MicroRNAs control the differentiation and function of B cells, which are considered key elements in the pathogenesis of systemic lupus erythematosus (SLE). However, a common micro(mi)RNA signature ...has not emerged since published data includes patients of variable ethnic background, type of disease, and organ involvement, as well as heterogeneous cell populations. Here, we aimed at identifying a miRNA signature of purified B cells from renal and non-renal severe SLE patients of Latin American background, a population known to express severe disease. Genome-wide miRNA expression analyses were performed on naive and memory B cells and revealed two categories of miRNA signatures. The first signature represents B cell subset-specific miRNAs deregulated in SLE: 11 and six miRNAs discriminating naive and memory B cells of SLE patients from healthy controls (HC), respectively. Whether the miRNA was up or down-regulated in memory B cells as compared with naive B cells in HC, this difference was abolished in SLE patients, and vice versa. The second signature identifies six miRNAs associated with specific pathologic features affecting renal outcome, providing a further understanding for SLE pathogenesis. Overall, the present work provided promising biomarkers in molecular diagnostics for disease severity as well as potential new targets for therapeutic intervention in SLE.
The underlying
mechanisms of rituximab action remain incompletely understood in chronic lymphocytic leukemia. Recent data suggest that circulating micro-ribonucleic acids correlate with chronic ...lymphocytic leukemia progression and response to rituximab. Our study aimed at identifying circulating micro-ribonucleic acids that predict response to rituximab monotherapy in chronic lymphocytic leukemia patients. Using a hierarchical clustering of micro-ribonucleic acid expression profiles discriminating 10 untreated patients with low or high lymphocyte counts, we found 26 micro-ribonucleic acids significantly deregulated. Using individual real-time reverse transcription polymerase chain reaction, the expression levels of micro-ribonucleic acids representative of these two clusters were further validated in a larger cohort (n=61). MiR-125b and miR-532-3p were inversely correlated with rituximab-induced lymphodepletion (
=0.020 and
=0.001, respectively) and with the CD20 expression on CD19
cells (
=0.0007 and
<0.0001, respectively).
analyses of genes putatively targeted by both micro-ribonucleic acids revealed a central role of the interleukin-10 pathway and CD20 (MS4A1) family members. Interestingly, both micro-ribonucleic acids were negatively correlated with
expression, while they were positively correlated with
and
Our results identify novel circulating predictive biomarkers for rituximab-mediated lymphodepletion efficacy in chronic lymphocytic leukemia, and suggest a novel molecular mechanism responsible for the rituximab mode of action that bridges miR-125b and miR-532-3p and CD20 family members. (
).
Cells from the mononuclear phagocyte system (MPS) act as systemic and local amplifiers that contribute to the progression of chronic inflammatory disorders. Transforming growth factor-β–activated ...kinase 1 (TAK1) is a pivotal upstream mitogen-activated protein kinase-kinase-kinase acting as a mediator of cytokine expression. It remains critical to determine in vivo the implication of TAK1 in controlling the innate immune system. Here, we describe a vehicle tailored to selectively deliver siRNAs into MPS cells after intravenous administration, and validate in vivo the potential of the RNAi-mediated TAK1 knock down for immunomodulation. In a mouse model of immune-mediated inflammatory disorder, we show that anti-TAK1 siRNA lipoplexes efficiently alleviate inflammation, severely impair the downstream c-Jun N-terminal kinase and nuclear factor-κB signaling pathways, and decrease the expression of proinflammatory mediators. Importantly, the systemic TAK1 gene silencing decreases the frequency of Th1 and Th17 cells, both mediating autoimmunity in experimental arthritis, demonstrating the immunomodulatory potential of TAK1. Finally, in vitro inhibition of TAK1 in myeloid cells decreases interferon-γ–producing T cells, suggesting that a delivery sys-tem able to target MPS cells and to silence TAK1 impacts on pathogenic T effector cells in autoimmunity.
Previous studies have reported that mesenchymal stem cells (MSC) may be isolated from the synovial membrane by the same protocol as that used for synovial fibroblast cultivation, suggesting that MSC ...correspond to a subset of the adherent cell population, as MSC from the stromal compartment of the bone marrow (BM). The aims of the present study were, first, to better characterize the MSC derived from the synovial membrane and, second, to compare systematically, in parallel, the MSC-containing cell populations isolated from BM and those derived from the synovium, using quantitative assays. Fluorescent-activated cell sorting analysis revealed that both populations were negative for CD14, CD34 and CD45 expression and that both displayed equal levels of CD44, CD73, CD90 and CD105, a phenotype currently known to be characteristic of BM-MSC. Comparable with BM-MSC, such MSC-like cells isolated from the synovial membrane were shown for the first time to suppress the T-cell response in a mixed lymphocyte reaction, and to express the enzyme indoleamine 2,3-dioxygenase activity to the same extent as BM-MSC, which is a possible mediator of this suppressive activity. Using quantitative RT-PCR these data show that MSC-like cells from the synovium and BM may be induced to chondrogenic differentiation and, to a lesser extent, to osteogenic differentiation, but the osteogenic capacities of the synovium-derived MSC were significantly reduced based on the expression of the markers tested (collagen type II and aggrecan or alkaline phosphatase and osteocalcin, respectively). Transcription profiles, determined with the Atlas Human Cytokine/Receptor Array, revealed discrimination between the MSC-like cells from the synovial membrane and the BM-MSC by 46 of 268 genes. In particular, activin A was shown to be one major upregulated factor, highly secreted by BM-MSC. Whether this reflects a different cellular phenotype, a different amount of MSC in the synovium-derived population compared with BM-MSC adherent cell populations or the impact of a different microenvironment remains to be determined. In conclusion, although the BM-derived and synovium-derived MSC shared similar phenotypic and functional properties, both their differentiation capacities and transcriptional profiles permit one to discriminate the cell populations according to their tissue origin.
