Back to Search
Start Over
Association of tumor necrosis factor receptor type II polymorphism 196R with Systemic lupus erythematosus in the Japanese: molecular and functional analysis
- Source :
- Arthritis and rheumatism. 44(12)
- Publication Year :
- 2002
-
Abstract
- 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.
- Subjects :
- Adult
Male
Adolescent
Genotype
medicine.medical_treatment
Immunology
Gene Expression
Biology
Transfection
Receptors, Tumor Necrosis Factor
Pathogenesis
Iodine Radioisotopes
Rheumatology
Gene Frequency
Japan
Antigens, CD
medicine
Immunology and Allergy
Cytotoxic T cell
Humans
Lupus Erythematosus, Systemic
Receptors, Tumor Necrosis Factor, Type II
Pharmacology (medical)
Interleukin 6
Allele frequency
Polymorphism, Single-Stranded Conformational
Aged
Lupus erythematosus
Interleukin-6
Tumor Necrosis Factor-alpha
Middle Aged
medicine.disease
Molecular biology
Culture Media
Cytokine
Phenotype
Amino Acid Substitution
Solubility
biology.protein
Leukocytes, Mononuclear
Tumor necrosis factor alpha
Female
Tumor necrosis factor receptor 2
HeLa Cells
Protein Binding
Subjects
Details
- ISSN :
- 00043591
- Volume :
- 44
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Arthritis and rheumatism
- Accession number :
- edsair.doi.dedup.....f730bab3b4be83dbf281457c20876f40