Regulatory T Cells in Systemic Sclerosis

In recent years, accumulating evidence suggest that regulatory T cells (Tregs) are of paramount importance for the maintenance of immunological self-tolerance and immune homeostasis, even though they represent only about 5–10% of the peripheral CD4+ T cells in humans. Their key role is indeed supported by the spontaneous development of autoimmune diseases after Tregs depletion in mice. Moreover, there is also a growing literature that investigates possible contribution of Tregs numbers and activity in various autoimmune diseases. The contribution of Tregs in autoimmune disease has opened up a new therapeutic avenue based on restoring a healthy balance between Tregs and effector T-cells, such as Treg-based cellular transfer or low-dose IL-2 modulation. These therapies hold the promise of modulating the immune system without immunosuppression, while several issues regarding efficacy and safety need to be addressed. Systemic sclerosis (SSc) is an orphan connective tissue disease characterized by extensive immune abnormalities but also microvascular injury and fibrosis. Recently, data about the presence and function of Tregs in the pathogenesis of SSc have emerged although they remain scarce so far. First, there is a general agreement in the medical literature with regard to the decreased functional ability of circulating Tregs in SSc. Second the quantification of Tregs in patients have led to contradictory results; although the majority of the studies report reduced frequencies, there are conversely some indications suggesting that in case of disease activity circulating Tregs may increase. This paradoxical situation could be the result of a compensatory, but inefficient, amplification of Tregs in the context of inflammation. Nevertheless, these results must be tempered with regards to the heterogeneity of the studies for the phenotyping of the patients and of the most importance for Tregs definition and activity markers. Therefore, taking into account the appealing developments of Tregs roles in autoimmune diseases, together with preliminary data published in SSc, there is growing interest in deciphering Tregs in SSc, both in humans and mice models, to clarify whether the promises obtained in other autoimmune diseases may also apply to SSc

Targeting CD226/DNAX accessory molecule-1 (DNAM-1) in collagen-induced arthritis mouse models

International audienceBackground: Genetic studies have pointed out that CD226 variants, encoding DNAM-1, could be associated with susceptibility to rheumatoid arthritis. Therefore, we aimed to determine the influence of DNAM-1 on the development of arthritis using the collagen-induced arthritis (CIA) mouse model. Methods: CIA was induced in mice on a DBA/1 background, treated in parallel with a DNAM-1 neutralizing monoclonal antibody, a control IgG and PBS, respectively. CIA was also induced in mice deficient for DNAM-1(dnam1−/−) and control dnam-1+/+ mice on a C57/BL6 background. Mice were monitored for clinical and ultrasound signs of arthritis. Histological analysis was performed to search for inflammatory infiltrates and erosions. The Mann–Whitney U test for non-related samples was used for statistical analysis. Results: There was a non-significant trend for a less arthritic phenotype in mice receiving anti-DNAM-1 mAb at both clinical, ultrasound and histological assessments. But, we did not observe any difference between dnam1+/+ and dnam1−/− mice for incidence nor severity of clinical arthritis. Histological analysis revealed inflammatory scores similar in both groups, without evidence of erosion. Collagen antibodies levels were similar in all mice, confirming immunization with collagen. Conclusion: Despite some clues suggesting a role of DNAM-1 in arthritis, these complementary approaches demonstrate no contribution of CD226/DNAM-1 in the arthritic phenotype. These results contrast with previous studies showing a role in vivo of DNAM-1 in some autoimmune disorders

Soluble CD163 as a Potential Biomarker in Systemic Sclerosis

Objective. To evaluate the performance of serum and urinary sCD163 concentrations as possible biomarker in systemic sclerosis (SSc). Methods. Urine and serum samples were obtained from SSc patients and age- and sex-matched controls. Serum and urinary sCD163 concentrations were measured by commercially available ELISA kit. SSc patients were assessed following international guidelines. Cross-sectional analyses were performed. Results. Two hundred and three SSc patients were included. The control group consisted of 47 age- and sex-matched patients having noninflammatory diseases, mainly osteoporosis. Serum sCD163 levels were significantly higher in SSc patients compared with controls (mean ± SD: 529 ± 251 versus 385 ± 153 ng/mL; p<0.001). Urinary sCD163 concentrations were higher in SSc patients than controls, but this did not reach significance (236 ± 498 versus 176 ± 173 ng/mg uCr; p=0.580). The sCD163 concentrations were not associated with clinical, laboratory, and instrumental characteristics of SSc patients. Conclusion. To our knowledge, this is the first evaluation of both serum and urinary sCD163 levels in SSc. Our results show a significant difference for sera values that should be prioritized for further studies as compared to urinary measurements. Our results further support that the M2 macrophages/CD163 signaling system may play a role in the pathogenesis of SSc, although we could not identify a subset of SSc patients with higher concentrations

