Cold agglutinins: specificity, idiotypy and structural analysis

Abstract

Cold agglutinins likely represent natural autoantibodies with precursors that arise early during ontogeny. Many use L chains derived from the germline kv325 gene, in association with H chains derived from the VHIV gene family. CAs probably represent an expression of the preimmune repertoire. The appearance of CAs in a variety of disorders may be due to the prevalence of CA B cell precursors, and the ubiquity of their target epitopes. CAs may arise independent of antigenic selection during Epstein-Barr virus infection in response to the expansion of immature B cells. In support, L chains bearing the markers for the kv325 gene are preferentially expressed during in vitro and in vivo Epstein-Barr virus infection. Certain CAs that arise in lymphoproliferative disorders represent a clonal expansion, produced by karyotypically abnormal lymphocytes. As such, antigenic selection may foster the early expansion of CA-producing clones. These cells are later more prone to become autonomous, and overt malignancy may then occur. Clues to the genetic origin of these antibodies are now being appreciated, but further study will be required to understand the defects responsible for the transformation of a natural autoantibody into a malignancy.