Stages of Hematopoietic Development

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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
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Stages of Hematopoietic Development
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Stages of Hematopoietic Development
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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.

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B and T lymphocytes derive from a common
lymphoid progenitor
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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.

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Stages of B Cell Development
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Stepwise V(D)J and VJ Joining

• H chain D-gtJ followed by V-gtDJ
• Lk chain V-gtJ
• Ll chain V-gtJ

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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?

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Stepwise V(D)J and VJ Joining
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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
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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.
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Stages of T Cell Development
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Successful B and T cell development is dependent
on appropriate V(D)J recombination

• Why????

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Pre-B cell receptor what is its function?
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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

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Hairpins cont
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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

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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.

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Clonal Selections Shapes the Immune Repertoire
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Clonal Selection
V(D)J Recombination
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B Cell Maturation Testing the BCR for function
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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.

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Receptor Editing occurs primarily on the Ig Lk
chain
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Why is receptor editing restricted to the L chain
loci?
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Can TCR undergo receptor editing?

• How many polypeptide chains comprise the TCR?

• Which TCR locus is subject to receptor editing?

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Zoom-out on B cell development Overview
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Two major types of mature B cells
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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

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Microarray analysis indicates that
different subsets of B cells express specific
gene signatures.
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Adaptive Immunity

• Central objective
• Protect against foreign invaders
• Create memory of invasion to prevent recurrent
  infection
• Response must be highly specific to the invader

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Ig Isotypes Classes and Subclasses

• Ig isotypes are defined by the C-terminal portion
  of the molecule
• There are 5 classes of Ig and there are 4
  sub-classes of IgG.
• Isotype class determines effector function.

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Ig Isotypes
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Ig Isotypes Localize to Different Anatomical
Sites in the Body
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Ig Isotypes Localize to Different Anatomical
Sites in the Body
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Ig Isotypes Have Different Effector Functions
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When Do Isotypes Matter?

• The primary -gt secondary
• immune response
• Increase Ig titer
• Switch from IgM to IgG
• Increase Ag binding affinity

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When Do Isotypes Matter?
Primary -gtSecondary Immune Response Transition
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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

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