Restricted diversity of the variable region nucleotide sequences of the heavy and light chains of a human rheumatoid factor

Ezaki, Ichiko; Kanda, Hidetoshi; Sakai, Kenji; Fukui, Nao; Sato, Masao; Nobunaga, Masashi; Watanabe, Takashi

doi:10.1002/art.1780340312

Cited by 42 publications

(18 citation statements)

References 30 publications

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“…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.…”

Section: Methodsmentioning

confidence: 99%

“…Humkv325(A27 in Zachau nomenclature [8]) is highly conserved among different individuals in several outbred populations, it is expressed early in fetal life (21), and is a common component of CD5+ B cells. In addition, Humkv325 is frequently expressed in chronic lymphocytic leukemia (for review see reference 22) and is often found in IgMK RF paraproteins (23,24) and RFs from patients with RA (18,25,26). Finally, as mentioned above, the initial RA synovial cDNA library we analyzed contained clonally expanded transcripts.…”

Section: Introductionmentioning

confidence: 99%

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

Bridges¹,

Lee²,

Johnson³

et al. 1995

J. Clin. Invest.

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Immunoglobulin secretion by plasma cells infiltrating syno-_ vial membranes is a prominent feature of RA. Previous analyses of a cDNA library generated from synovium of RA patient BC revealed immunoglobulin K light chain transcripts with extensive somatic mutation, frequent N region addition, and unexpected variation in the lengths of CDR3 regions which form the center of the antigen binding site. To determine if these characteristics are present in other individuals, we performed reverse transcription-polymerase chain reaction amplification and sequenced -10 VKcontaining amplicons from nine tissue samples: synovia of three individuals with long-standing RA (including patient BC), PBLs of two of these individuals, and PBLs or splenocytes of four normal individuals. Increased levels of somatic mutation in PBLs appeared to correlate with increased age, which may reflect accumulation of circulating memory cells and/or decreased bone marrow production of naive B lymphocytes. Two of three RA synovial samples and both RA PBL samples exhibited increased proportions of clones with unusual CDR3 lengths. Enrichment for these antibody binding sites could be due to abnormal regulation of the emerging repertoire or to selection for B lymphocytes bearing antibodies of unusual specificity, and may play a role in the pathogenesis of RA. (J. Clin. Invest. 1995.96:831-841.)

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Bridges¹,

Lee²,

Johnson³

et al. 1995

J. Clin. Invest.

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“…To date, many monoclonal RFs from patients have been generated and characterized (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). The results show that these patient-derived RFs use a large number of V genes from many different gene families.…”

Section: Introductionmentioning

confidence: 99%

“…The names and the complementary sequences ofthese primers are given in Figs. [1][2][3][4][5][6]. In all cases, the upstream primers had SalI sites at their 5'-ends, while downstream primers had either BamHI, PstI, NotI, or KpnI sites at their 5'-ends.…”

Section: Introductionmentioning

confidence: 99%

Defining the genetic origins of three rheumatoid synovium-derived IgG rheumatoid factors.

Deftos

Olee²,

Carson³

et al. 1994

J. Clin. Invest.

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A major diagnostic marker in most rheumatoid arthritis (RA) patients is the rheumatoid factor (RF), an autoantibody that binds to the Fc region of IgG. To delineate the Ig genes and the underlying mechanism for RF production in RA patients, we applied a systematic approach to define the genetic origins of three IgG RFs derived from the synovial fluid of two RA patients. The results show that two of three IgG RF have substantial numbers of somatic mutations in their variable (V) regions, ranging from 13 to 23 mutations over a stretch of 291-313 nucleotides, resulting in a frequency of 4.4-7.8%. However, one IgG RF has only one mutation in each V region. This result indicates that an IgG RF may arise from a germline gene by very few mutations. The mutations occur mainly in the complementarity-determining regions (CDRs), and the mutations in the CDRs often lead to amino acid substitutions. Five of the six corresponding germline V genes have been found to encode either natural autoantibodies or autoantibodies in other autoimmune disorders; and three of the six V genes have been found in fetal liver. Taken together with other results, the data show that (a) several potentially pathogenic RFs in RA patients arise from natural autoantibodies, and (b) only a few mutations are required to convert the natural autoantibodies to IgG RFs. (J. Clin. Invest. 1994. 93:2545-2553

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“…The finding of unmutated germline V-rcgion genes in a RF producing hybridoma of a patient with RA [30] does not contradict the above findings as the somatic diversification starts from unmutated germline genes so that these genes and RF with the typical cross-reacting idiotypes should also be found.…”

Section: Discussionmentioning

confidence: 62%

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

Gause

Küppers²,

Mierau

1992

Clinical and Experimental Immunology

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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.

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Restricted diversity of the variable region nucleotide sequences of the heavy and light chains of a human rheumatoid factor

Cited by 42 publications

References 30 publications

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

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

Defining the genetic origins of three rheumatoid synovium-derived IgG rheumatoid factors.

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

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