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chapter
35
Molecular Immunology
FIGURE 35-20
(Also see color figure.) Immunoglobulin heavy chain gene structure and gene processing. Exons of the heavy chain
genes that encode the variable regions of the immunoglobulin molecule are shown in orange and labeled V], V
2
, .
. .V„.
Selection from these V exons during embryonic development produces the unique sequences of each B-cell clone. The
germline genes for the immunoglobulin heavy chains contain an additional group of exons, the D (diversity, light blue;
labelled D], D
2
,... Dn) exons. Recombination between the V and D regions occurs more frequently than that between
the V and J exons in the light chain exons. Introns between the V and D and between the D and J exons contain signal
sequences that regulate the expression of the enzyme recombinase. This enzyme is responsible for the efficient
recombination that gives rise to the epitope-specific B-cell clones with their individual Ig genes. The heavy chain genes
contain exons that encode all of the isotype heavy chains. Class switching, i.e., the change in chain expression that
occurs during antibody synthesis after B-cell activation, results from alternative splicing between the J exons and the
exons for the various heavy chain isotypes.
heavy chain constant regions (Table 35-2). In a rearrange-
ment process similar to that of the light chain genes, com-
binations of 1000 V exons, 10 D exons, and 4 J exons
lead to more than 40,000 different polypeptide sequences.
The constant-region exons, of which there are eight, create
the different classes of antibodies. Recombination among
the V, D, and J exons creates additional diversity. And,
because there is “imprecision” in the regions joining these
exons, even greater diversity is obtained. The processing of
the germline genes that generate Ig heavy chains is shown
in Figure 35-20.
The genes for T-cell receptors are also rearranged by
mechanisms similar to the immunoglobulin genes. V, D,
and J regions recombine to form the multiplicity of TcR
variants that specifically recognize the peptides presented
on the MHC proteins. The genes for the
a
and
y
TcR pro-
teins do not contain D regions. TcR genes also differ from
Ig genes in that they do not commonly undergo changes
during T-cell division.
The genes for Ig and TcR protein chains are located
on different chromosomes. The genes for
k
chains are
located on chromosome
2
and for
X
chains on chromo-
some 22. The genes for Ig heavy chains are on chromo-
some 14. Similarly, the TcR genes are distributed among
different chromosomes. The genes for the
a
and
S
chains
are on chromosome 14; the genes for
ji
and
y
chains are
on chromosome 7.
Class (Isotype) Switching
Immunoglobulin synthesis by B cells in response to an
antigen initially results in the production of IgM. This is
followed after a period of
1 - 2
weeks by the formation
and appearance of IgG with the same epitope specificity
as the original IgM. This “class switching” results from
a change in the expression from
/1
(mu) to
y
(gamma)
heavy chain genes. Although the specificity of the an-
tibody produced by a B-cell clone is determined dur-
ing embryonic development, the class of antibody pro-
duced by the clone is influenced by T-cell communication
with the B cell. This B-cell maturation is mediated by
cytokines.
