Immune System Genetics

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The immune system is the set of cells and glands that protects the body from invasion and infection by viruses, bacteria, and other pathogens. The immune system must be able to recognize any foreign target, or antigen, of which there are potentially millions. Pathogenic organisms change over time, and new antigens evolve that must also be targeted. At the same time, the immune system must distinguish pathogenic antigens from the body's own tissues, attacking the former and sparing the latter. The key to the scope and specificity of the immune system response is in the genes that give rise to it.

Overview of the Immune System

The immune system includes several interacting components. Nonspecific immunity (protection against any invasion) is provided by the barriers of the skin and mucous membranes lining the lungs and gut. Additional non-specific defenses are provided by the inflammatory response and the complement proteins in the bloodstream. We shall not deal further with these defenses.

Specific immunity is the set of defenses mounted against a specific invader. It involves the action of three major types of cells: B cells, T cells, and macrophages. In broad, somewhat oversimplified terms, B cells make proteins called antibodies that attach to foreign antigens, serving as warning flags. T cells coordinate the immune attack and destroy virus-infected cells. Macrophages consume flagged antigens and clean up the debris from a T cell attack on infected cells.

An antibody binds to an invader when its shape fits some shape (the antigen) on the invader's surface. Any particular invader, such as a bacterial cell, may have dozens of such antigens.

The Puzzle of Antibody Diversity

B cells are created in the bone marrow. Many millions of different B cells are made, each containing a unique gene for the specific antibody that it (and all its descendants) will make. A group of B cells with all its descendants is called a clone. Thus, the antibody made by one B cell clone differs from that made by any other B cell clone. T cells develop along a slightly different pathway but also contain a unique protein, called the T cell receptor, which is coded for by a gene unique to that T cell clone.

Antibodies are proteins, and like all of the body's proteins, must be encoded by genes. However, the number of distinct antibodies each of us makes (many millions) is vastly greater than the total number of genes in our entire genome (30,000-70,000). How is all this diversity encoded? To understand the answer, it is helpful to look at the structure of an antibody.

Antibody Structure

The antibody is formed from four polypeptides that link up in the shape of a Y. There are two identical long heavy (H) chains and two identical short light (L) chains. The tips of each branch of the Y form a pocket, and it is here the antibody binds antigen. Thus, these twin pockets are called the antigen-binding regions of the antibody.

By comparing the amino acid sequences of antibodies from different B cell clones, several important features can be discovered. Light chains, for instance, have a constant region, with amino acid sequences that differ little from clone to clone, and a variable region, with sequences that differ considerably. The constant region comes in two different forms, termed "kappa" and "lambda." The amino acid sequence of one kappa constant sequence differs little or not at all from clone to clone; similarly, all lambda constant sequences are essentially identical. The variable region does differ considerably between clones. The heavy chain also has a constant region (of which there are five forms) and a variable region.

The constant regions of all the chains are found toward the bottom of the Y, while the variable regions are found toward the tip. Furthermore, within each variable region, there are three hypervariable regions, whose five to ten amino acids differ even more than the other portions of the variable region. These hypervariable regions form the actual points of contact between antibody and antigen.

Gene Segments Combine Randomly to Generate Diversity

The fundamental principle governing antibody generation is combinatorial diversity. A large number of genes are generated by choosing from among a smaller pool of differing gene segments and combining them in different ways. This process, known as somatic recombination, is similar in principle to constructing words. The alphabet's twenty-six letters can be combined to make 676 (26²) two-letter words and almost 12 million five-letter words.

To understand the molecular details of somatic recombination, let us focus on the creation of a kappa-type light chain. The process is similar for lambda light chains and only marginally more involved for a heavy chain.

We noted that the light chain has both a variable and a constant region. There are forty gene segments that can code for the variable (V) region and a single segment that codes for the constant (C) region. In addition, there are five possible coding segments for the J region, a short region that is also present on light chains. All of these genes and segments are located in sequence on chromosome 2. Each V and J segment is flanked by special noncoding sequences that facilitate the next stage, in which specific segments are joined.

Somatic recombination begins when special recombining proteins randomly bring together the downstream end of one V segment and the upstream end of one J segment. They do this by attaching to the flanking sequences and bending the intervening DNA into a loop. The loop is cut out and degraded, and the remaining DNA is spliced together. The product is the mature antibody gene.

Note in the diagram on the right that the resulting gene may still have some extra upstream V segments. An ingenious mechanism prevents such segments from being transcribed to make messenger RNA, however.

Each V segment contains a promoter, the region to which RNA polymerase binds to start transcription. The promoter is inactive, though, until it is brought close to an "enhancer" region between the J and C segments. Thus, transcription will begin at the V segment closest to the enhancer, and only this one V segment is transcribed—the others are too far from the enhancer. The gene may also have extra downstream J segments and intron sequences between J and C. These are transcribed, but they are removed by RNA processing.

Other Sources of Diversity

The random combination of V and J segments alone can produce millions of possible combinations. More diversity arises because the joining of V and J chains is done imprecisely, with the possible loss or gain of several nucleotides, resulting in added or deleted amino acids.

Remember also that each antibody includes both light and heavy chains. Heavy chains are produced by a similar combinatorial process, using a different, larger set of gene segments. The combination of a randomly produced light chain with a randomly produced heavy chain produces even more diversity. Finally, when a B cell multiplies in response to antigens, the rearranged gene can mutate, making some members of the clone different from others. The number of possible antibodies available through all these processes is in the trillions.

T Cell Receptors

As mentioned above, T cells help control the immune response and kill infected cells. Infected cells are recognized because they chop up foreign proteins from the invader and display the bits on their surface. These bits, which are antigens, are held aloft by surface proteins, called MHC (major histocompatibility complex) proteins. The MHC-antigen complex is recognized by the T cell receptor, in cooperation with one or more other T cell surface molecules.

When a T cell discovers a cell whose MHC proteins contain foreign antigens, it marks the cell for destruction. The T cell receptor interacts with antigens in much the same way as an antibody does, although the size of the antigen it recognizes is smaller. T cell receptors come in as many diverse forms as antibodies do, and, while the details differ, their diversity is generated in much the same way, with random recombination of gene segments.

The Major Histocompatibility Complex

The T cell-MHC interaction serves another, related function: It confirms that the cell is part of the self that the immune system should be protecting. Thus, MHCs serve as self-recognition markers. When a T cell recognizes foreign MHCs, as would occur in an organ transplant, it sets in motion an immune attack to reject the foreign tissue. Indeed, "histocompatibility" means compatibility of tissues, and these proteins control that process.

There are two major classes of MHC proteins, called class I and II, with different functions in antigen presentation. Class I contains three members, each coded for by different genes, and class II contains four members. For almost every gene, there are multiple alleles. The number of alleles per gene ranges from a handful to more than 100. Since each person will inherit and express a unique set of MHC alleles, once again we can see the combinatorial possibilities: There are millions of different combinations of MHC alleles, and very few people are likely to have exactly the same set. This is what makes organ transplants so difficult. Matching MHC types is the key to success, but even close relatives may have different allele sets.

Bibliography

Alberts, Bruce, et al. Molecular Biology of the Cell, 4th ed. New York: Garland Science, 2002.

Janeway, Charles A., Jr., et al. Immunobiology: The Immune System in Health and Disease, 5th ed. New York: Garland Publishing, 2001.

—Richard Robinson