LECTURE #6 B CELL DEVELOPMENT

After studying lecture #6, you should be familiar with the following concepts.
1. Somatic Recombination. B lymphocytes are predicted to generate a large number of
distinct antigen receptors (approximately 1 X 1011). This is made possible through a
process known as somatic recombination. The BCR locus does not contain a linear
arrangement of 1 X 1011 genes. Instead, the BCR locus consists of a sequential
arrangement of gene segments. For example, the Ig Heavy chain locus consists of
tandem arrangements of variable (V), diversity (D) and joining (J) gene segments. There
are approximately 100 V segments, 27 D segments and 6 J segments. During B cell
development a single D segment combines with a single J segment. The DJ segment
then combines with a single V segment. The choice of gene segments for each
recombination event is entirely random. The result is a VDJ segment that encodes the
antigen-binding variable domain of the mature heavy chain of the BCR/Ig. A similar
event occurs at the light chain, with the exception that light chains lack D gene
segments. Each recombination event generates a novel BCR/Ig variable region with a
novel antigen specificity.
2. B Cell Development. B cells develop from bone marrow stem cells. Somatic
recombination occurs in the bone marrow to generate a mature, nave B cell. Nave B
cells exit the bone marrow and enter peripheral lymphoid organs in search of antigen. B
cells that fail to encounter antigen undergo apoptosis. B cells that encounter antigen and
receive a second signal become activated. Activated B cells undergo clonal expansion.
Some of the activated B cells start to produce and secrete antibodies. The antibodies
retain the antigen specificity of the BCR from the activated B cell. Other activated B cells
differentiate into memory cells. Memory cells are a population of long-lived lymphocytes
that persist after clearance of infection and mediate a faster, more potent immune
response upon re-exposure to antigen. Other B cells undergo class-switching to produce
a new Ig Isotype.
3. Class Switching. The heavy chain constant region gene segments are arranged
downstream of the VDJ segments in a defined order - (For IgM), (For IgD) (For
IgG), (For IgE) and (For IgA). In a nave B cell, transcription terminates after the first
constant gene segment, meaning that the first Ig Isotype expressed in B cells is IgM.
Activation can cause a rearrangement at the heavy chain locus where the DNA encoding
some constant regions are deleted. For example, B cell activation often causes the
deletion of and constant gene segments, placing the constant gene segment
downstream of the variable gene segment. In this case, the B cell begins to produce
IgG. Variable gene segments remain unaltered during class switching, ensuring that the
B cells retains its original antigen specificity. Importantly, the change in constant regions
means that the new class of antibody executes different effector function. Thus, class
switching allows the immune system to fine tune the immune response to the antigen.
Prepared by E. Foley