Fc. Mills et al., HUMAN IG S-GAMMA REGIONS AND THEIR PARTICIPATION IN SEQUENTIAL SWITCHING TO IGE, The Journal of immunology, 155(6), 1995, pp. 3021-3036
The Ig isotype switch from IgM to IgE is accompanied by a DNA recombin
ation that joins S mu, the highly repetitive ''switch'' region upstrea
m of the C mu gene, to the S epsilon region upstream of C epsilon, the
reby creating a composite S mu-S epsilon region. In human B cells cult
ured in vitro with IL-4 to promote the switch to IgE, we previously de
scribed evidence for S mu-S gamma-S epsilon structures, suggesting tha
t some B cells can switch sequentially from mu to gamma and then to ep
silon; similar sequential switching to epsilon occurs routinely in the
mouse. To identify which of the four human gamma genes might be invol
ved in this mu-gamma-epsilon switching pathway, we cloned and analyzed
nine S mu-S gamma-S epsilon composite switch regions and studied S ep
silon-S gamma junctions from reciprocal deletion circles. Since only t
he S gamma 4 sequence had previously been described, our investigation
required determination of the germline S gamma 1, S gamma 2, and S ga
mma 3 sequences. This analysis showed that S gamma 1 is the longest an
d most highly repetitive switch region, including nearly identical 79-
bp repeats partially homologous to the 49-bp repeat of murine S gamma
sequences. Of nine cloned chromosomal S mu-S gamma-S epsilon junctions
, seven were derived from S gamma 1, and one each from S gamma 3 and S
gamma 4 (both of which were in inverted orientation). Analysis of rec
iprocal S epsilon-S gamma junctions demonstrated contributions of S ga
mma 1, S gamma 2, and S gamma 4. Thus, all four of the human gamma loc
i can participate in sequential switching to IgE, arguing against a mo
del of directed switching from a specific subtype, such as was propose
d in the murine system.