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

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

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 L  chain: V->J L 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????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

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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

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

ClonalSelection 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 L  chain

Why is receptor editing restricted to the L chain loci?

Can TCR undergo receptor editing? Which TCR locus is subject to receptor editing? How many polypeptide chains comprise the TCR?

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 memoryCreate memory of invasion to prevent recurrent infection specificResponse must be highly specific to the invader

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.

Ig Isotypes

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? Slide 2 Primary ->Secondary Immune Response Transition

Primary/Secondary Immune Response Slide 2 Events associated with an immune response over time Events associated with an immune response over time:  Increase of IgM titer  Increase of IgM titer is specific to the immunizing Ag