Immunoglobulin Vkappa light chain gene analysis in patients with Sjögren's syndrome.

Abstract

Patients with Sjögren's syndrome (SS) have characteristic lymphocytic infiltration of the salivary glands with a previously reported predominance of Vkappa-bearing B cells and produce a variety of autoantibodies, indicating that there is a humoral autoimmune component in this syndrome. This study was undertaken to determine whether there are primary deviations of immunoglobulin V gene usage, differences in somatic hypermutation, defects of selection, or indications for perturbances of B cell maturation in SS. Individual peripheral B cells from patients with SS were analyzed for their Ig V gene usage, and the findings were compared with results in normal controls. Molecular differences, as reflected by findings in the nonproductive Vkappa repertoire of the patients, were identified by an enhanced usage of Jkappa2 gene segments and a lack of mutational targeting toward RGYW/WRCY sequences compared with controls. A greater usage of Vkappa1 family members and a reduced frequency of Vkappa3 gene segments in the productive 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, similar to that found in controls, was detected. Disturbances of strictly regulated B cell maturation, during early B cell development as indicated by prominent Jkappa2 gene usage and during germinal center reactions as indicated by a lack of targeting of the hypermutation mechanism, might contribute to the emergence of autoimmunity in SS.