Immunoglobulin V-kappa light chain gene analysis in patients with Sjogren's syndrome

Objective. Patients with Sjogren's syndrome (SS) have characteristic lympho cytic infiltration of the salivary glands with a previously reported predom inance of V-kappa-bearing B cells and produce a variety of autoantibodies, indicating that there is a humoral autoimmune component in this syndrome. T his study was undertaken to determine whether there are primary deviations of immunoglobulin V gene usage, differences in somatic hypermutation, defec ts of selection, or indications for perturbances of B cell maturation in SS . Methods. Individual peripheral B cells from patients with SS were analyzed for their Ig V gene usage, and the findings were compared with results in n ormal controls. Results. Molecular differences, as reflected by findings in the nonproducti ve V-kappa repertoire of the patients, were identified by an enhanced usage of J(kappa)2 gene segments and a lack of mutational targeting toward RGYW/ WRCY sequences compared with controls. A greater usage of V(kappa)1 family members and a reduced frequency of V(kappa)3 gene segments in the productiv e repertoire suggested differences in selection, possibly driven by antigen . Overall positive selection for mutations, especially for replacements in the complementarity-determining region and for mutations in RGYW/WRCY, simi lar to that found in controls, was detected. Conclusion. Disturbances of strictly regulated B cell maturation, during ea rly B cell development as indicated by prominent J(kappa)2 gene usage and d uring germinal center reactions as indicated by a lack of targeting of the hypermutation mechanism, might contribute to the emergence of autoimmunity in SS.