Diversification, notuse, of the immunoglobulin V^H Gene repertoire is restrictedin digeorge syndrome

Immunoglobulin (Ig) genes were isolated from unamplified conventional as well as polymerase chain reaction-generated cDNA libraries constructed from the peripheral blood cells of a patient with complete DiGeorge syndrome. Comparison of the sequences of 36 heavy chain clones to the recently expanded database of human V_H genes permitted identification of the germline V_H genes that are expressed in this patient as well as placement of 19 ofthese genes in a partially resolved 0.8-mb region of the human V_H locus. The pattern of V_H geneuse does not resemble the fetal (early) repertoire. However, as in the fetal repertoire, there are a number of cDNAs derived from germline genes that previously have been identified as autoantibodies. Two Dμ sequences also were identified, as was another sequence resulting from a unique recombination event linking J_H to an unidentified sequence containing a recombination signal sequence-like heptamer. All of the DiGeorge cDNAs are closely related to germline V_H genes, showing little or no evidence of somatic mutation. In contrast, comparably selected IgM V_H sequences derived from normal adult and age-matched human libraries, and from a second DiGeorge syndrome patient in whom the degree of thymic dysfunction is much less severe, exhibit considerable evidence of somatic mutation. The absence of somatic mutation is consistent with the atypical development of functional antibody responses associated with complete DiGeorge syndrome and implicates a role for T cells in the generation of diversity within the B cellrepertoire.