Characterization of a germline Vk gene encoding cationic anti-DNA antibody and role of receptor editing for development of the autoantibody in patients with systemic lupus erythematosus.

Abstract

We found previously that cationic anti-DNA autoantibodies (autoAbs) have nephritogenic potential and usage of a specific germline Vk gene, A30, has major influences on cationic charge of the autoAb in human lupus nephritis. In the present study, we have characterized A30 germline Vk gene using cosmid cloning technique in patients with SLE. A30 gene locus locates in less than 250 kb from the Ck region, and the cationic anti-DNA mRNA used the upstream Jk2 gene, indicating that cationic anti-DNA mRNA is a product of primary gene rearrangement. By using PCR technique, we found that A30 gene locus in the genome was defective in eight out of nine SLE patients without nephritis.

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

“…It is perhaps relevant that 2 IGKV1-17 and 1 IGKV1-39/1D-39 in-frame rearrangements from our series shared identical KCDR3s with public autoantibody sequences (43,44). The IGKV1-17 gene, rarely expressed by normal cells, is critically implicated in the development of SLE-nephritis (48). It has been argued that normal B cells may edit IGKV1-17 rearrangements by receptor editing so as to avoid self-reactivity, whereas SLE B cells may have a defect in this mechanism (48).…”

“…The IGKV1-17 gene, rarely expressed by normal cells, is critically implicated in the development of SLE-nephritis (48). It has been argued that normal B cells may edit IGKV1-17 rearrangements by receptor editing so as to avoid self-reactivity, whereas SLE B cells may have a defect in this mechanism (48). In this context, it would perhaps be possible that primary IGK rearrangements with autoreactive potential in CLL clonogenic cells were followed by a secondary light-chain rearrangement in the context of a receptor "dilution" (21) or "editing" process (1,(49)(50)(51), which would eventually lead either to expression of more than one κ light chain or to a shift to λ production.…”

Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus

“…This selective process, termed receptor editing, alters B cell receptor (BcR) specificity and leads to negative selection of autoreactive immature B cells (3,4). In humans, the structure and organization of the V locus are suitable for studying successive V gene rearrangements (14)(15)(16)(17). This locus is organized in two clusters separated by Ͼ800 kb and consisting of 76 V genes (18).…”

“…In lupus, most patients fail to efficiently remove polyreactive B cells and reveal defects at early B cell tolerance checkpoints (28,29). Their L-chain autoAb sequences show an increase in downstream V genes associated with the most upstream J , suggesting inefficient secondary recombination and therefore a potential defect in receptor editing (14,15). In RA patients, central and peripheral B cell tolerance checkpoints are also defective, and this loss of tolerance is, at least in part, due to receptor editing impairments (30).…”

Selection of antigen receptors in splenic marginal-zone lymphoma: further support from the analysis of the immunoglobulin light-chain gene repertoire

“…This is supported by studies demonstrating that IG LCs may be critically implicated in recognition of and selection by antigen. Examples include: (i) significant LC sequence restrictions among estradiol-specific antibodies; 2 (ii) impaired responses to Haemophilus influenzae in individuals lacking a specific allelic variant of the IGKV2D-29 gene; and, (iii) biased IG LC gene usage in autoimmunity (for example, IGKV1-17 and IGLV1-47 in lupus, [3][4] IGKV1-39/1D-39 in Graves disease 5 ). Furthermore, the BcR specificity may drastically change through genetic processes affecting LCs, including secondary rearrangements in the context of receptor editing 6 or distinctive SHM patterns.…”