Cloning and sequence determination of a human rheumatoid factor light-chain gene.

Abstract

The contribution of germ-line variable regions to autoantibody formation in humans is poorly understood. To study the gene structure of a human autoantibody, chronic lymphatic leukemia (CLL) cells from a patient with an IgM anti-IgG (rheumatoid factor, RF) paraprotein were utilized. The rearranged immunoglobulin gene encoding the K light chain for the RF was cloned, and the nucleic acid sequence of its variable region was determined. As demonstrated by Southern blot analysis using a Kjoining-region probe, the CLL cells, stable CLL-WIL2-729-HF2 RF-secreting hybridomas, and the cloned light-chain gene all had an identical restriction fragment containing the rearranged light-chain gene. The CLL RF light chains reacted weakly with an antipeptide antibody against a primary structure-dependent idiotype present on the light chains of the majority of IgM RF paraproteins. The nucleotide and predicted amino acid sequences of the CLL light-chain gene place it in the K Im variable-region subgroup, and a comparison to known RF paraproteins reveals marked homology to the light-chain amino acid sequence of the IgM RF paraprotein Pom. Both Pom and the CLL light chain appear to identify a second K Ill gene or gene group that is able to encode RF paraprotein light chains.

Evidence of antigen receptor-influenced oligoclonal B lymphocyte expansion in the synovium of a patient with longstanding rheumatoid arthritis.

“…In germline form, the Humkv325 gene segment encodes a CRI that can be detected by the 17.109 mAb (52). As is typical for patients with RA, the 17.109 CRI could be detected on less than 1% of serum RF, synovial cell-derived RF, or synovial cell-derived total immunoglobulin from this patient ( 11).…”

Clonal dominance among T-lymphocyte infiltrates in arthritis.

“…The synovitis is frequently accompanied by extraarticular manifestations and is associated with cellular and humoral immunological abnormalities (1,2). Recent studies have suggested that the anti-IgG autoantibodies (rheumatoid factors), which are found in high frequency in classical rheumatoid arthritis, have a limited sequence diversity (3). Rheumatoid synovial membranes are characterized histologically by proliferating synovial lining cells and infiltrates of activated T cells, predominantly of the CD4+ phenotype (4)(5)(6).…”

Human rheumatoid factor cross‐idiotypes

“…Thus, the prevalence of the VK and VH subgroups among BLA XId RF can only be determined at present by the Bla mRF may be the first reported sequenced serum IgM that expresses the apparently rare vH4 gene. It is possible that the serum LES RF from the patient with chronic lymphocytic leukemia whose cloned B cell line has the vH4 gene belongs to the vH4 subgroup (11,12). However, there are 2 unresolved points in the studies of LES: 1) It has never been definitively established whether the serum LES RF is produced by this cell line.…”

“…Only the light chain FRI amino acid sequence of this protein has been determined. Comparative studies of the RF secreted by the cell line with the serum RF have not been reported (11). 2) The peptide used to produce the anti-peptide heavy chain I1 (PH2) that reacts with serum LES RF was designed from the deduced vH4 amino acid sequence from the cellular immunoglobulin gene.…”