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International audience; OBJECTIVE:the two related TNF members APRIL and BAFF are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to an unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.METHODS:APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.RESULTS:APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan (CSPG) bearing sometimes chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset had also an effect.INTERPRETATION:our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. This article is protected by copyright. All rights reserved.

International audience; Complex metallic alloys having isolated transition-metal elements in the surface layer have been reported to work well as selective hydrogenation catalysts. We report an experimental determination of the surface structure of one such compound Al13Fe4(010). The structure was determined using low-energy electron diffraction. The best-fit structure terminates in a layer similar to the puckered bulk layer but lacking some of the Al and Fe atoms. Protruding Fe atoms are located in the middle of adjacent pentagonal Al formations, connected to each other by Al " glue " atoms. The top interlayer spacing is compressed relative to the bulk with oscillating relaxations observed for subsequent layers at the surface.

OBJECTIVE: Regulatory interleukin-10 (IL-10)-producing B cells (B10 cells) have been shown to prevent and cure collagen-induced arthritis in mice. In humans, very little is known about B10 cells in rheumatoid arthritis (RA). Several B cell subsets, such as CD24(high) CD38(high) , CD24(high) CD27+, and CD5+ B cells, were suggested to be precursors of B10 cells. We aimed to analyze these B cell subsets and B10 cells in RA patients and healthy controls. METHODS: B10 cells were generated from peripheral blood mononuclear cells stimulated for 24 hours with CpG and for 4 hours with phorbol 12-myristate 13-acetate/ionomycin/brefeldin A. Intracellular B cell IL-10 was assessed by flow cytometry. Thirty-one controls and 99 RA patients were included. RESULTS: After multiple adjustments, levels of CD24(high) CD38(high) , CD24(high) CD27+, and CD5+ B cells were found to be similar in RA patients and controls. Levels of B10 cells were lower in RA patients than in controls, especially in patients with RA of \textless/=5 years' duration. Levels of B10 cells correlated inversely with the Disease Activity Score in 28 joints. This was more pronounced in patients with RA of \textless/=5 years' duration, in whom B10 cells also correlated inversely with C-reactive protein levels. Moreover, B10 cells correlated inversely with rheumatoid factor levels. CD24(high) CD38(high) and CD24(high) CD27+ B cells induced more Treg cells than did CD24(low) B cells in controls but not in RA patients. CONCLUSION: The ability of B cells to produce IL-10 was altered in RA, and this impairment influenced disease activity, biologic inflammation, and autoantibody levels, especially in patients with RA of \textless/=5 years' duration. This strongly suggests a role of B10 cells in RA initiation.

Objective: Injection of agonistic anti-Fas antibody was shown to decrease disease symptoms in arthritic mouse models. Additionally, membrane bound FasL is able to induce cell death in fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients. However, levels of soluble FasL are increased in the joint of RA patients and were associated with disease severity. These results indicate that membrane-bound and soluble FasL have opposing roles in RA and we therefore analyzed the effect of FasL on RA FLS responses. Methods: In the present study, we analyzed the responses of FLS from RA and OA patients to soluble and oligomeric FasL, the latter mimicking membrane-anchored FasL. For this, we used three different FasL variants. In addition, we characterized the signaling pathways triggering FasL-responses. Results: We found that membrane-bound and soluble FasL have distinct roles on RA FLS, as crosslinked FasL preferentially induces apoptosis, whereas soluble FasL stimulates proliferation. Moreover, we found that soluble FasL activates several signaling pathways in RA FLS such as ERK1/2, PI3K, caspase 8 and JNK, with a prominent role for JNK, as only blockage of this pathway renders FLS more susceptible to FasL induced apoptosis. Finally, crosslinked FasL-induced apoptosis in FLS from OA patients, but soluble FasL failed to stimulate their proliferation. Conclusion: Our findings suggest that soluble FasL is a disease promoter in RA, thus concurring with previous reports describing a tumor-promoting role for FasL. Therefore, blocking of sFasL could be a therapeutic strategy for treatment of RA patients. (c) 2014 American College of Rheumatology.

International audience; We have investigated the structure of the Al13Fe4(010) surface using both experimental and ab initio computational methods. The results indicate that the topmost surface layers correspond to incomplete puckered (P) planes present in the bulk crystal structure. The main building block of the corrugated termination consists of two adjacent pentagons of Al atoms, each centered by a protruding Fe atom. These motifs are interconnected via additional Al atoms referred to as "glue" atoms which partially desorb above 873 K. The surface structure of lower atomic density compared to the bulk P plane is explained by a strong Fe-Al-Fe covalent polar interaction that preserves intact clusters at the surface. The proposed surface model with identified Fe-containing atomic ensembles could explain the Al13Fe4 catalytic properties recently reported in line with the site-isolation concept [M. Armbrüster et al., Nat. Mater. 11, 690 (2012)].