BIOCHEMISTRY - L. Stryer - 1984

VOLUME 3

PART V. MOLECULAR PHYSIOLOGY

CHAPTER 33. IMMUNOGLOBULINS

33.25. Antibody Diversity Results from Somatic Recombination of Multiple Germline Genes and Somatic Mutation

Let us now summarize the mechanisms responsible for antibody diversity. Germline Cells contain a fairly large repertoire of variable-region genes. The light chain x is encoded by several hundred (say, 300) V genes and five J genes. There are at least three reading frames in which V and J genes can join. It follows that the total number of complete V_x genes formed by all possible combinations of V and J genes is 300 • 5 • 3 = 4500. A comparable number of heavy-chain variants can arise in a similar manner. Joining 4500 L chains with 4500 H chains yields 4500 • 4500 = 2 • 10⁷ Antibodies differing in antigen Specificity. This number is sufficiently large to account for the vast diversity of antibodies produced within an animal Organism.

As mentioned above, there are far fewer Vӽ genes than V genes. For instance, mice appear to possess only two V₁ genes. However, a much greater number of Amino acid sequences corresponding to this Gene have been detected. It seems likely that % light-chain diversity arises through somatic Mutations. Overall, as we can see, nature employs each of the three sources of diversity discussed earlier (Section 33.19)—a large set of germline genes, somatic recombination, and somatic mutations—ultimately generating the rich repertoire of antibodies essential for defending the organism against foreign invaders.

33.26. The Clonal Selection Theory of Antibody Formation

In the 1950s, Niels Jerne, Macfarlane Burnet, David Talmage, and Joshua Lederberg formulated the clonal Selection theory, which provides a comprehensive framework for the Immune Response.

The core tenets of this now universally accepted theory are as follows.

1. An antibody-producing Cell contains DNA with a unique base sequence that dictates the Amino Acid Sequence characteristic of the immunoglobulin chains it synthesizes. Antibody specificity is determined entirely by The amino acid sequence.

2. Each individual cell produces antibodies of a single specificity only. Consequently, the capacity to synthesize a specific antibody is ingrained in The Cell prior to any contact with the antigen.

3. A maturing cell produces small quantities of antibodies of a single specificity, some of which become attached to the cell surface. If such an immature cell encounters an antigen directed against its surface antibodies, it dies. As a result, an animal typically does not produce antibodies against its own macromolecules; that is, it exhibits self-tolerance. Indeed, cells producing antibodies against self-Antigens are eliminated during embryonic development. In contrast to immature cells, mature cells respond to antigen contact in a stimulatory manner: antibody synthesis is upregulated, and Cell Division is triggered. The progeny of a single cell constitute a clone possessing all the genetic CHARACTERISTICS OF THE parent cell. Consequently, cell division initiated by antigen contact gives rise to a clone of cells synthesizing antibodies of the identical specificity.

4. The clone tends to persist even after the antigen has cleared. Upon a subsequent encounter with the same antigen, these cells are stimulated, which forms The basis of immunological memory.

33.27. Antigen Receptors Are Present on the Surface of Antibody-Producing Cells

Specific antibody molecules are located On the surface of the cells that produce them. Lymphocytes serve as the precursor cells. Under normal conditions, they divide slowly. However, upon antigenic stimulation, a lymphocyte transforms into a plasma cell, which synthesizes and secretes antibodies at a very high rate. If a population of lymphocytes is passed through a Column containing covalently attached dinitrophenyl (DNP) groups, only a very small fraction of the cells will bind to the column—specifically, those that synthesize antibodies against DNP and bear such antibody molecules on their surface. Lymphocytes that pass through without binding do not produce such anti-DNP antibodies.

How are lymphocytes stimulated by specific antibodies? In the absence of an antigen, antibody molecules on the lymphocyte surface are distributed randomly. The addition of an antigen has a striking effect: the surface-bound antibodies, along with their attached antigens, cluster together at one pole of the cell, forming a so-called "cap". Following this redistribution, the antibody molecules are internalized. Cap formation is an energy-dependent process that involves the cell's contractile elements. Thus, The formation of an antigen-antibody lattice on the cell surface leads to cap formation, which in turn stimulates cell division. The antigen must be polyvalent (i.e., bearing more than one specific determinant) to cross-link antibody molecules on the lymphocyte surface. The question of how nuclear mitotic events depend on these surface-membrane processes constitutes an interesting and vital area of research.

Class="center">Fig. 33.35. Scanning electron micrograph of sheep erythrocytes bound to a human T lymphocyte (center). The surface of this lymphocyte bears receptors specific for components of sheep erythrocytes

Fig. 33.36. Autoradiograph of IMMUNOGLOBULINS forming a "cap" on the surface of a B lymphocyte. Dark spots represent ¹²⁵I-labeled antibodies against immunoglobulins added to B lymphocytes from mouse Spleen. A - at 4°C, immunoglobulin molecules are uniformly distributed over the cell surface; B - following incubation at 37°C, the label concentrates into a "cap" at one pole of the cell and is subsequently internalized via endocytosis

33.28. Biological Significance of Clonal Selection

The Essence of Burnet's clonal selection theory is as follows: No antigen-binding site is evolutionarily tailored to fit any particular antigenic determinant. The Structure of the antigen-binding site exists as a given preformed entity, and if it proves "fit"—meaning that its affinity for a given antigenic determinant exceeds a certain threshold—an immunologically significant response is triggered. The selection of preexisting, randomly generated variants is not a novel theme in biology; indeed, it is the very foundation of Darwinian theory. It is curious to note that instructive theories preceded selectionist theories: Lamarckian theory preceded Darwinism in evolution, and the instructive theory of immunology was formulated before the clonal selection theory.

Jerne suggested that selection mechanisms might also operate in The Nervous system, for instance, in memory mechanisms. Essentially, instructive and selectionist theories of learning were formulated long ago. John Locke believed that the human mind is a blank slate (tabula rasa) upon which experience writes nearly endless patterns. Socrates, by contrast, argued that "all learning is merely a recollection of what is already in the mind." Hopefully, this chapter feels like something you already knew well!