Abstract
Heterozygous truncating mutations in CXCR4 have been identified as a cause of WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency and myelokathexis). The receptor truncations have been proposed to lead to altered lymphocyte trafficking. The purpose of the described studies was to characterize the B-cell repertoire in WHIM subjects. We confirmed profound B-cell lymphopenia and demonstrated oligoclonality of the circulating B-cell pool by HCDR3 spectratyping. The response to immunization was studied in one subject utilizing a bacteriophage PhiX174 immunization protocol. Spectratyping showed oligoclonality at baseline with normalization of the HCDR3 length distribution by 5 months after immunization with PhiX174 with eventual return to the baseline state. Isotype switching from phage specific neutralizing antibody of the IgM class to IgG was markedly reduced. Overall, these data suggest that impaired CXCR4 signaling in WHIM syndrome results in defective B-cell function and abnormal isotype switching, possibly through effects on germinal center trafficking of lymphocytes.
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