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immunoglobulin evolution 370 immunoglobulin function
Immunoglobulin E (IgE) molecule.
four-domain (designated C H1, C H2, C H3, and C H4) constant
region. This heavy chain does not possess a hinge region. In
humans, the ε heavy chain has 428-amino-acid residues in
the constant region. The ε chains have no carboxyl terminal
portions. Two ε heavy polypeptide chains, together with
two κ or two λ light chains fastened together by disulfide
bonds, comprise an IgE molecule.
immunoglobulin evolution
Like mammalian immunoglobulins, dogfish and shark
immunoglobulins contain two light and two heavy
polypeptide chains that express charge diversity. Shark
immunoglobulin most closely resembles mammalian IgM.
All vertebrates synthesize antibodies that have classic
immunoglobulin structures. They consist of two kinds of
polypeptide chains that are linked covalently by disulfide
bonds and are polydisperse in charge. Immunoglobulins of
all classes of vertebrates derived from the primitive jawed
fish (placoderms) are now known, such as those from
elasmobranches that include sharks and rays; teleost fish
that include goldfish; amphibians that include bullfrogs
and Xenopus; reptiles; and birds. All of these synthesize
antibodies comparable to the IgM isotypes of mammals.
The IgM molecules of bony fish teleosts occur as tetramers
rather than pentamers. Lungfish, amphibians, reptiles,
and birds develop other classes of immunoglobulins
characterized by distinct heavy chains that resemble γ
chains. Distinct immunoglobulin monomers of amphibians,
reptiles, and birds have larger heavy chains than the
mammalian γ chain and may represent gene duplications.
These non-IgM immunoglobulins are designated IgY
(amphibians, reptiles, chickens). Other distinct immunoglobulin
classes are present in amphibians (IgX), lungfish
(IgN), reptiles (IgN), and birds (IgN). Light chains are
designated as κ or λ, and their relative frequencies vary
from one species to another. Sharks possess a second
major immunoglobulin class termed IgW or IgNARC (new
antigen receptor from cartilaginous fish). It has a heavy
chain that possesses one variable and six constant domains
and may be the primitive immunoglobulin in evolution.
IgW variable domains are similar to those of heavy
chains but differ in that they vary in sequence consistent
with diversity through recognized many antigens. Two
genes are requisite early in T and B cell development for
recombination of variable, diversity, and joining segments
of immunoglobulin light and heavy chains and T cell
receptor chains to take place. The most primitive living
vertebrates, the cyclostomes (hagfish and lampreys) synthesize
antibodies equivalent to those of higher vertebrates
in their possession of heavy and light polypeptide chains,
disulfide covalent bonding, and charge dispersity.
immunoglobulin fold
An immunoglobulin domain’s three-dimensional configuration.
An immunoglobulin fold has a sandwich-like structure
comprised of two β-pleated sheets that are nearly parallel.
One sheet has four antiparallel chain segments, and the
other has three. Approximately 50% of the amino acid residues
of the domain are in the β-pleated sheets. The other
50% are situated in polypeptide chain loops and terminal
segments. The turns are sites of invariant glycine residues.
Hydrophobic amino acid side chains are situated between
the sheets.
immunoglobulin fragment
A term reserved for products that result from the action
of proteolytic enzymes on immunoglobulin molecules.
Intrachain disulfide bonds can be severed by reduction in
the presence of denaturing agents such as urea, guanidine,
or detergents. Peptide bonds in intact domains are
not easily split by proteolytic enzymes. Light chains can
be cleaved at the V–C junction, giving rise to large segments
that correspond to the V L and C L domains. Similar
cleavage of the heavy chain is more difficult to achieve.
Papain cleaves H chains at the N terminus of the H–H
disulfide bonds, giving two individual portions of the
terminus of the molecule, called Fab, and the fragment
of the C terminus region, Fc, which is crystallizable. In
contrast, pepsin cleaves H chains at the C terminus of the
H–H disulfide bonds; thus, the two Fab fragments will
remain joined and are called F(ab′) 2. Pepsin degrades the
C H2 domains but splits the C H3 domains, which remain
noncovalently bonded in dimeric form and are called
pFc′. Further digestion of the pFc′ with papain results in
smaller dimeric fragments called Fc′. Plasmin has been
found to cleave the immunoglobulin molecule between
C H2 and C H3, giving rise to a fragment designated Facb.
The heavy chain portion of the Fab, designated Fd, and
the heavy chain portion of the Fab′ fragment, designated
Fd′, result from the breakdown of an F(ab′) 2 fragment
produced by pepsin digestion of the IgG molecule. The
Fv fragment consists of the variable domain of heavy
and light chains on an immunoglobulin molecule where
antigen binding occurs.
immunoglobulin function
Links an antigen to its elimination mechanism (effector
system). Antibodies induce complement activation and
cellular elimination mechanisms that include phagocytosis
and antibody-dependent, cell-mediated cytotoxicity
(ADCC). This type of activation usually requires antibody
molecules clustered together on a cell surface rather than
as free unliganded antibody. Antibodies can combine with
virus particles to render them noninfectious in vitro through
neutralization. IgG catabolism is regulated by IgG concentration.
All immunoglobulin classes can be expressed on B
cell surfaces, where they act as antigen receptors, although
this is mainly a function of IgM and IgD. Surface immunoglobulin
has an extra C terminal sequence compared to
secreted immunoglobulin containing linker, transmembrane,
and cytoplasmic segments.