title: TP53 mutations coincide with the ectopic expression of activation-induced cytidine deaminase in the fibroblast-like synoviocytes derived from a fraction of patients with rheumatoid arthritis.
abstract: Main features of rheumatoid arthritis (RA), hyperplasia of fibroblast-like synoviocytes (FLS) and joint destruction are caused by inflammatory cytokines produced in chronic autoimmune inflammation. Cell-intrinsic acquisition of tumour-like phenotypes of RA-FLS could also be responsible for the aggressive proliferation and invasion, which are supported by the fact that in some cases RA-FLS has mutations of a tumour suppressor gene TP53. However, the underlying molecular mechanism for TP53 mutations in RA-FLS has not yet been clarified. Recently it has been reported that the non-lymphoid cells in the inflammatory tissues express ectopically the activation-induced cytidine deaminase (AID) gene that induces somatic hypermutations, not only at the immunoglobulin (Ig) gene variable regions in germinal centre B lymphocytes but also at coding regions in TP53. Real-time polymerase chain reaction (PCR) analyses revealed more than half (five of nine) of the RA-FLS lines we established showed the markedly increased expression of AID. AID transcription in RA-FLS was augmented by tumour necrosis factor (TNF)-alpha and even by physiological concentration of beta-oestradiol that could not induce AID transcription in osteoarthritis-FLS. Furthermore, AID-positive RA-FLS presented a higher frequency of somatic mutations in TP53. Cytological and immunohistochemical analyses demonstrated clearly the ectopic expression of AID in the FLS at the RA synovium. These data suggested strongly a novel consequence of RA; the ectopic expression of AID in RA-FLS causes the somatic mutations and dysfunction of TP53, leading to acquisition of tumour-like properties by RA-FLS.
authors.affiliation: Department of Immunology and Molecular Genetics, Kawasaki Medical School, Kurashiki City, Okayama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Igarashi
authors.forename: J
authors.initials: J
authors.lastname: Hashimoto
authors.forename: T
authors.initials: T
authors.lastname: Tomita
authors.forename: H
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: K
authors.initials: K
authors.lastname: Ishihara
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002461:Cell Line, Transformed / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D003199:Computer Systems; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000502:physiology*; D004790:Enzyme Induction; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010003:Osteoarthritis / Q000235:genetics / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C495901:TP53 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase