B cell Developmental Stages When Different Genetic Processes Occur

Early B Cell Development

V(D)J Recombination:

• Occurs very early in B cell development, in the bone marrow
• Takes place in Pro-B and Pre-B cell stages
• Rearranges one V, D, and J gene segment to produce the BCR heavy chain
• Then rearranges one V and J segment for the BCR light chain
• This generates the initial BCR specificity on immature B cells

V(D)J Selection:

• Occurs immediately after V(D)J recombination, in immature B cells
• The newly generated BCR is tested for functionality and self-reactivity
• Cells with non-functional or strongly self-reactive BCRs undergo receptor editing or apoptosis
• Only non-self-reactive immature B cells with a functional BCR survive

Further B Cell Development

Class Switching:

• Occurs much later in activated B cells, after antigen encounter
• Takes place in germinal centers of peripheral lymphoid organs
• Enzymatic deletion of constant region genes upstream of a new constant region
• Allows switching from IgM to IgG, IgA or IgE isotypes

Somatic Hypermutation:

• Also occurs in germinal center B cells after antigen activation
• Introduces point mutations within rearranged V gene segments
• Increases BCR affinity for the antigen that initially activated the B cell
• Allows affinity maturation to produce high affinity antibodies

The Importance of AID (aka AICD)

The enzyme Activation-Induced Cytidine Deaminase (AID) is critically important for both class switching and somatic hypermutation.

For class switching, AID initiates DNA damage that triggers deletion of the intervening DNA to rejoin the rearranged VDJ to a new downstream constant region.

For somatic hypermutation, AID deaminates cytosine nucleotides in the V gene segments, triggering mutations during repair.

So in summary, the initial BCR specificity is set in the bone marrow by V(D)J recombination/selection, while the mature effector functions of high affinity IgG/IgA/IgE isotypes are acquired later in activated B cells through AID-mediated class switch recombination and somatic hypermutation.

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Source: Claude 3 Sonnet response prompted and edited by Joel Graff.

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