Download Zoom-out on B cell development

Stages of Hematopoietic
Development
The hematopoietic system generates blood cells.
The hematopoietic differentiation is unique
because it does not require stable association with
supporting tissue.
Specific transcription factors function as master
switches to promote differentiation of blood cells
Stages of Hematopoietic
Development
Stages of Hematopoietic
Development
Lymphocytes arise from HSC
through CLP
•Pluripotent hematopoietic stem cells (HSC) are self-renewing
•HSE can differentiate into any cell type found in blood.
•One pathway to become a lymphocyte is for a HSC to pass
through the CLP stage.
B and T lymphocytes derive from a
common lymphoid progenitor
Pro-T
PU.1
HSC
MLP
CLP
CMP
PU.1
GLPro-B
Stages of B Cell Development
•The generation of B cells in the BM
proceeds through several well defined
differentiation stages.
•B cell development is dependent on
successful V(D)J rearrangement.
•V(D)J joining occurs as a stepwise
process.
Stages of B Cell Development
Stepwise V(D)J and VJ
Joining
• H chain: D->J followed by V>DJ
• Lk chain: V->J
• Ll chain: V->J
Stepwise V(D)J and VJ Joining
• Is there a relationship
between the steps of VJ
joining of H and L chains and
B cell differentiation?
Stepwise V(D)J and VJ Joining
BCR and TCR Break the Rules
of Mendelian Genetics
Monospecific Ag receptors:
Only one H chain and one L
chain is expressed per B/T cell
whereas each cell has 2 alleles
for H and L chains
Stages of T Cell Development
The generation of T cells in the thymus
proceeds through several well defined
differentiation stages.
T cell development is dependent on
successful V(D)J and VJ rearrangement
on the 2 chains of the TCR.
Stages of T Cell Development
Successful B and T cell
development is dependent on
appropriate V(D)J recombination
•Why????
Pre-B cell receptor: what is its function?
Successful B and T cell development
is dependent on appropriate VJ
recombination
•The pre-B/T cell receptor may be used to test the
functionality of the rearranged H chain and to
determine whether it specifies a self-reactive
Ag-binding entity
Hairpins cont…
Hypomorphic Mutations
•Hypomorphic mutations give rise to a partial loss of function
•Ommens syndrome arises from a hypomorphic mutations in the
•Rag genes
•A leaky form of SCID arises from a hypomorphic mutation
• in DNA-PK
The Self vs. Non-self
Dichotomy
• Auto-reactive B cells die as a result of negative selection
•B cells must also experience a positive signal through
the BCR (in the BM) to ensure the presence of a receptor
capable of transducing a functional signal to the cell.
Clonal Selections Shapes the Immune Repertoire
Clonal
Selection
V(D)J
Recombination
B Cell Maturation: Testing the BCR for function
Receptor Editing: a means to
salvage self-reactive B cells
• Self-reactive B cells die as a result of negative selection
•Receptor editing is focused on Ig L chains
•Receptor editing allows for a second attempt at VJ joining
to generate a functional L chain which contributes to Ag
recognition but is not self-reactive.
Receptor Editing: occurs primarily on the Ig Lk chain
Why is receptor editing restricted
to the L chain loci?
Can TCR undergo receptor
editing?
•How many polypeptide chains comprise the TCR?
•Which TCR locus is subject to receptor editing?
Zoom-out on B cell development: Overview
Two major types
of mature B cells
B Cell Malignancies
• Malignant transformation of a B cell can occur at any
stage of differentiation
• The stage at which transformation occurs has both
diagnostic and prognostic implications
Microarray analysis
indicates that different
subsets of B cells express
specific “gene signatures.”
Adaptive Immunity
• Central objective:
• Protect against foreign invaders
• Create memory of invasion to prevent
recurrent infection
• Response must be highly specific to
the invader
Ig Isotypes: Classes and Subclasses
Ig isotypes are
defined by the Cterminal portion of
the molecule
There are 5 classes
of Ig and there are 4
sub-classes of IgG.
Isotype class
determines effector
function.
Ig Isotypes
Ig Isotypes Localize to Different
Anatomical Sites in the Body
Ig Isotypes Localize to Different
Anatomical Sites in the Body
Ig Isotypes Have Different Effector
Functions
When Do Isotypes
Matter?
The primary -> secondary
immune response:
•Increase Ig titer
•Switch from IgM to IgG
•Increase Ag binding affinity
When Do Isotypes Matter?
Primary ->Secondary Immune Response Transition
Slide 2
Primary/Secondary Immune
Response
Events associated with
an immune response
over time:
Increase of IgM titer
Increase of IgM titer is
specific to the
immunizing Ag
Slide 2