Overgrowth of human synovial cells driven by the human T cell leukemia virus type I tax gene.

Abstract

One of the salient pathological features of rheumatoid arthritis is synovial cell proliferation with bone erosion. Despite extensive investigation, the factors essential for synovial cell proliferation remain to be identified. Recent studies suggest that human T cell leukemia virus type I (HTLV-I) may play an important role in synovial overgrowth observed in patients with one type of chronic inflammatory synovitis. In order to confirm and extend these observations, we have established synovial cell clones (SCCs) from three HTLV-I carriers who demonstrated synovial overgrowth but were otherwise asymptomatic. HTLV-I proviral DNA randomly integrated into the cellular genome was present in 20-30% of SCCs. The SCCs carrying HTLV-I proviral DNA and expressing the tax gene exhibited high levels of proliferative potential. HTLV-I was found to function as a transcriptional trans-activator in these SCCs. Moreover, transfection of the tax expression plasmid into SCCs resulted in the same phenotype of increased proliferation and cytokine expression as exhibited by HTLV-I provirus-carrying and tax-expressing SCCs. These data suggest that tax plays a critical role not only in leukemogenesis but also in synovial overgrowth in humans. (J. Clin. Invest. 1993. 92:186-193.)

Human T lymphotropic virus type I in arthropathy and autoimmune disorders

“…Howevcr, a characteristic histopathologic finding in HTLV-I arthropathy was the accumulation of atypical lymphocytes with nuclcar indentation, which are commonly observed in the PBMC of paticnts with ATL, either in SF or in synovial tissue, but not in cells obtained from peripheral blood. Occasionally, typical nuclear-convoluted cells adjacent to synovial stromal cells were identified by electron microsImmunohistochemical analysis of the synovial tissue revealed thc presence of HTLV-I tax together with several proto-oncogenes, namely, c-fos, c-myc, and IL-1 p. Moreover, using reverse transcriptasepolymerase chain rcaction (RT-PCR), we clearly demonstrated that these proto-oncogenes had been transcribed in synovial tissue in situ (20). Based on these clinical and laboratory findings, we proposed that HI'LV-I arthropathy is a destructive arthropathy, indistinguishable from idiopathic RA (1 3,14).…”

“…Our results demonstrated that the sizes of amplified DNA products, representing sequences joining thc 5' HTLV long terminal repeat (LTR) V3 region, of 6 synovial clones established from 1 patient were different from each other (20). This indicated that thc synovial cell clones with HTLV-I integration originated from multiple clones that had been randomly integrated by HTLV-I in vivo.…”

“…Clone SK-P (HTLV-I positivc) exprcssed remarkably higher levels of mRNA for c-fos, IL-lp, and IL-6 as well as tax, even in serum-free medium, than did clone SK-N (HTLV-I negative). These results strongly suggest that overexprcssion of functional Tax protein in synoviocytes is directly associated with the expression of mRNA of several cytokine genes, including IL-lp, IL-6, tumor necrosis factor a (TNFa), and several proto-oncogenes, by activation of DNA binding proteins (20).…”

“…'l'hcse findings allowcd us to spcculate that HTLV-I may potentially induce complex disease spectra which manifest as primary autoimmune disorders. Further investigations from our laboratory revealed that the HTLV-I tax gene (Figure l), known as a transregulatory gene, contributes not only to the induction of synovial cell hyperplasia, but also to the immune response, both in vivo and in vitro (16)(17)(18)(19)(20). The results of thcsc studics strongly suggest that HTLV-I is the etiologic agcnt in HTLV-I-associatcd autoimmune disorders.…”

“…We also cxamincd the messenger RNA (mRNA) expression of HTLV-I gag, pol, env, and tax genes in synovial stromal cells derived from 3 patients with HTLV-I arthropathy, using RT-PCR (20). Products of the HTLV-I pX genes, mainly tax mRNA, were markedly expressed in fresh and cultured synovial stromal cells, but not in PBMC or SFMC.…”