The Questions of Developmental Biology

This would take up an enormous amount of chromosomal space. Moreover, how could
the immune system "know" how to make an antibody to some foreign molecule (antigen) that
isn't even found outside the laboratory? They eventually discovered that the genome of the B cell
does not contain DNA encoding for any of the antibody proteins. Rather, the DNA is rearranged
during the development of the B cell to create the antibody-encoding genes. Moreover, while the
mammalian organism has the ability to synthesize over 10 million different types of antibody
proteins, each B cell can synthesize only one.
All immunoglobulins secreted from the B cells have a very similar structure. Each
consists of two pairs of polypeptide subunits. There are two identical heavy chains and two
identical light chains; the chains are linked together by disulfide bonds (Figure 4.12). The
specificity of the immunoglobulin molecule (i.e., whether it will bind to a poliovirus, an E. coli
cell, or some other antigen) is determined by the amino acid sequence of the variable regions at
the amino-terminal ends of the heavy and light chains. The variable regions of the
immunoglobulin molecule are attached to constant regions that give the antibody its effector
properties needed for inactivating the antigen.
The genes that encode the immunoglobulin heavy and light chains are organized in
segments. Mammalian light chain genes contain three segments (Figure 4.12). The first gene
segment, V, encodes the first 97 amino acids of the light chain variable region. There are about
300 different V sequences linked tandemly on the mouse genome. The second segment, J,
consists of 4 or 5 possible DNA sequences for the last 15 17 residues of the variable region. The
third segment, C, encodes the constant region of the light chain. During B cell differentiation,
which occurs as the B cells are maturing in the bone marrow, one of the 300 V segments and one
of the 5 J segments combine to form the variable region of the antibody gene. This is done by
moving a V segment sequence next to a J segment sequence, a rearrangement that eliminates the
intervening DNA (Hozumi and Tonegawa 1976).
The heavy chain genes contain even more segments than the light chain genes. Heavy
chain genes include a V segment (200 different sequences for the first 97 amino acids), a D
segment (10 15 different sequences encoding 3 14 amino acids), and a J segment (4 sequences
for the last 15 17 amino acids of the variable region). The next segment, C, codes for the
constant region. The heavy chain variable region is formed by adjoining one V segment and one
D segment to one J segment (Figure 4.12). This VDJ variable region sequence is now adjacent to
the first constant region of the heavy chain genes the C m region, which is specific for antibodies
that can be inserted into the plasma membrane.
Thus, an immunoglobulin molecule is formed from two genes created during the antigenindependent
stage of B lymphocyte development. About 10 3 different light chain genes and about
10 4 different heavy chain genes can be formed. Since each is formed independently of the other,
about 10 7 types of immunoglobulins can be created from the union of the light chain and the
heavy chain within a cell. Each cell makes only one of these 10 7 antibody types.
The B cell is not the only cell type that alters its genome during differentiation. The other
major cell type of the immune system, the T cell, also recombines and deletes a portion of its
genome in the construction of its antigen receptor (Fujimoto and Yamagishi 1987). The enzymes
responsible for mediating these DNA recombination events appear to be the same in the B and T
cell lineages. Called recombinases (Agrawal et al. 1998), these two proteins recognize the signal
regions of DNA immediately upstream from the recombinable DNA segments and form a
complex there that initiates the double-stranded breaks. Moreover, the genes for these