Inconclusive Evidence for or against Positive Antigen Selection in the Shaping of Human Immunoglobulin E Repertoires: A Call for New Approaches.

The mechanisms driving the development of
immunoglobulin E (IgE) antibody repertoires are a matter of
debate. Alternatives to the classical view on antibody development,
involving somatic mutation and antigen-driven selection
of high-affinity variants in germinal centers, have
been proposed. Methods: We have re-analyzed the pattern
of mutations in previously isolated and characterized human
clonally unrelated IgE-encoding transcripts using the validated
focused binomial methodology to find evidence in
such genes of antigen-specific selection. Results: As expected
there is a selection against replacement mutations in IgE
framework regions. In contrast, in all examined cases but one
(assessing IgE repertoires of parasite-infected individuals)
there was no evidence in favor of either positive or negative
selection in complementarity determining regions. Importantly,
however, the validated method also failed to detect
selection for replacement mutations in two, non-IgE, hypermutated
antibody populations targeting tetanus toxoid and
vaccinia virus, respectively. Conclusions: Current methodology
is unable to define with certainty, using commonly assessed IgE repertoire sizes, whether antigen selection is or is
not a major driving force in the establishment of human IgE.
New approaches are needed to address this matter.