Immunoglobulin V? light chain gene usage in patients with Sj�gren's syndrome

Abstract

Objective To determine whether patients with Sjögren's syndrome (SS) have abnormalities in Ig Vλ and Jλ gene usage, differences in somatic hypermutation, defects in selection, or indications for perturbations of B cell maturation. Methods Individual peripheral B cells from SS patients were analyzed for their Vλ gene usage by single‐cell polymerase chain reaction amplification of genomic DNA and compared with those from normal controls. Results Molecular differences from controls in Vλ–Jλ recombination were identified that were reflected by findings in the nonproductive Vλ repertoire of the patients, including enhanced rearrangement of Vλ10A and Jλ2/3 gene segments. In addition, a number of abnormalities in the productive repertoire were identified, indicating disordered selection. A greater usage of 4 Vλ genes (2A2, 2B2, 2C, and 7A), representing 56% of all productive Vλ rearrangements, was observed, suggesting positive selection of these genes. Overutilization of Jλ2/3 and underutilization of Jλ7 in both nonproductive and productive Vλ rearrangements of SS patients compared with controls suggested decreased receptor editing in SS. The mutational frequency did not differ from that in controls, and positive selection of mutations into the productive V gene repertoire was found, similar to that in controls, although mutational targeting toward RGYW/WRCY motifs, typically found in controls, was not found in SS patients. Conclusion Disturbed regulation of B cell maturation with abnormal selection, defects in editing Ig receptors, and abnormal mutational targeting may contribute to the emergence of autoimmunity in SS.

Analysis of Expressed and Non-Expressed IGK Locus Rearrangements in Chronic Lymphocytic Leukemia

“…The existence of mutated, in-frame, nonexpressed IGKV-J rearrangements might be considered as indirect evidence for secondary rearrangements after the onset of somatic hypermutation (SHM). Chronic antigen stimulation may trigger secondary rearrangements at the IGH or the IGK/IGL loci (53,(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66). Although the occurrence of secondary rearrangements in normal peripheral B cells was considered as doubtful or-at best-limited (67), several studies indicate that secondary rearrangements may occur following SHM, particularly in a setting of autoimmunity or neoplasia (58,60,62,66,68).…”

Immunoglobulin variable-region gene usage in systemic autoimmune diseases

“…In contrast to RA patients, patients with SS appear to have decreased receptor editing/revision as identified by enhanced usage of V proximal-located J L segments, likely reflecting a defect in or infrequent usage of receptor editing (40,41). In this regard, a recent analysis of 6 monoclonal antibodies with RF activity obtained from the peripheral blood of SS patients showed that all used V -proximal J 2/3 gene segments (74), consistent with the conclusion that receptor editing/revision may be defective in SS.…”

“…The majority of available data do not support this hypothesis but rather suggest an absence of genetic abnormalities, causing B cells to generate an autoreactive repertoire in patients with systemic autoimmune diseases (38)(39)(40)(41)(42)76,77). Thus, no genetic polymorphisms of the heavy and light chain Ig V gene loci and no fundamental abnormalities in the V(D)J recombination process underlie the generation of autoantibodies.…”

“…Thus, no genetic polymorphisms of the heavy and light chain Ig V gene loci and no fundamental abnormalities in the V(D)J recombination process underlie the generation of autoantibodies. However, there are major distortions of the V gene repertoire that result from the impact of selection and somatic hypermutation (38)(39)(40)(41).…”

“…DÖ RNER AND LIPSKY Analysis of the nonproductive V gene repertoire in 2 patients with SLE and 3 patients with SS has revealed minimal abnormalities in the nonproductive V H , V , and V gene repertoires (36,(38)(39)(40)(41)(42). Although only a few patients with SLE or SS have been analyzed using this approach to assess the overall repertoire, the data indicate that V gene usage in the nonproductive repertoire is not significantly different from normal, suggesting that the basic process of Ig V gene recombination is largely normal in patients with these autoimmune diseases.…”