BIOCHEMISTRY - L. Stryer - 1984

VOLUME 3

PART V. MOLECULAR PHYSIOLOGY

CHAPTER 33. IMMUNOGLOBULINS

Summary

An antibody is a protein synthesized by an animal Organism in response to the Introduction of a foreign macromolecular compound (termed an antigen or immunogen), characterized by a high affinity for it. Small foreign molecules (haptens) elicit The formation of specific Antibodies only when attached to macromolecules. Antibody synthesis is governed by Selection rather than instruction. The antigen binds to The surface of those lymphocytes that initially synthesize antibodies specific to that given antigen. Attachment of the antigen to The Cell-surface receptor triggers Cell Division and the synthesis of large amounts of the specific antibody. Antibodies directed against a specific determinant are generally heterogeneous because they are produced by different Cells. Antibodies produced by a single cell or a single cell clone are homogeneous. There are five classes of antibodies in serum, with the major Class being IMMUNOGLOBULINS D. Following antigen administration, antibodies belonging to the immunoglobulin M class appear first in the serum. Immunoglobulins A constitute a class of antibodies secreted into external secretions. The Physiological Role of immunoglobulins D and E has not yet been established.

Antibodies are composed of light (L) and heavy (H) chains. Immunoglobulin G, which has an L₂H₂ subunit Structure, contains two antigen-binding sites. Enzymatic Cleavage of immunoglobulin G yields two F_ab fragments that bind the antigen without precipitating it, as well as one F_c fragment endowed with effector function (specifically, Complement binding). A comparison of Amino acid sequences in myeloma immunoglobulins has shown that both L and H chains consist of a variable (V) region (an N-terminal sequence, typically of 108 residues) and a constant (C) region. The antigen-binding sites are formed from amino acid residues belonging to the hypervariable regions of both L and H chain variable domains. Antibody molecules fold into compact domains, each containing approximately 108 amino acid residues arranged in homologous sequences. It is believed that the constant region domains, which carry out effector Functions, arose during evolution through duplication and subsequent divergence of the Gene encoding the antigen-binding (variable) domain.

The Variable and constant regions are encoded by separate genes that join during Cell Differentiation. There are several hundred genes for the variable regions of L and H chains. The complete light-chain variable region gene is formed by the recombination of an incomplete V gene and one of several J genes, which encode the final hypervariable segment. A tandemly arranged group of J genes is located adjacent to the C gene. The primary transcript contains intervening sequences. These intervening sequences are excised to yield an mRNA encoding the variable and constant Regions of the immunoglobulin, along with an N-terminal hydrophobic leader sequence that is subsequently cleaved from the newly synthesized polypeptide chain. The Synthesis of the heavy μ chain of IgM is encoded by a complete gene also formed by the joining of V and J genes. Heavy chains of other immunoglobulin classes (such as IgG) are synthesized following the translocation of the complete V_H gene to another C gene (Cγ). This gene translocation is known as C_H switching. The Diversity of light κ chains, as well as heavy chains, results from somatic recombination of a fairly large number of germline variable-region and joining-segment genes. The degree of diversity is further amplified by gene joining in various reading frames. Light-chain diversity appears to be largely driven by somatic Mutations. The combination of several thousand types of L chains with a similar number of H chains provides the vast repertoire of distinct antibodies synthesized within the animal organism.