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Gene A2b, Which Is Associated with Increased Susceptibility of Navajos to Haemophilus influenzae Type b Disease1
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
Navajos and genetically related populations have a 10-fold
increased incidence of Haemophilus influenzae type b
(Hib) disease compared with control populations. The V
gene A2 is
used to encode the majority of anti-Hib Abs, and these are the
highest affinity anti-Hib Abs. Navajos carry a different allele of
the A2 gene segment (A2b) that is defective in its ability to undergo
V-J recombination. The A2b allele has only three nucleotide changes
from the commonly occurring A2a allele, two of which could potentially
affect its ability to recombine. In this study we used two independent
in vitro assays to test whether the nucleotide change found in the A2b
promoter and/or in the A2b recombination signal sequence (RSS) might be
responsible for the decrease in recombination frequency observed in
vivo. Using a luciferase reporter gene assay, we found no significant
difference between A2a and A2b promoter activities. However, the
competition recombination substrate assay showed a 4.5-fold reduction
in the relative frequency of recombination of the A2b RSS compared with
A2a. We show that this decreased frequency is due to a synergistic
effect of the unique nucleotide change present in the heptamer of the
A2b RSS and the shared nucleotide change present in the nonamer of both
A2b and A2a. This in vitro relative frequency of rearrangement is not
significantly different from that observed in vivo; therefore, the A2b
RSS is probably the factor associated with the increased susceptibility
to Hib disease among individuals carrying the A2b
allele.
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