cell
4. Pre-B cell (precursor)
-IL-7 production by stromal cells

5. Pre- B cell
-m Heavy chain done surrogate L chain(vPreB/l5) signals L-chain rearrangement

6. Light chain begins

7. Pre-B cell expreses
RAG1/2 expression
Iga/Igb expression
B cell development: Immature to Mature B cell
8. Immature B cell
-IgM epression
-B cell is Ag specific

9. Receptor editing
-“rescue” self-reactive B cells
-B cell can rearrange remaining V region genes

10. IgM and IgD co-expressed

11. B cell leaves BM

12. Entry into “Ag-dependent phase”
Iga/Igb are
signalling molecules
Self-reactive cells
membrane Ig that binds self Ags early in development should be eliminated
-if IgH + IgL bind, then B cell will again rearrange the Light chain V region genes
-self-reactive cells in periphery should become anergic (= non-responsive)
Light chain editing
-if IgH + IgL bind, then B cell will again rearrange the Light chain V region genes

-feature of Light chains because they only join together the V genes and the J genes where as H chains have V, D, and J
Allelic exclusion
with appropriate signals (cytokines and signaling molecules), IgH gene rearrangement begins.
once IgH associates with surrogate light chain and binds stromal cell marker, then IgH stops and light chain starts cannot rearrange other H-chain allele
B cell can proliferate (yielding 32-64 progeny with IgH already rearranged)
all of these cells with the same IgH can then rearrange the L chains (potentially giving 32-64 different Ag specificities)
Increases potential B cell diversity
B cell diversity after allelic exclusion
B cell can proliferate (yielding 32-64 progeny with IgH already rearranged)
all of these cells with the same IgH can then rearrange the L chains (potentially giving 32-64 different Ag specificities)
Importance of interaction with BM stromal cells in B cell development
Various receptor-ligand interactions control sequential process
-adhesion molecules (VLA-4/VCAM-1)
-cytokines/growth factors (e.g. IL-7)
Importance of gene expression in telling us where we are in the life of B cell
different proteins/enzymes will be produced at different times
e.g., TdT is important in heavy chain rearrangement NOT light chain rearrangemnt so shouldn't be seen after pre-B cell stage
Ig genes and cancer
Promoters and enhancers in B cells are associated with Ig gene control & expression.
Cell cycle regulatory genes next to these promotors and enhancers can cause cancer of the B cell.
e.g., c-myc gene next to Ig enhancer = B cell lymphoma (Burkitt’s lymphoma)
Stage of B cell development and cancer
B cell tumors at many
different stages of B
cell development
2 Major types of B cell Ag
1) Thymus dependent (TD) Ags
2) Thymus independent (TI) Ags
Thymus dependent Ag
-efficient and produce memory
-usually in in response to protein Ab
-B cell needs T cell help via
cytokines & co-stimulation
Thymus independent (TI) Ags-Type I
-Bacterial cell wall components (e.g. LPS from Gram – bacteria)
-Not Ag specific (mitogens)--polyclonal B cell activators
Thymus independent TI-2 – type 2 TI antigens
-Repetitious cell wall components (e.g. polysaccharides, flagellin)
-Ag specific
-Get crosslinking of mIg (polyvalent Ag)
Two signals for B cell activation
1) Signal 1:
Ab-Ag binding: requires crosslinking of IgM.
Single epitope Ag are not as effective. Requires BCR signalling --IGM + Ig alpha/beta (sends transcription factor signal to nucleus)

Signal 2:
CD40 signaling molecule interacts with CD40L on T cells.

Cytokines can also serve as second signal
-one heterodimer associates with a mIg
-BCR = ligand-binding domain AND the signal-transducing molecule
-Cytoplasmic portions have an 18-a.a. motif called the: immunoreceptor tyrosine-based activation motif (ITAM)
-phosphorylation of the tyrosines within ITAM is an early event in B cell activation
-get activation of second messengers to start their signaling pathways
-Signaling results in changes in gene expression
– areas on Ig alpha/beta that can be Phos or de-Phos --cascade –transcription factors to nucleus
BCR co-receptor
interacts with complement protein to amplify activation,
B cell activation - summary
-Ig binding Ag (crosslinking)
-signaling via Iga/Igb
-signaling via co-receptor (if complement proteins present)
-Changes in gene expression
-Internalization of Ig/Ag complex (30-60 minutes)
-Ag presentation to T cells
-MHC class II presentation of Ag peptides
-activation of T cells
-co-stimulation of B cell (CD40-CD40L)
-B cell differentiation:
-class switching, memory cell and plasma cell production
Co-stimulators for the T cell
T cells need two signals as well:
1. TCR – Ag/MHC
2. CD28 – B7
The role of Cytokines in isotype switch
T cell cytokines can induce and/or inhibit the production
of various isotypes.
e.g., IL4 plays a role in IgE
“Unusual” B cells
-some B cells express CD5 on their surface (normally a marker for T cells)
-these B cells called B1 B cells (develop before the “B2” B cells which are the “typical” B cells)
-a/k/a CD5+ B cells
-V region genes are those typically closest to the “D” locus ( = less diversity)
-find B1 B cells in higher concentrations in the pleural and peritoneal cavities (elsewhere, B1 B cells are in very low concentrations)
-Often have low affinity and high rate of cross-reactivity (they have polyspecificity)
-typically react against polysaccharide Ags on bacteria
How are CD5+ B cells/ "unusual" B cells/B1 B cells different from other B cells
-limited diversity
-self renewing
-Secrete the IgM isotype much more than the IgG
-Respond very much to carbohydrate Ag
-don't require T cell help
-usually don't get class switch
B cell effector response - primary response
-when a naïve B cell first “sees” its Ag
-characterized by IgM production
-slower response (~7-10 days)
-during/after this response, B cells often class switch
-doesn’t have to have T cell help (although works better with it)
B cell effector response - secondary response
-a/k/a Memory response
-production of IgG or other isotypes
-affinity maturation(somatic hypermutation)
-quicker response (starts in 1-3 days)
-needs T cell help
Primary/secondary Ab response
Primary response is when you are introduced to the Ag and produce Igm/ Secondary response is all subsequent exposures to Ag where you still produce moderate amounts of IgM but produce massive amounts if IgG/IgA/whatever
B cell activation- summary
1)Ag enters secondary lymph tissue through afferent lmphatic vessels
2)Ag goes into the paracortex via HEV or blood vessel and there is initial T cell & B cell activation
3)Goes the Primary folicle for B cell activation
4) Goes to germinal center – B cell proliferation & differentiation
5)Medula- plasma cell secretion of Ab – Abs leave LN
Germinal center
-area where mature B cell development occurs
-Follicular dendritic cells (FDC) helps activate B cells via cytokines
-do not present Ag to T cells (don’t express MHC class II)
-Germinal center develops in lymph tissue near the site of Ag
Ab functions
-Neutralization (cells, viruses, toxins)

-Agglutination (cells) and Precipitation (soluble Ags)

-ADCC and opsonization
-recognition and destruction by phagocytic cells and NK cells

-Complement activation
-Cell lysis, opsonization, inflammation

-Allergic response