Page 311 - Color Atlas of Biochemistry

302 Tissues and organs
Antibody biosynthesis
The acquired (adaptive) immune system (see
p. 294) is based on the ability of the lympho-
cytes to keep an extremely large repertoire of
antigen receptors and soluble antibodies
ready for use, so that even infections involv-
ing new types of pathogen can be combated.
The wide range of immunoglobulins (Ig) are
produced by genetic recombination and addi-
tional mutations during the development and
maturation of the individual lymphocytes.
A. Variability of immunoglobulins
8
It is estimated that more than 10 different
antibody variants occur in every human
being. This variability affects both the heavy
and the light chains of immunoglobulins.
There are five different types of heavy (H)
chain, according to which the antibody classes
are defined (α, δ, ε, γ, µ), and two types of light (see p. 230). The Vsegments,of which there
(L) chain (κ and λ;see p. 300).The various Ig
types that arise from combinations of these
chains are known as isotypes. During immu-
noglobulin biosynthesis, plasma cells can
switch from one isotype to another (“gene
switch”). Allotypic variation is based on the
existence of various alleles of the same
gene—i. e., genetic differences between indi-
viduals. The term idiotypic variation refers to single Csegment codes for the constant part
the fact that the antigen binding sites in the
F ab fragments can be highly variable. Idiotypic
variation affects the variable domains (shown
here in pink) of the light and heavy chains. At each B cell. One of the 150 L/V tandem seg-
certain sites—known as the hypervariable re-
gions (shown here in red)—variation is partic-
ularly wide; these sequences are directly in-
volved in the binding of the antigen.
B. Causes of antibody variety
There are three reasons for the extremely
wide variability of antibodies:
1. Multiple genes. Various genes are avail-
able to code for the variable protein domains.
Only one gene from among these is selected
and expressed.
2. Somatic recombination. The genes are
divided into several segments, of which there
are various versions. Various (“untidy”) com-
binations of the segments during lymphocyte
Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
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maturation give rise to randomly combined
new genes (“mosaic genes”).
3. Somatic mutation. During differentiation
of B cells into plasma cells, the coding genes
mutate. In this way, the “primordial” germ-
line genes can become different somatic genes
in the individual B cell clones.
C. Biosynthesis of a light chain
We can look at the basic features of the ge-
netic organization and synthesis of immuno-
globulins using the biosynthesis of a mouse κ
chain as an example. The gene segments for
this light chain are designated L, V, J, and C.
They are located on chromosome 6 in the
germ-line DNA (on chromosome 2 in humans)
and are separated from one another by in-
trons (see p. 242) of different lengths.
Some 150 identical Lsegments code for the
signal peptide (“leader sequence,” 17–20
amino acids) for secretion of the product
are 150 different variants, code for most of the
variable domains (95 of the 108 amino acids).
L and V segments always occur in pairs—in
tandem, so to speak. By contrast, there are
only five variants of the Jsegments (joining
segments) at most. These code for a peptide
with 13 amino acids that links the variable
part of the κ chains to the constant part. A
of the light chain (84 amino acids).
During the differentiation of B lympho-
cytes, individual V/J combinations arise in
ments is selected and linked to one of the five
J segments. This gives rise to a somatic gene
that is much smaller than the germline gene.
Transcription of this gene leads to the forma-
tion of the hnRNA for the κ chain, from which
intronsand surplusJ segments are removed
by splicing (see p. 246). Finally, the completed
mRNA still contains one each of the L–V–J–C
segments and after being transported into the
cytoplasm is available for translation. The
subsequent steps in Ig biosynthesis follow
the rules for the synthesis of membrane-
bound or secretory proteins (see p. 230).