A DEFECTIVE V-KAPPA A2 ALLELE IN NAVAJOS WHICH PLAY PLAY A ROLE IN INCREASED SUSCEPTIBILITY TO HAEMOPHILUS-INFLUENZAE TYPE DISEASE

The antibody response to H. influenzae type b (Hib) is pauciclonal, an d is dominated by antibodies using the V(k)A2 gene. Navajos have a 5-1 0-fold increased incidence of Hib disease compared with control popula tions. We hypothesized that a polymorphism in one of the genes in this oligoclonal response may lead to increased disease susceptibility. Si nce the predominant A2(+) anti-Hib antibodies have high avidity for Hi b and can be unmutated, the A2 V-k gene was analyzed, Over half of the Navajos studied, but only one control individual, had a new allele of A2, termed A2b, with three changes from the published A2 germline seq uence, One of the changes was in the recombination signal sequence, su ggesting that the A2b allele might not undergo V-J rearrangement very frequently. This possibility was confirmed by analyzing the relative f requency of non-productive A2 rearrangements in A2a/b heterozygous Nav ajos. Many fewer A2b rearrangements were observed, showing that the A2 b allele is defective in its ability to undergo rearrangement. The pre valence of this allele in Navajos may play a role in their increased s usceptibility to invasive Hib disease. If so, it would underscore the importance of the germline Ig repertoire for protective antibody respo nses to pathogenic bacteria in unimmunized children.