MOLECULAR CHARACTERIZATION OF A HUMAN V-LAMBDA-VIII GERMLINE GENE

Human lambda light chains of the recently recognized variable region ( V-L) subgroup V-lambda VIII can be distinguished from proteins of othe r V-lambda gene families on the basis of distinctive chemical and sero logic properties and by their preferential association with certain ty pes of autoantibodies, i.e. rheumatoid factors (RFs). We now report th at we have cloned from a human placental library a V-lambda VIII-encod ing germline gene, designated IGLV8A1, using as a molecular probe a pa rtial V-lambda VIII fragment generated by polymerase chain reaction (P CR) from genomic DNA. IGLV8A1 contained all the requisite elements of a potentially functional gene, including a V-lambda exon with an open reading frame encoding 103 residues. Its expressed products were ident ified through analyses of cDNA cloned from two different monoclonal la mbda VIII B-cell populations. The primary structure of lambda VIII lig ht chains differed from that of lambda I, lambda II, lambda III, lambd a IV and lambda VI proteins by the presence of distinctive residues wi thin the first framework region (FR1) and an 11- rather than 7-residue second complementarity-determining region (CDR2). Remarkably, the IGL V8A1 gene was more homologous to the two functional rabbit V-lambda ge rmline genes, RV lambda 2 and RV lambda 3 (including the presence of o ne extra codon within the leader sequence), and to the murine V-lambda x gene. Light chains encoded by the human, rabbit and mouse lambda VI II-related genes shared certain unique primary structural features, no tably the four additional CDR2 residues. The evolutionary conserved na ture of the human V-lambda gene and, in particular, the apparently nov el tertiary structural effects induced by an elongated CDR2 provide ev idence for the biological and functional importance of the V-lambda VI II subgroup.