Association of tumor necrosis factor receptor type II polymorphism 196R with systemic lupus erythematosus in the Japanese molecular and functional analysis

Chika Morita, Takahiko Horiuchi, Hiroshi Tsukamoto, Nobuaki Hatta, Yuji Kikuchi, Yojiro Arinobu, Takeshi Otsuka, Takuya Sawabe, Shin Ichi Harashima, Kohei Nagasawa, Yoshiyuki Niho

研究成果: ジャーナルへの寄稿記事

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Objective. To investigate whether a polymorphism(s) or mutation(s) in the tumor necrosis factor receptor II (TNFRII) gene is involved in the pathogenesis of systemic lupus erythematosus (SLE). Methods. All 10 exons of the TNFRII gene were analyzed by exon-specific polymerase chain reaction-single-strand conformation polymorphism, followed by nucleotide sequencing of exons that displayed aberrant bands. To analyze the function of the TNFRII polymorphisms, the full-length TNFRII complementary DNA of each allele was transfected in HeLa cells and then studied for specific binding of 125I-TNFα, as well as interleukin-6 (IL-6) production and cytotoxic activity after treatment with recombinant human TNFα. Results. We identified 4 polymorphisms, at codons 56, 181, 196, and 232. The latter 2 had amino acid substitutions M196R and E232K, respectively. Only the 196R allele was significantly associated with SLE in our 105 Japanese SLE patients, with an allele frequency of 20.5%, compared with 12.6% in 99 healthy controls (P = 0.0335). More importantly, using TNFRII-transfected HeLa cells, we demonstrated significantly increased IL-6 production by 196R TNFRII compared with 196M TNFRII. The cytotoxic activity induced by 196R TNFRII was also increased compared with that of 196M TNFRII. This increase was achieved without affecting the binding affinity of TNFα to TNFRII, as demonstrated by the finding that specific TNFα binding to the HeLa transfectants of 196R and 196M TNFRII was similar, with Kd values of 3.12 × 10-10M and 4.34 × 10-10M, respectively. Conclusion. These results suggest that 196R TNFRII, which transduces the signals of TNFα more effectively than does 196M TNFRII, is involved in the pathogenesis of SLE.

元の言語英語
ページ(範囲)2819-2827
ページ数9
ジャーナルArthritis and rheumatism
44
発行部数12
DOI
出版物ステータス出版済み - 12 1 2001

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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