Analysis of Immunoglobulin lambda Light Chain Repertoire in Systemic Lupus Erythematosus

ABSTRACT

BACKGROUND: Immunoglobulin (Ig) light chain repertoire has been implicated as a critical determinant in regulation of autoreactive B cells and production of pathogenic anti-DNA antibodies in systemic lupus erythematosus (SLE). We analyzed the impact of Ig lambda chain repertoire on development of autoimmunity in patients with SLE. METHODS: We obtained genomic DNA from individual peripheral CD19+ B cells of 3 untreated active SLE patients, and amplified Vlambda rearrangements from each single cell by polymerase chain reaction. RESULTS: A total number of 208 VlambdaJlambda rearrangements were analyzed. Analyzed sequences included 158 productive rearrangements and 50 nonproductive rearrangements. The differences in Vlambda gene usage in the productive and nonproductive repertoire of SLE patients were found compared to the non-autoimmune individuals. Vlambda gene, 9A was significantly overrepresented in nonproducative repertoire of SLE patients (P=0.016). In the productive repertoire, Vlambda genes, 3L and 1E were found more often in the SLE patients (P=0.001, P=0.043). When the productive and the nonproductive repertoires were compared, 9A was found significantly less in the productive repertoire in the SLE patients (P=0.000). There were no significant differences in the Jlambda gene usage between SLE patients and non-autoimmune individuals, but Jlambda2/3 gene was the most frequently used in SLE, whereas Jlambda7 gene was the most frequently used in the normal subjects. In the productive SLE Vlambda repertoire, 9.4% of the total sequences employed identical CDR3. It was particularly striking to find 7 identical versions of the 1G-Jlambda2/3 VlambdaJlambda rearrangements from one patient and 3 of the same sequence from another patient. Notably, identical Vlambda junctions in the SLE patients utilized significantly more homologous joining compared to Vlambda junctions of the normal adults (P=0.044). CONCLUSION: These data demonstrate regulation of lambda light chain expression in the SLE patients by selection of unique Vlambda genes. Also, biased selection and clonal expansion of particular Vlambda rearrangements are apparent in the SLE lambda repertoire.