Like other tissues, joints contain resident macrophages, and their diversity is only beginning to be characterized. Based on the highlights of recent studies, we discuss where current challenges lie ...and propose new avenues for future research in the osteoarticular field.
Gene therapy holds great promise for the treatment of rheumatoid arthritis (RA). In this article, we focus on innovation in vector, promoter or target genes. Gene therapy is defined as an ...introduction of nucleic acids into a host cell for therapeutic purposes; the option may be the overexpression of therapeutic gene or an underexpression of a target gene highly expressed in disease (small interfering RNA (siRNA)). The proof of principle in animal models of arthritis has shown convincingly that gene therapy can be an advantageous strategy in the treatment of RA. A gene therapy approach is advantageous over biologics for joint-specific targeting and long-term expression of an anti-arthritic molecule, replacing the frequent administration of recombinant proteins. We also discuss the currently used gene therapy clinical trials and define optimal strategies for success.
ObjectivesEvidence on the current status of gender equity in academic rheumatology in Europe and potential for its improvement is limited. The EULAR convened a task force to obtain empirical evidence ...on the potential unmet need for support of female rheumatologists, health professionals and non-clinical scientists in academic rheumatology.MethodsThis cross-sectional study comprised three web-based surveys conducted in 2020 among: (1) EULAR scientific member society leaders, (2) EULAR and Emerging EULAR Network (EMEUNET) members and (3) EULAR Council members. Statistics were descriptive with significance testing for male/female responses assessed by χ2 test and t-test.ResultsData from EULAR scientific member societies in 13 countries indicated that there were disproportionately fewer women in academic rheumatology than in clinical rheumatology, and they tended to be under-represented in senior academic roles. From 324 responses of EULAR and EMEUNET members (24 countries), we detected no gender differences in leadership aspirations, self-efficacy in career advancement and work–life integration as well as the share of time spent on research, but there were gender differences in working hours and the levels of perceived gender discrimination and sexual harassment. There were gender differences in the ranking of 7 of 26 factors impacting career advancement and of 8 of 24 potential interventions to aid career advancement.ConclusionsThere are gender differences in career advancement in academic rheumatology. The study informs a EULAR task force developing a framework of potential interventions to accelerate gender-equitable career advancement in academic rheumatology.
RNA interference (RNAi) is one of the most exciting and important discoveries of the past few decades. Small interfering RNAs (siRNAs) can silence gene activity and be used to interfere with ...pathophysiological processes. Substantial research has focused on introducing 'drug-like' properties-stability, selectivity and potency-to RNAi molecules, and clinical trials have been initiated. Despite initial success, the current challenge that remains is to develop optimized vehicles that avoid off-target effects whilst efficiently delivering the therapeutic siRNA to specific cell types. As for many other diseases, siRNA-based therapy is emerging as a promising approach for the treatment of rheumatic disorders. Although the pathogenesis of rheumatic diseases is complex, identification of candidate genes able to influence either inflammation or structural damage has been successful. Here, we will discuss advances in the field and potential applications of siRNA therapeutics in clinical trials for rheumatic conditions.
Abstract MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression at the post-transcriptional level. Currently, there are 939 mature human miRNA sequences listed ...in the Sanger updated miRNA registry. There are approximately 1500 predicted miRNAs in the human genome that may regulate the expression of one third of our genes. By controlling the accumulation of the target protein(s) in cells, these regulatory RNA molecules participate in key functions in many physiological networks and their deregulation has been implicated in the pathogenesis of serious human disorders, such as cancer and infection. The implication of miRNAs in immune-mediated disorders such as rheumatoid arthritis (RA) has recently emerged suggesting that miRNA-based therapeutic approaches may have a promising potential in these diseases. Here, we provide an overview of the state-of-the-art on miRNAs in RA, focusing on both systemic and local features of the pathology.
•Recent single cell RNA sequencing studies of human and mouse joint tissue revealed high heterogeneity of lining and interstitial macrophages in health and disease.•Human and mouse tissue resident ...macrophages partially resemble one another.•Adult synovial tissue resident macrophages comprise a mixture of cells arising from embryonic and adult precursors.•Embryonic origin of synovial tissue resident macrophages subsets remain to be formally demonstrated.•Arthritis disrupts lining and sub-lining macrophage niches and extends macrophages heterogeneity.
Rheumatoid arthritis (RA) is a prototypic autoimmune disease that primarily affects joints. Clinical studies and animal models evidenced that mononuclear phagocytes including monocytes and macrophages are crucial to RA pathogenesis, contributing to inflammation and destruction of cartilage and bone. The last decade of research has tremendously changed our view on the origin of tissue-resident macrophages. In light of the recent publications that reveal important phenotypic and functional heterogeneity among macrophages, it is of paramount importance to identify the synovial macrophage subsets that might amplify the inflammatory response or promote the restoration of tissue homeostasis. In this review, we highlight latest studies applying single-cell RNA sequencing that provide deeper insights in macrophage subsets and their putative functions within both human and mouse synovial joint tissue.
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