Immunotherapy for Infectious Diseases

Humoral Immunity 11
ficity. In light chains, these are the J genes, which link V to C, i.e., we have V-J-C.
Joining is imprecise, causing further variation, or combinatorial diversity. In the case
of H chains, there is yet another region interposed between V and J, the D (for diversity)
gene segment. Thus, in H chains, we have V-D-J-C, again with combinatorial
diversity. So, if there are 25 � light chain V genes, and 5 J genes, constituting light
chain variable regions, there are already 125 possible combinations, disregarding
imprecision of joining. For � light chains, there are 5 V genes and 70 J genes, yielding
350 combinations. For H chains, there are 100 V genes, 50 D genes, and 6 J genes,
giving 30,000 combinations. Overall, disregarding combinatorial diversity, this yields
more than 109 combinations. When we multiply this by joining imprecision, plus a
heightened mutation rate of genes in the hypervariable region, we can see that from
261 genes, we can easily exceed 1018 variations.
The C regions are also genetically encoded, there being four genes for � light chains,
one for � light chains, and nine H chain C genes (IgM, IgD, IgG1–4, IgA1, IgA2,
and IgE).
IgG is the only class of immunoglobulin capable of crossing the placenta (an Fcmediated
event) (Table 1).
The mechanisms for generating antibody diversity may be summarized as follows:
1. Multiple germline V genes
2. V-J and V-D-J recombinations
3. Combinatorial diversity (� recombinational inaccuracies)
4. Somatic point mutation
5. Pairing of heavy and light chains.
Millions of antibody genes come from diverse combinations of gene parts. (Fig. 5).
Antibodies have a variable region (binding site) and a constant region (holds binding
sites together, interacts with cells). B-cell maturation joins V (variable), D (diversity),
and J (segments) to form a variable gene region, connected to a constant region. Posttranscriptional
processing removes introns (and extra J regions) to form mRNA.
Class switching changes the constant region type (Fig. 6). Each stem cell produces
an antibody with a different specificity, because it combines a different combination of
V, D, and J exons for both light and heavy chains (Fig. 7).
ANTIBODY ENGINEERING YESTERDAY AND TODAY
The discovery of monoclonal antibody (MAb) technology in the late 1970s and
early 1980s opened a new era in human therapeutics (3). The economic promise of
MAbs was said to be limitless. In fact, MAbs, could be selected with exquisite specificity.
They were found to orchestrate various components of the immune system such
as ADCC and complement, and they showed a high biologic half-life in blood and tissues,
rendering them effective for prophylactic use. The toxicity of infused MAbs was
expected to be low because of their biologic nature. This concept was further supported
by the successful clinical results of mouse antiidiotypic MAbs in the treatment
of lymphoma and leukemias and by U.S. Food and Drug Administration (FDA)
approval in 1986 of the OKT3 and anti-CD3 mouse MAb for acute renal transplant
rejection.