JAK inhibitors and risk of major cardiovascular events or venous thromboembolism: a self-controlled case series study

PURPOSE: JAK-inhibitors (JAK-i) might be associated with venous (VTE) and arterial thromboembolic events (ATE). To evaluate the association between JAK-i and the risk of VTE and ATE. METHODS: A self-controlled case series was performed using data from the nationwide French healthcare insurance system database SNDS. We included all patients treated with JAK-i (baricitinib or tofacitinib), and having presented at least one VTE or ATE between November 1, 2017 and June 30, 2019. Associations were estimated using the incident rate ratio (IRR). Two post-exposure periods (until day 30 and until day 60) were individualized. RESULTS: Among 5870 patients with JAK-i dispensing, 92 had an incident VTE or ATE within the study period. Their median age at JAK-i initiation was 65.7 years [IQR: 56.1-75.8] and 65.2% were female (n = 60). Before event incidence, 65.2% (n = 60) received baricitinib, 32.6% (n = 30) tofacitinib and 2.2% (n = 2) had both medications. Moreover, 41.3% (n = 38) presented a VTE and 58.7% (n = 54) an ATE. The median time-to-onset after JAK-i initiation was 4.6 months [IQR: 2.5-9.2] for VTE and 6.1 months [IQR: 3.0-8.5] for ATE. An IRR of 8.27 (95% CI 3.41-20.04) for VTE was detected during JAK-i treatment and remained increased over the 30-day period of post-exposure (6.52 [2.02-21.11]). An IRR of 9.27 (3.68-23.34) was also found for ATE, which remained increased over the 30-day period of post-exposure (10.12 [3.27-31.37]). No increased risk was detected during long-term post-exposure for either VTE or ATE. CONCLUSIONS: This study shows evidence of an increased risk of VTE and ATE associated with the use of baricitinib and tofacitinib

Extracting and separating different sources of hydrology-induced deformation in geodetic datasets (Invited)

International audienceSpace-based geodesy offers a new, complementary way to observe hydrological processes that deform the solid Earth. Known sources of hydrogeodetic deformation include changes in localized hydrological loads such as lakes, larger-scale variations in terrestrial water storage linked to climate as well as fluctuations in groundwater levels which can activate a poroelastic or inelastic porous response. Discriminating between these distinct sources of deformation in geodetic datasets such as GNSS and InSAR is essential to accurately invert for regional fluctuations in water mass and constrain aquifer hydromechanical properties. Blind source separation techniques such as Independent Component Analysis (ICA) help in isolating hydrology-induced deformation from other sources of deformation and noise in geodetic datasets but cannot necessarily distinguish between statistically-correlated hydrological processes. Here, we propose a general framework to accomplish this task by relying on continental-scale gravimetric observations and local field measurements. We first account for deformation due to long-wavelength loads by considering the response of a spherical elastic PREM Earth to hydrological loads inferred from GRACE. We then project the residual geodetic time series onto temporal functions representative of local hydrology and hence extract the associated deformation. The temporal functions may be sampled at a single point (e.g., lake level time series) or may require statistical analysis to be extracted from a heterogeneous dataset (e.g. network of groundwater monitoring wells). The final step consists in validating the extracted signals with simple elastic, poroelastic and inelastic deformation models. We demonstrate the methodology through case studies in different hydrological settings

Combined effect of genetic background and gender in a mouse model of bleomycin-induced skin fibrosis

