Biochemistry of immunoglobulins

Figure 14.3 shows a diagram of the basic immunoglobulin molecule. This consists of four polypeptide chains arranged as two L (light) chains and two identical H (heavy) chains. The

Figure 14.3 Structure ofthe basic immunoglobulin molecule.

light and heavy chains are usually held together by disulphide (S-S) bonds. IgG and serum IgA molecules are mainly monomers of this basic immunoglobulin structure; secretory IgA is mainly dimeric. IgM molecules are pentamers, with the basic immuno-globulin molecules held together by S-S bonds and a J (joining) chain (Figure 14.4).

There are two distinct types of light chain, kappa (k) and lambda (X). These are common to all immunoglobulins. Either of these chains may combine with any heavy chain, but in any one immunoglobulin both light chains are of the same type and are identical. Kappa chains occur in about 65% and lambda chains in about 35% of the normal immunoglobulins in each class. Each class has an immunologically distinct heavy chain: y for IgG, |i for IgM, a for IgA, 8 for IgD and e for IgE (Figure 14.4). There are four subclasses of human IgG (IgGI, IgG2, IgG3 and IgG4, with y1, y2, y3 and y4 heavy chains), and two IgA subclasses (IgA1 and IgA2, with al and a2 chains).

Analyses of various light chains from different sources show that the amino acid sequence differs in one-half of the chain (variable region), whereas in the other half the sequence remains remarkably constant (constant region) between light chains of the appropriate kappa or lambda groups. Similarly, in the corresponding heavy chain, there is a variable region and a constant region when different chains are analysed.

Papain can split the basic Ig molecule into three fragments at a site near the S-S bonds that hold the heavy chains together (Figure 14.3). One fragment contains the C-termini of the heavy chains and is called the Fc fragment. The other two are called Fab fragments, each of which consists of the N-terminus of the heavy chain (Fd portion) and the whole of the light chain, and contains the antigen binding site of the molecule.

Repetition of amino acid sequences within the heavy chain constant regions indicates that there are either three (for IgG and IgA) or four (for IgM, IgD, IgE) constant region domains for H chains. These are designated CH1, CH2, CH3 and CH4. In

Immunoglobulin Ch2 Ch3

Figure 14.3 Structure ofthe basic immunoglobulin molecule.

Figure 14.4 Structure of IgG, IgM and IgA molecules.

65% k light chains

35% X light chains

Hinge Area Immunoglobulin

10% as dimers

— a contrast, there is only one constant region domain for light chains and only one variable region domain for heavy and light chains. The segment between the CH1 and CH2 is called the hinge region. This area imparts flexibility to the immunoglobulin molecule so that antigen binding sites can span varying distances.

The vast majority of the differences between antibodies of various specificities occur in three or four short amino acid sequences in the L- and H-chain variable regions. These hypervariable sequences contact the antigen on binding and provide the basis of antibody specificity.

The remaining sequences within the variable region are known as the framework determinants. These are believed to provide the general skeleton of the antigen-recognizing region, within which variations in and between hypervariable sequences generate specificity for the different epitopes bound by different antibodies.

Amino acid sequences within framework and hypervariable segments can sometimes be recognized by specific antisera, usually from another species, raised by deliberate immunization with a particular antibody. The sequences recognized are referred to as idiotopes, and the sera that define them are called anti-idiotypes.

The idiotype of the particular immunoglobulin molecule represents the sum of all the idiotopes of all its framework and hypervariable sequences.

The binding of anti-idiotype sera that recognize idiotopes within hypervariable sequences of the immunizing immuno-globulin can be inhibited by the specific hapten recognized by that immunizing antibody. This is because contact between the hapten and the hypervariable sequences blocks access of the idiotype-specific antibody. In contrast, binding of anti-idiotypes to framework determinants of the immunizing antibody is usually not blocked by the binding of the hapten recognized by that antibody.

The great diversity in the repertoire of antibodies generated by the immune system in response to the immense variety of antigens that it encounters is a direct reflection of the immune system's ability to generate variations within the three hypervariable sequences. This ability is partly genetic in origin and arises from the random selection and joining of several separate genetic elements that produce a single intact variable region gene coding for the final variable region amino acid sequence.

The variable region genes comprise: (i) genes coding for a large number of V-region sequences, with approximately 150 K-chain, 125 X-chain and 500 or so H-chain variable region genes; each of these genes is arranged in three exons, the random joining of which provides the variations that generate the first and second hypervariable sequences; (ii) in H chains only, approximately 10-20 D ('diversity') genes; and (iii) in both H and L chains, five or six J ('joining') genes.

The random joining of numerous choices, in a variety of combinations of V-J genes in L chains and V-D-J genes in H chains, during ontogeny of the immune response, generates the third hypervariable sequence and provides an additional somatic contribution for increasing the repertoire of the immune system. Following V-J/V-D-J joining, which is achieved by splicing together of certain DNA sequences and deletion of others during B-cell maturation, a further increase in antibody diversity is achieved by mutation in the spliced V gene DNA of mature B cells, during their proliferation in an ongoing immune response.

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