Stages of Hematopoietic Development The hematopoietic system generates blood cells. The...

Stages of Stages of Hematopoietic Hematopoietic DevelopmentDevelopment

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 Stages of Hematopoietic Hematopoietic DevelopmentDevelopment

Stages of Stages of Hematopoietic Hematopoietic DevelopmentDevelopment

Lymphocytes arise from Lymphocytes arise from HSC through CLPHSC 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 B and T lymphocytes derive from aderive from a

common lymphoid common lymphoid progenitorprogenitor

HSC MLP CLP GL- Pro-B

CMP

Pro-T

PU.1

PU.1

Stages of B Cell Stages of B Cell DevelopmentDevelopment

•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 Stages of B Cell DevelopmentDevelopment

Stepwise V(D)J and Stepwise V(D)J and VJ JoiningVJ Joining

•H chain: D->J followed by V->DJ

•L chain: V->J•L chain: V->J

Stepwise V(D)J and VJ Stepwise V(D)J and VJ JoiningJoining

•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 Stepwise V(D)J and VJ JoiningJoining

BCR and TCR Break the BCR and TCR Break the Rules of Mendelian Rules of Mendelian

GeneticsGeneticsMonospecific Ag Monospecific Ag receptors:receptors:

Only one H chain and one L chain is expressed per B/T cellwhereas each cell has 2 alleles for H and L chains

Stages of T Cell Stages of T Cell DevelopmentDevelopment

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 Stages of T Cell DevelopmentDevelopment

Successful B and T Successful B and T cell development is cell development is

dependent on dependent on appropriate V(D)J appropriate V(D)J recombinationrecombination

•Why????Why????

Pre-B cell receptor: Pre-B cell receptor: what is its function?what is its function?

Successful B and T cell Successful B and T cell development is dependent development is dependent

on appropriate VJ on appropriate VJ recombinationrecombination

•The pre-B/T cell receptor may be used to test the functionality of the rearranged H chain and todetermine whether it specifies a self-reactive Ag-binding entity

Hairpins cont…Hairpins cont…

Hypomorphic MutationsHypomorphic 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-The Self vs. Non-self Dichotomyself 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 receptorcapable of transducing a functional signal to the cell.

Clonal Selections Shapes the Immune RepertoireClonal Selections Shapes the Immune Repertoire

Clonal Clonal SelectionSelection

V(D)JRecombination

B Cell Maturation: Testing the BCR for functionB Cell Maturation: Testing the BCR for function

Receptor Editing: a Receptor Editing: a means to salvage self-means to salvage self-

reactive B cellsreactive 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 joiningto generate a functional L chain which contributes to Ag recognition but is not self-reactive.

Receptor Editing: occurs primarily on the Ig LReceptor Editing: occurs primarily on the Ig L chain chain

Why is receptor Why is receptor editing restricted to editing restricted to

the L chain loci?the L chain loci?

Can TCR undergo Can TCR undergo receptor editing?receptor editing?

•Which TCR locus is subject to receptor editing?

•How many polypeptide chains comprise the TCR?

Zoom-out on B cell Zoom-out on B cell development: development: OverviewOverview

Two major Two major types types of mature B of mature B cellscells

B Cell MalignanciesB 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 differentsubsets of B cells expressspecific “gene signatures.”

Adaptive ImmunityAdaptive Immunity•Central objective:

•Protect against foreign invaders

•Create memorymemory of invasion to prevent recurrent infection

•Response must be highly specificspecific to the invader

Ig Isotypes: Classes and Ig Isotypes: Classes and SubclassesSubclasses

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.

Ig IsotypesIg Isotypes

Ig Isotypes Localize to Ig Isotypes Localize to Different Anatomical Different Anatomical Sites in the Body Sites in the Body

Ig Isotypes Localize to Ig Isotypes Localize to Different Anatomical Sites Different Anatomical Sites

in the Body in the Body

Ig Isotypes Have Different Ig Isotypes Have Different Effector FunctionsEffector Functions

When Do When Do Isotypes Isotypes Matter?Matter?

The primary -> secondary immune response:

•Increase Ig titer

•Switch from IgM to IgG

•Increase Ag binding affinity

When Do Isotypes Matter?When Do Isotypes Matter?

Slide 2

Primary ->Secondary Immune Response TransitionPrimary ->Secondary Immune Response Transition

Primary/Secondary Primary/Secondary Immune ResponseImmune Response

Slide 2

Events Events associated with associated with an immune an immune response over response over timetime:

Increase of IgM titer

Increase of IgM titer is specific to the immunizing Ag