ALLOTYPE-ASSOCIATED VARIATION IN THE HUMAN GAMMA-3 SWITCH REGION AS ABASIS FOR DIFFERENCES IN IGG3 PRODUCTION

High and low serum concentrations of IgG3 are associated with the huma n G3 m(b) and G3 m(g) allotypes, respectively, We previously hypothesi zed that a low frequency of switching is the most likely defect in (g) allotype-positive individuals, and therefore analyzed the structure, recombination breakpoints, and binding of nuclear proteins to the swit ch (S)gamma 3 regions of these two allotypes. There are no allotype-as sociated differences in the length and basic structure of the S gamma 3, since both contain eighteen 79-bp repeats, However, we found a numb er of allotype-associated nucleotide changes, As in the mouse system, there is a preferential switching to the B site, or switch nuclear pro tein/nuclear factor-kappa B motif, with a clustering of switch breakpo ints at the most 5' residue of the B site. The B site sequence used mo st frequently in switching was found to be mutated at this nucleotide in the (g) allotype-associated S gamma 3. This change was shown by ele ctrophoretic mobility shift assay to alter the binding of the switch n uclear protein/nuclear factor-kappa B protein to the B site. Taken tog ether, these data suggest that polymorphism within S gamma 3 may contr ibute to allotype-associated differences in IgG3 switching, and that s pecific sequences within the S gamma 3 79-bp repeats could be mechanis tically important for switch recombination.