Rheumatoid factors from the peripheral blood of two patients with rheumatoid arthritis are genetically heterogeneous and somatically mutated.

Abstract

We report the DNA sequences of the heavy and light chain immunoglobulin genes of 11 monoclonal rheumatoid factor (RF)-secreting lines derived from the peripheral blood of two patients with rheumatoid arthritis (RA). It is evident from immunogenetic analysis of these lines that RA-associated RF activity can arise from a wide variety of heavy and light chain genes and gene combinations. Although the RF response from our two patients shows a bias in gene usage toward those genes used to encode monoclonal RF, particularly VkIII, relatively few of these RFs are reactive with the monoclonal antiidiotypes 6B6.6 and 17.109 that define VkIII germline-encoded light chains and the loss of this idiotypic reactivity is clearly related to somatic mutation. Finally, RFs derived from peripheral blood of RA patients show a similar heterogeneity of epitope binding to Fc as that seen for synovium-derived RF and some are clearly different in binding specificity from the restricted RF population found in patients with B cell malignancies. Somatic mutations as well as different VH /VL combinations contribute to the heterogeneity in the binding patterns of these RA-derived RF. (J. Clin. Invest. 1994. 93:852-861.)

VH usage and somatic hypermutation in peripheral blood B cells of patients with rheumatoid arthritis (RA)

“…These observations suggest that in some RA patients, the fraction of B cell repertoire that has been antigendriven is substantially larger than in normal controls. Observations by others are consistent with this conclusion [19,21,22].…”

“…However, the exact mechanisms involved in the pathologic autoantibody response in RA remain unclear. Studies of antibody structure may help to decipher the aetiology of a potentially pathologic autoantibody response in RA [8][9][10][17][18][19][20][21][22].…”

Analysis of VH gene rearrangements from synovial B cells of patients with rheumatoid arthritis reveals infiltration of the synovial membrane by memory B cells

“…Recently, it has been confirmed that the corresponding germline gene 1 -69 [19] or DP10 [18] is indeed the main heavy chain gene encoding RF from healthy human immunized donors, from peripheral blood lymphocytes (PBL) from RA patients and from paraproteins [27]. Some of the RF-encoding germline genes reported by other authors, mainly from studies of RF-secreting hybridomas [24,28,29], occurred recurrently in our investigation, namely the 3.23/DP-47/VH26, the 3.53/DP-42, the 4.59/DP-71/4.11 and the 4.18 germline gene.…”

Somatic mutation and CDR3 lengths of immunoglobulin kappa light chains expressed in patients with rheumatoid arthritis and in normal individuals.

“…However, despite the apparent enrichment for 1 1-codon VK CDR3s in some patients with autoimmune disease, the majority of autoantibodies do not exhibit unusual K light chain CDR3 length. Most CDR3 domains of K light chains of RFs from patients with RA contain 8, 9, or 10 codons (25,(47)(48)(49)(50). Although 11-amino acid CDR3s are therefore not required for RF activity, the frequent presence of K chains with 11-amino acid CDR3s in some patients with autoimmune diseases may be a marker for an antibody repertoire that has been abnormally regulated or abnormally activated.…”