A somatically mutated VκIV gene encoding a human rheumatoid factor light chain

Abstract

SUMMARY The light chain of an IgA K rheumatoid factor (RF) produced by a hybridoma derived from a patient with rheumatoid arthritis (RA) has been shown to belong to the VκIV family. This RF light chain has 31 nucleotide differences compared with the single VκIV germline gene reported for the human genome. The patient's VκIV germline gene was sequenced, using the polymerase chain reaction (PCR), and shown to be identical to that previously reported. This demonstrates that the RF light chain is the product of a somatically mutated gene. A comparison with other known VκIV sequences shows that the RF light chain has more replacement mutations than most of the known VKIV light chains.

Persistence of a rheumatoid factor (RF)-producing B cell clone with a somatically mutated Igκ chain in a patient with rheumatoid arthritis

“…The consensus sequence of eight clones shown in Fig. 2 is identical to the published RF light chain sequence [13,16]. Altogether there were three nucleotide exchanges: one from C to T (nucleotide position 63), one from T to C (nucleotide position 184) and one from A to G (nucleotide position 104).…”

“…Figure 2 shows the consensus sequence of seven independent clones. It is identical to the pubhshed RF light chain sequence [13,16]. In almost 2000 bp sequenced, there were only four individual nucleotide differences at different positions.…”

“…The sequence analysis of the VKIV germ-line gene of the patient from whom the RF-producing hybridoma cell line had been established definitely proved that the gene encoding the VKIV chain of the RF is somatically mutated [13]. The demonstration of a somatic mutation of this gene was facilitated by the fact that there is only one member of the VKIV family [20,21].…”

“…Therefore, the VH gene of the RF was initially classified as a member of the VH 1 family. The light chain is encoded by a VKIV gene which is known to be the only member of the VKIV gene family [20,21], VKIV germ-line polymorphism could be excluded by comparing the RF-encoding K gene with the VKIV germ-line gene analysed in the same patient [13], We were able to show that the RF light chain had undergone 31 somatic mutations [13,16], Ten of these mutations were arranged in blocks of two mutations next to each other. This phenomenon of block mutations was recently described as characteristic of somatically mutated n genes [22],…”

“…Monoreactive, highaffinity RF, and RF of IgG and IgA isotype, are common. The cross-reacting idiotypes (CRI) and V-genes often found to be involved are distinct from those expressed in the naturally occurring RF [6], There is evidence that the pathological RF in RA undergo affinity maturation and are the product of an antigen-driven response [10][11][12][13][14]. Especially IgG RF isolated from synovial tissue have been shown to be encoded by somatically mutated V-region genes [11,14] and thus resemble RF characterized in the MRL/lpr mouse model of RA [15].…”