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SUPERFAMILY
Antibodies are produced in response to invasion by foreign compounds
(antigens) that can be proteins, carbohydrates, nucleic acids or microorganisms
(viruses, bacteria). Antibody binding to an antigen initiates a process that
eliminates the foreign substance.
Antigens may have several antigenic determinant regions in them; in proteins,
this can be as small as 6 or 7 amino acids.
Each human can produce about 10 million different antibody structures. All
antibodies have similar structures but differ in specificity.
In autoimmune diseases, the bodys own molecule is recognized by the immune
system.
Basic structure of immunoglobulins
Immunoglobulin molecules consist of four polypeptide chains, two identical
copies of two different chains, designated L and H.
Two light chains (L) of identical sequence combine with two heavy chains (H) of
identical sequence to form the structure (LH)2.
The four chains are covalently interconnected by disulfide bonds. One L binds to
one H, and the two heavy chains are also interconnected. The latter is called
the hinge region, which gives the molecule flexibility upon antigen binding.
Each H is associated with an L in such a way that the N termini are close to each
other.
In the most common immunoglobulin, IgG, the H chains have about 440 amino
acids (50 kDa) while the L has about 220 (25 kDa) amino acids.
In the other types of immunoglobulins, the H chains are different from those in
IgGs, and they can form dimers to pentamers.
Figure 9.1, Devlin. Linear Representation of four-chain IgG antibody molecule Two H chains
and two L chains in C to N terminal directions. Interchain disulfides link H and L chains together.
Domains of the constant C region of the H chain are CH1, CH2, and CH3. The constant region of
L is designated CL and variable, V, regions are VH and VL of H and L chains, respectively.
Sequences of the N terminal half of the L chains and the N terminal quarter of
the H chains are highly variable between different antibody molecules.
These N-terminal sequences are the variable (V) regions and are designated
VH and VL.
Within the V regions, certain segments are hypervariable.
These regions are termed the complementarity-determining regions (CDRs)
since they form the antigen binding sites.
Thus, variable regions give the antibody its specificity.
In contrast, the C-terminal three quarters of the H chains and the C terminal
half of the L chains are homologous in sequence with the other H or L chains
of the same class of antibodies.
These constant (C) regions with a homologous primary structure are
designated CH and CL in the H and L chains, respectively.
The CH regions determine the antibody class, provide binding site for
complement proteins and are the site necessary for antibodies to cross the
placental membrane.
Figure 9.2, Devlin. Diagrammatic of Structure for IgG. L chains are divided into domains VL and
CL. H chains are divided into domains VH and CH1, CH2, CH3. Antigen binding is in VH-VL.
Figure 9.4, Devlin. Immunoglobulin Fold. (a) is scheme for folding of a CL domain, showing pleated sheet structure. Blue shows cystine bond. Light arrows are strands in plane above, dark
are below.
The H and L chains finally fold over each other and stabilized by disulfide bonds.
This gives the final 3D structure to the molecule.
Figure 9.6, Devlin. Model of an IgG antibody molecule. The two L are light gray spheres and the
H chains are lavender. Carbohydrates are green and orange. The CDR of the VH-VL are dark
red in the H chains and pink in the L. The heptapeptide hinge connecting the Fab and Fc are
dark red.
Antibody classes
Immunoglobulins in a single class contain common homologous regions.
Characteristics of each class are due to differences in the heavy chains.
The different H chains are designated as , , , , and occur in IgG,
IgA, IgD, IgE and IgM classes, respectively.
Two types of L chains are made, lambda () and kappa (), either of which
are found combined with the five classes of H chains.
IgDs, IgEs and IgGs are monomers (LH) 2 , containing delta, epsylon and gamma
heavy chains, respectively.
IgAs in serum are mostly monomeric (LH) 2 (alpha heavy chains), however, in
seromucosal secretions are covalently linked dimeric structures ((LH)2)2 kept together
by the so-called J-chain. These secretory IgA molecules also contain an additional
secretory component (a short polypeptidet), which facilitates transport of the secretory
IgA across the mucosal epithelium and protects the secretory IgA from proteolysis.
IgMs are pentamers ((LH)2)5 kept together by the so-called J-chain (same as in
IgA).
IgG is the major immunoglobulin in plasma, it is monomeric (LH) 2.
Biosynthesis of a specific IgG in significant levels takes about 10 days
after exposure to a new antigen.
IgMs are made first and faster and serve as the first line of defense until IgGs are
made.
Figure 9.3 Devlin. Time course of specific antibody IgM and IgG response to antigen
IMMUNIZATION
An immunizing vaccine can consist of killed bacterial cells, inactivated viruses, killed
parasites, a nonvirulent form of live bacterium related to a virulent bacterium or
denatured bacterial toxin or recombinant protein.
Antigens not only cause differentiation of lymphoid cells so they produce antibody but
also cause differentiation of some of the cells into memory cells. Memory cells do not
secrete antibody but place antibody on the outer surface and serve as radar. Later,
when infection occurs, the binding of antigen to memory cells stimulates memory cells to
divide into antibody producing cells and new memory cells. This reduces the time
needed for defense and increases the concentration of antigen specific antibody. Newer
vaccines for adults include pneumococcal vaccine, hepatitis B and influenza vaccine.
SUMMARY:
(1) The heavy and light chains fold into multiple domains each; these domains
are called the immunoglobulin fold;
(2) The 4 chains associate non-covalently to form the 3D structure of the
molecule and then stabilized by disulfide bonds;
(3) The antigen binding sites (CDRs) contain multiple loops at the N-terminal
hypervariable regions of VL and HL to bind antigen;
(4) The interactions between antigen and antibody are non-covalent;
(5) Small conformational changes occur in the VL-VH domains upon binding to
antigen;
(6) This antigen binding induces conformational changes in distant regions such
as the Fc region and exposes the complement or C1q binding domain.
(7) Conformational change in the antibody structure is crucial to trigger the
elimination of the antigen.
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