Immunoglobulin heavy chain variable region gene usage in bone marrow transplant recipients: Lack of somatic mutation indicates a maturational arrest

Abstract

Many recipients of bone marrow transplant (BMT) make normal amounts of serum immunoglobulin but are deficient in generating specific antibody responses to exogenous stimuli. To determine if abnormal usage of V(H) genes contributes to this immunodeficiency, the usage of V(H) genes was determined in peripheral blood B cells of four BMT recipients, two of whom had developed chronic graft versus host disease. The pattern of usage of V(H)3 or V(H)4 genes assessed at either 90 days or approximately 1 year after transplant was similar to that observed in healthy subjects and was marked by the over utilization of two elements, one V(H)3 and one V(H)4. However, the repertoires of each of the four BMT recipients appeared to be less complex than the repertoires of healthy subjects. The differences were a consequence of the accumulation of somatic mutations among rearrangements in the controls but not in the BMT recipients. The failure to accumulate somatic mutations in rearranged V(H) genes is consistent with a defect in antigen driven B-cell responses. These results indicate that although the V(H) gene content of the repertoire has normalized by 90 days posttransplant, a maturational arrest in B-cell differentiation associated with antigen activation persists for at least 1 year after BMT.