This is the first report of IL-10 antagonist administration to humans. The study shows the involvement of IL-10 in the pathogenesis of SLE, and indicates that the use of IL-10 antagonists may be beneficial in the management of refractory SLE.

The occurrence and characteristics of remissions in patients with systematic lupus erythematosus (SLE) have not been determined. We therefore studied this in a cohort of 667 patients and found that 156 patients had achieved at least 1 period of 1 year or more of treatment-free clinical remission. This represents an incidence density of 0.028 new cases/person/year. Remission occurred within the first 2 years of disease in 62 patients. The mean duration of first remission was 4.6 years (range, 1-21 yr), and 81 patients were still in the initial remission up until cutoff time. Half of the remaining 75 patients who flared after achieving remission have not entered again in remission. Twenty-six of the 38 patients who did remained in remission, and the remaining 12 had subsequent flares and remissions. Treatment-free remission accounted for a mean of 5.8 years, corresponding to half the time of follow-up. Remission was not limited to patients with mild disease: at least 41 patients achieved remission despite renal involvement, 19 had had neuropsychiatric lupus, 15 had had thrombocytopenia, and 8 had had hemolytic anemia. We also found that the longer the time lapse between the initial manifestation and the diagnosis of SLE, the less likely it was for a patient to enter into remission. There was a continuous increase in likelihood of achieving a first remission from the beginning of disease up to 30 years of disease duration, when it reached 70%. Patients who achieved remission had increased survival, independently of the effect of other disease manifestations that cause increased mortality. We conclude that a significant proportion of patients with SLE, including those with severe organ involvement, may become symptom-free and in need of no more medication, perhaps indefinitely. Our findings support the notion that, in general, SLE is a more benign disease than previously considered.

PITX2 is a homeobox transcription factor involved in embryonic left/right signaling and more recently has been associated to cardiac arrhythmias. Genome wide association studies have pinpointed PITX2 as a major player underlying atrial fibrillation (AF). We have previously described that PITX2 expression is impaired in AF patients. Furthermore, distinct studies demonstrate that Pitx2 insufficiency leads to complex gene regulatory network remodeling, i.e. Wnt>microRNAs, leading to ion channel impairment and thus to arrhythmogenic events in mice. Whereas large body of evidences has been provided in recent years on PITX2 downstream signaling pathways, scarce information is available on upstream pathways influencing PITX2 in the context of AF. Multiple risk factors are associated to the onset of AF, such as e.g. hypertension (HTN), hyperthyroidism (HTD) and redox homeostasis impairment. In this study we have analyzed whether HTN, HTD and/or redox homeostasis impact on PITX2 and its downstream signaling pathways. Using rat models for spontaneous HTN (SHR) and experimentally-induced HTD we have observed that both cardiovascular risk factors lead to severe Pitx2 downregulation. Interesting HTD, but not SHR, leads to up-regulation of Wnt signaling as well as deregulation of multiple microRNAs and ion channels as previously described in Pitx2 insufficiency models. In addition, redox signaling is impaired in HTD but not SHR, in line with similar findings in atrial-specific Pitx2 deficient mice. In vitro cell culture analyses using gain- and loss-of-function strategies demonstrate that Pitx2, Zfhx3 and Wnt signaling influence redox homeostasis in cardiomyocytes. Thus, redox homeostasis seems to play a pivotal role in this setting, providing a regulatory feedback loop. Overall these data demonstrate that HTD, but not HTN, can impair Pitx2>>Wnt pathway providing thus a molecular link to AF.

Cardiovascular development is a complex developmental process in which multiple cell lineages are involved, namely the deployment of first and second heart fields. Beside the contribution of these cardiogenic fields, extracardiac inputs to the developing heart are provided by the migrating cardiac neural crest cells and the proepicardial derived cells. The proepicardium (PE) is a transitory cauliflower-like structure located between the cardiac and hepatic primordia. The PE is constituted by an internal mesenchymal component surrounded by an external epithelial lining. With development, cells derived from the proepicardium migrate to the neighboring embryonic heart and progressive cover the most external surface, leading to the formation of the embryonic epicardium. Experimental evidence in chicken have nicely demonstrated that epicardial derived cells can distinctly contribute to fibroblasts, endothelial and smooth muscle cells. Surprisingly, isolation of the developing PE anlage and ex vivo culturing spontaneously lead to differentiation into beating cardiomyocytes, a process that is enhanced by Bmp but halted by Fgf administration. In this study we provide a comprehensive characterization of the developmental expression profile of multiple microRNAs during epicardial development in chicken. Subsequently, we identified that miR-125, miR-146, miR-195 and miR-223 selectively enhance cardiomyogenesis both in the PE/ST explants as well as in the embryonic epicardium, a Smurf1- and Foxp1-driven process. In addition we identified three novel long non-coding RNAs with enhanced expression in the PE/ST, that are complementary regulated by Bmp and Fgf administration and well as by microRNAs that selectively promote cardiomyogenesis, supporting a pivotal role of these long non coding RNAs in microRNA-mediated cardiomyogenesis of the PE/ST cells.