International audienceSystemic sclerosis (SSc) is a connective tissue disorder characterised by the development of skin fibrosis. Our current understanding of the disease pathogenesis is incomplete and the study of SSc is hindered, at least partially, by a lack of animal models that fully replicate the complex state of human disease. Murine model of bleomycin-induced dermal fibrosis encapsulates important events that take place early in the disease course.METHODS:To characterise the optimum in vivo parameters required for the successful induction of dermal fibrosis we subjected three commonly used mouse strains to repeated subcutaneous bleomycin injections. We aimed to identify the effects of genetic background and gender on the severity of skin fibrosis. We used male and female Balb/C, C57BL/6, and DBA/2 strains and assessed their susceptibility to bleomycin-induced fibrosis by measuring dermal thickness, hydroxyproline/collagen content and number of resident myofibroblasts, all of which are important indicators of the severity of skin fibrosis. All data are expressed as mean values ± SEM. The Mann-Whitney U test was used for statistical analysis with GraphPad Prism 6.04 software.RESULTS:Dermal fibrosis was most severe in Balb/C mice compared to C57BL/6 and DBA/2 suggesting that Balb/C mice are more susceptible to bleomycin-induced fibrosis. Analysis of the effect of gender on the severity of fibrosis showed that male Balb/C, C57BL/6, DBA/2 mice had a tendency to develop more pronounced fibrosis phenotype than female mice. Of potential importance, male Balb/C mice developed the most severe fibrosis phenotype compared to male C57BL/6 and male DBA/2 as indicated by significantly increased number of dermal myofibroblasts.CONCLUSION:Our study highlights the importance of genetic background and gender in the induction of murine dermal fibrosis. Robust and reproducible animal models of fibrosis are important research tools used in pharmacological studies which may lead to better understanding of the pathogenesis of fibrotic diseases and assist in identification of new drugs

Major temporal variations in shortening rate absorbed along a large active fold of the southeastern Tianshan piedmont (China)

International audienceThe investigation of deformation rates on a mountain piedmont can provide key information for improving our understanding of the overall dynamics of a mountain range. Here, we estimate the shortening rate absorbed by a Quaternary emergent detachment fold on the southeastern piedmont of the Tianshan (China). Our work is primarily based on new 10Be cosmogenic exposure dating of deformed alluvial surfaces. The method we have developed combines depth profiling with sampling of surface cobbles, thereby allowing exposure time, erosion rate and inheritance to be simultaneously constrained. The exposure ages of the uppermost uplifted alluvial surfaces are around 140±17 ka140±17 ka, 130±9 ka130±9 ka and 47±9 ka47±9 ka, from west to east. A terrace lying below the 140 ka surface is dated at 65±5 ka65±5 ka. The ages of the uplifted and folded alluvial surfaces were then combined with estimates of shortening obtained using two distinct methods: (1) the excess area method, where sedimentation rates, extracted from magnetostratigraphic studies, are used to determine the amount of sedimentation after the abandonment of the river; and (2) a folding model derived from sandbox experiments. The late Pleistocene shortening rates are shown to be between 0.4±0.1 mm/yr0.4±0.1 mm/yr and 0.8±0.5 mm/yr0.8±0.5 mm/yr on the western part of the fold and 2.1±0.4 mm/yr2.1±0.4 mm/yr along its central part. The central part of the frontal Yakeng anticline therefore accommodates up to 25% of the total shortening currently absorbed across the whole Eastern Tianshan range (8 mm/yr). However, this situation seems to have prevailed for only the last 150 ka, as the shortening rate absorbed by this nascent fold was previously ten times slower. While the initiation of folding of the Yakeng anticline can be traced back to 5.5 Ma ago, the basinward migration of the active deformation front onto the Yakeng fold is a relatively recent phenomenon and appears to be diachronous from west to east, probably in relation to the tectonic activity of the folds in the hinterland

Monitoring and modeling of the Sacramento Valley aquifer (California) using geodetic and piezometric measurements

Changes in groundwater levels associated with hydroclimatic variations and anthropogenic water extraction can deform the solid Earth, both elastically and inelastically. Satellite-based geodetic techniques which measure the Earth’s surface displacements can thus be used to track changing conditions in aquifer systems. However, accurately extracting groundwater-induced deformation signals still poses a challenge as geodetic techniques like GNSS and InSAR also record noise, systematic errors and other sources of deformation. In this study, we take advantage of the relatively dense in situ groundwater monitoring network of the Sacramento Valley aquifer in California to constrain its deformation and hydromechanical properties. We start by characterizing the main seasonal and multiannual fluctuations in groundwater levels with an Independent Component Analysis (ICA) and exploit the resulting temporal signature to extract the associated deformation field from GNSS and InSAR time series. We then develop a poroelastic model of the aquifer to invert for its elastic storage capacity and estimate the respective contributions of elastic and inelastic processes to long-term subsidence. Our modeling also suggests that depth-dependent elastic properties are necessary to explain the spatial distribution of horizontal poroelastic displacements measured by GNSS. This work has important implications for the sustainable management of heavily-stressed Californian aquifers but also serves as a calibration between in situ and remote sensing techniques, which is essential for the successful deployment of satellite-based groundwater monitoring in areas with sparse field-based instrumentation