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To clarify the association of clinical and prognostic features with dermatomyositis (DM)specific autoantibodies (Abs) in adult Japanese patients with DM.

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Objective. To identify the 140-kd autoantigen recognized by anti-155/140 autoantibodies that are associated with adult cancer-associated dermatomyositis (DM) and juvenile DM and to determine the clinical relevance of anti-155/140 antibodies in a large cohort.Methods. Sera from 456 DM patients were assessed for the presence of anti-155/140 antibodies by immunoprecipitation using K562 cell extracts as substrate. Using immunoprecipitation and Western blotting, we then examined whether anti-155/140-positive sera recognized transcription intermediary factor 1␣ (TIF-1␣), TIF-1␤, and TIF-1␥. The clinical associations of antigen reactivity were also evaluated.Results. Anti-155/140-positive sera reacted with 140-kd TIF-1␣ in addition to 155-kd TIF-1␥. Among sera from 456 DM patients, 52 were reactive with both TIF-1␣ and TIF-1␥, while another 25 were reactive with TIF-1␥ alone. Additionally, 7 were reactive with TIF-1␤. Malignancy was more frequently found in adult patients with both anti-TIF-1␣ and anti-TIF-1␥ antibodies than in those with anti-TIF-1␥ antibodies alone (73% versus 50%; P < 0.05). In addition to juvenile DM patients and middle-aged and older DM patients with high percentages of malignancy, 8 "young adult" DM patients without malignancy had these autoantibodies.Conclusion. Anti-155/140 antibodies target TIF-1 family proteins, TIF-1␣ and TIF-1␤, in addition to TIF-1␥. Since TIF-1 proteins have significant roles in oncogenesis, these antibodies may be produced during misdirected antitumor immunity.Polymyositis (PM) and dermatomyositis (DM) are idiopathic inflammatory disorders that mainly affect the muscle and/or skin (1). Clinical manifestations of PM/DM are heterogeneous, with varying degrees of myositis, skin rash, and accompanying symptoms such as interstitial lung disease and internal malignancy. The association of malignancy with PM/DM, which is termed cancer-associated myositis, is well appreciated, particularly in patients with DM (2-6). Since malignant disease is one of the main causes of mortality in these patients, diagnosing occult cancer in them is important and challenging for clinicians.

This novel MSA is associated with cancer-associated DM and may serve as a diagnostic serological marker for this specific subset.

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Systemic sclerosis (SSc) is manifested by fibrosis, vasculopathy and immune dysregulation. So far, a unifying hypothesis underpinning these pathological events remains unknown. Given that SSc is a multifactorial disease caused by both genetic and environmental factors, we focus on the two transcription factors, which modulate the fibrotic reaction and are epigenetically suppressed in SSc dermal fibroblasts, Friend leukemia integration 1 (Fli1) and Krüppel-like factor 5 (KLF5). In addition to Fli1 silencing-dependent collagen induction, simultaneous knockdown of Fli1 and KLF5 synergistically enhances expression of connective tissue growth factor. Notably, mice with double heterozygous deficiency of Klf5 and Fli1 mimicking the epigenetic phenotype of SSc skin spontaneously recapitulate all the three features of SSc, including fibrosis and vasculopathy of the skin and lung, B cell activation, and autoantibody production. These studies implicate the epigenetic downregulation of Fli1 and KLF5 as a central event triggering the pathogenic triad of SSc.

Vascular smooth muscle cell (VSMC) proliferation is a key event in the progression of arteriosclerosis. Clinical studies show that uremic toxins deteriorate the arteriosclerosis in renal failure patients. Indoxyl sulfate (IS) is a strong protein-bound uremic toxin, but the effect of IS on VSMC proliferation has not been studied. We examined the effect of IS on rat VSMC proliferation, assessed by a cell counting kit (4-[3-[4-lodophenyl]-2-4(4-nitrophenyl)-2H-5-tetrazolio-1,3-benzene disulfonate] assay) and by [(3)H]thymidine incorporation in vitro. We further evaluated a contribution of mitogen-activated protein kinase (MAPK; p44/42 MAPK) to VSMC proliferation by IS. Immunohistochemical staining was performed for VSMCs using antirat organic anion transporter (OAT)3 antibody. The mRNA expressions of platelet-derived growth factor (PDGF)-A and -C chains, and PDGF-beta receptor were evaluated by real-time PCR. IS stimulated the proliferation of VSMCs in a concentration-dependent manner and activated p44/42 MAPK. Concentration of IS needed to stimulate the proliferation of rat VSMC was about 250 microM, which is compatible with that in the serum of end-stage renal failure patients. PD98059 (10 microM), a selective inhibitor of MAPK/extracellular signal-regulated kinase, inhibited the IS-induced (250 microM) VSMC proliferation and phosphorylation of MAPK. Probenecid (0.5 mM), an inhibitor and substrate of OAT, inhibited the IS-induced (250 microM) VSMC proliferation. Rat OAT3 was detected in VSMCs. The mRNA expressions of PDGF-C chain and PDGF-beta receptor were significantly increased by IS. We conclude that IS directly stimulates rat VSMC proliferation and activates MAPK in vitro. This might be one of the mechanisms underlying the progression of atherosclerotic lesions in end-stage renal disease patients.