Allelic Exclusion Ensures a Single Antigenic Specificity

B cells, like all somatic cells, are diploid and contain both maternal and paternal chromosomes. Even though a B cell is

Productive rearrangements

Glu Asp Ala Thr Arg _ I II II II II I © GAGGATGCGACTAGG

Productive rearrangements

Nonproductive rearrangements

Glu Asp Ala Thr Arg _ I II II II II I © GAGGATGCGACTAGG

Glu Asp Gly Thr Arg I II II II II I (2 GAGGATGGGACTAGG

Glu Asp Trp Thr Arg I II II II II I GAGGATTGGACTAGG

Glu Asp Ala Asp Stop I II II II II I © GAGGATGCGGACTAGG

Glu Val Asp Stop ^ I II II II I © GAGGTGGACTAGG

FIGURE 5-9

Junctional flexibility in the joining of immunoglobulin gene segments is illustrated with Vk and Jk. In-phase joining (arrows 1, 2, and 3) generates a productive rearrangement, which can be translated into protein. Out-of-phase joining (arrows 4 and 5) leads to a nonproductive rearrangement that contains stop codons and is not translated into protein.

Allelic Exclusion

Maternal H chain

FIGURE 5-10

Maternal H chain

Paternal X chain

FIGURE 5-10

Because of allelic exclusion, the immunoglobulin heavy- and light-chain genes of only one parental chromosome are expressed per cell. This process ensures that B cells possess a single antigenic specificity. The allele selected for rearrangement is chosen randomly. Thus the expressed immunoglobulin may contain one maternal and one paternal chain or both chains may derive from only one parent. Only B cells and T cells exhibit allelic exclusion. Asterisks (*) indicate the expressed alleles.

diploid, it expresses the rearranged heavy-chain genes from only one chromosome and the rearranged light-chain genes from only one chromosome. The process by which this is accomplished, called allelic exclusion, ensures that functional B cells never contain more than one VHDHJH and one VLJL unit (Figure 5-10). This is, of course, essential for the antigenic specificity of the B cell, because the expression of both alleles would render the B cell multispecific. The phenomenon of allelic exclusion suggests that once a productive VH-DH-JH rearrangement and a productive VL-JL rearrangement have occurred, the recombination machinery is turned off, so that the heavy- and light-chain genes on the homologous chromosomes are not expressed.

G. D. Yancopoulos and F. W. Alt have proposed a model to account for allelic exclusion (Figure 5-11). They suggest that once a productive rearrangement is attained, its encoded protein is expressed and the presence of this protein acts as a signal to prevent further gene rearrangement. According to their model, the presence of ^ heavy chains signals the maturing B cell to turn off rearrangement of the other heavy-chain allele and to turn on rearrangement of the k light-chain genes. If a productive k rearrangement occurs, k light chains are produced and then pair with ^ heavy chains to form a complete antibody molecule. The presence of this antibody then turns off further light-chain rearrangement. If k rearrangement is nonproductive for both k alleles, rearrangement of the X-chain genes begins. If neither X allele rearranges productively, the B cell presumably ceases to mature and soon dies by apoptosis.

Two studies with transgenic mice have supported the hypothesis that the protein products encoded by rearranged heavy- and light-chain genes regulate rearrangement of the remaining alleles. In one study, transgenic mice carrying a rearranged ^ heavy-chain transgene were prepared. The ^ transgene product was expressed by a large percentage of the B cells, and rearrangement of the endogenous immunoglobulin heavy-chain genes was blocked. Similarly, cells from a transgenic mouse carrying a k light-chain transgene did not

Allelic Exclusion Immunoglobulin

Progenitor B cell

Nonproductive allele #1

Nonproductive allele #2

Nonproductive allele #2

Progenitor B cell

Nonproductive allele #1

Nonproductive allele #2

Cell death

Nonproductive allele #2

Cell death

FIGURE 5-11

Model to account for allelic exclusion. Heavy-chain genes rearrange first, and once a productive heavy-chain gene rearrangement occurs, the ^ protein product prevents rearrangement of the other heavy-chain allele and initiates light-chain gene rearrangement. In the mouse, rearrangement of k light-chain genes precedes rearrangement of the \ genes, as shown here. In humans, either k or \ rearrangement can proceed once a productive heavy-chain rearrangement has occurred. Formation of a complete immunoglobulin inhibits further light-chain gene rearrangement. If a nonproductive rearrangement occurs for one allele, then the cell attempts rearrangement of the other allele. [Adapted from G. D. Yancopoulos and F. W. Alt, 1986, Annu. Rev. Immunol. 4:339.]

rearrange the endogenous K-chain genes when the k transgene was expressed and was associated with a heavy chain to form complete immunoglobulin. These studies suggest that expression of the heavy- and light-chain proteins may indeed prevent gene rearrangement ofthe remaining alleles and thus account for allelic exclusion.

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Responses

  • Louise Walker
    What is allelic exclusion antigen specificity?
    8 years ago
  • Alfredina
    Why heavy chains only rearrange once?
    8 years ago
  • negassi
    What is allelic exclusion phenomenon?
    8 years ago

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