Class Switching among Constant Region Genes

After antigenic stimulation of a B cell, the heavy-chain DNA can undergo a further rearrangement in which the VhDhJh unit can combine with any CH gene segment. The exact mechanism of this process, called class switching or isotype switching, is unclear, but it involves DNA flanking sequences (called switch regions) located 2-3 kb upstream from each CH segment (except C8). These switch regions, though rather large (2 to 10 kb), are composed of multiple copies of short repeats (GAGCT and TGGGG). One hypothesis is that a protein or system of proteins that constitute the switch recombinase recognize these repeats and upon binding carry out the DNA recombination that results in class switching. Intercellular regulatory proteins known as cytokines act as "switch factors" and play major roles in determining the particular immunoglobulin class that is expressed as a consequence of switching. Interleukin 4 (IL-4),

L VDJ

Cy2b

Cy2a

Sy2b

Sy2a

DNA looping

L VDJ

DNA looping

S Cy1

Cy2b Cy2a

Sy2b

Recombination at S^ and Sy1

Cy2b Cy2a

Sy2b

Sy2a

DNA looping and recombination at Sy1 and Se

5'Sy1

3'Si

L VDJ

5'Sy1

3'Si

SY2a

Cy2b

Cy2a

SY2a

Cy2b

Cy2a

Sy2b

3'Sy1

Sy2b

3'Sy1

FIGURE 5-15

Proposed mechanism for class switching induced by interleukin 4 in rearranged immunoglobulin heavy-chain genes. A switch site is located upstream from each CH segment except Cs.

Identification of the indicated circular excision products containing portions of the switch sites suggested that IL-4 induces sequential class switching from C^ to C71 to Ce.

C5 Ca

for example, induces class switching from C^ to C71 or Ce. In some cases, IL-4 has been observed to induce class switching in a successive manner: first from C^ to C71 and then from C71 to Ce (Figure 5-15). Examination of the DNA excision products produced during class switching from C^ to C71 showed that a circular excision product containing C^ together with the 5' end of the 71 switch region (S71) and the 3' end of the ^ switch region (S^) was generated. Furthermore, the switch from C71 to Ce produced circular excision products containing C71 together with portions of the 7, and e switch regions. Thus class switching depends upon the interplay of three elements: switch regions, a switch recombinase, and the cytokine signals that dictate the isotype to which the B cell switches. A more complete de-

scription of the role of cytokines in class switching appears in Chapter 11.

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