Immunotherapy for Infectious Diseases

68 Kunert and Katinger
Fig. 4. Humoral defense of invading antigens. ADCC, antibody-dependent cellular
cytotoxicity.
genomic segments rearranged on the RNA transcripts. The rearranged VL and VH mRNAs are then translated as variable regions, as shown in Fig. 5. In the light chain,
FR1, FR2, and FR3, as well as CDR1, CDR2, and a part of CDR3 are determined by
the genomic variable segment (VL). The C terminus of CDR3 and the FR4 are translated
from the genomic J segment. The variability of VH is enhanced by an additional
D segment that forms the CDR3 loop and generates more diversity.
The affinity of binding to the antigen is determined by multiple noncovalent bonds,
whereby the forces depend on the distance between the interacting groups. To ensure
maximun versatility of humoral immunity against a maximum number of antigens, the
number of potential antibodies in humans must be high. This is achieved by additional
mechanisms of genetic recombinations.
Genetic Basis of Antibody Diversity
Antibody VLs are genetically determined by the V and J segments; VHs are formed
by the recombination of V, D, and J segments on the chromosome. Figure 3 shows an
unrearranged and a rearranged human HC locus. Seven families of VH gene segments
provide about 50 VH regions. More than 30 D segments and 6 JH regions can be
rearranged. In vivo recombination of gene segments for heavy and light chain variable
regions during B-cell maturation allows the generation of specific antibodies directed
against numerous antigens from a limited pool of genes. Splicing allows the combination
of any of the genetic segments of V, D, and J with each other owing to recombinases.
During B-cell differentiation, chromosomal rearrangement of heavy-chain V-D-J
and light-chain V-J takes place. To generate a maximum of different antibodies, the
immune system acquired additional mechanisms that increased the diversity of the