Patterns and determinants of response to novel therapies in juvenile and adult-onset polyarthritis

Biological and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) have revolutionized the management of multiple rheumatic inflammatory conditions. Amongst these, polyarticular Juvenile-Idiopathic Arthritis (pJIA) and Rheumatoid Arthritis (RA) display similarities in terms of disease pathophysiology and response pattern to b/tsDMARDs. Indeed, therapeutic efficacy of novel targeted drugs is variable among individual patients, in both RA and pJIA. Mechanisms and determinants of this heterogeneous response are diverse and complex, such that development of true “precision”-medicine strategies has proven highly challenging. In this review, we will discuss pathophysiological, patient-specific, drug-specific and environmental factors contributing to individual therapeutic response in polyarticular JIA in comparison to what is known in RA. Although some biomarkers have been identified that stratify for the likelihood of either therapeutic response or non-response, few have proved useful in clinical practice so far, likely due to the complexity of treatment-response mechanisms. Consequently, we propose a pragmatic, patient-centered and clinically-based approach, i.e. personalized instead of biomarker-based precision medicine in JIA

TranscriptomeBrowser: A Powerful and Flexible Toolbox to Explore Productively the Transcriptional Landscape of the Gene Expression Omnibus Database

International audienceAs public microarray repositories are constantly growing, we are facing the challenge of designing strategies to provide productive access to the available data.\ We used a modified version of the Markov clustering algorithm to systematically extract clusters of co-regulated genes from hundreds of microarray datasets stored in the Gene Expression Omnibus database (n = 1,484). This approach led to the definition of 18,250 transcriptional signatures (TS) that were tested for functional enrichment using the DAVID knowledgebase. Over-representation of functional terms was found in a large proportion of these TS (84%). We developed a JAVA application, TBrowser that comes with an open plug-in architecture and whose interface implements a highly sophisticated search engine supporting several Boolean operators (http://tagc.univ-mrs.fr/tbrowser/). User can search and analyze TS containing a list of identifiers (gene symbols or AffyIDs) or associated with a set of functional terms.\ As proof of principle, TBrowser was used to define breast cancer cell specific genes and to detect chromosomal abnormalities in tumors. Finally, taking advantage of our large collection of transcriptional signatures, we constructed a comprehensive map that summarizes gene-gene co-regulations observed through all the experiments performed on HGU133A Affymetrix platform. We provide evidences that this map can extend our knowledge of cellular signaling pathways

TLR4 and NKT Cell Synergy in Immunotherapy against Visceral Leishmaniasis

NKT cells play an important role in autoimmune diseases, tumor surveillance, and infectious diseases, providing in most cases protection against infection. NKT cells are reactive to CD1d presented glycolipid antigens. They can modulate immune responses by promoting the secretion of type 1, type 2, or immune regulatory cytokines. Pathogen-derived signals to dendritic cells mediated via Toll like Receptors (TLR) can be modulated by activated invariant Natural Killer T (iNKT) cells. The terminal β-(1–4)-galactose residues of glycans can modulate host responsiveness in a T helper type-1 direction via IFN-γ and TLRs. We have attempted to develop a defined immunotherapeutic, based on the cooperative action of a TLR ligand and iNKT cell using a mouse model of visceral leishmaniasis. We evaluated the anti-Leishmania immune responses and the protective efficacy of the β-(1–4)-galactose terminal NKT cell ligand glycosphingophospholipid (GSPL) antigen of L. donovani parasites. Our results suggest that TLR4 can function as an upstream sensor for GSPL and provoke intracellular inflammatory signaling necessary for parasite killing. Treatment with GSPL was able to induce a strong effective T cell response that contributed to effective control of acute parasite burden and led to undetectable parasite persistence in the infected animals. These studies for the first time demonstrate the interactions between a TLR ligand and iNKT cell activation in visceral leishmaniasis immunotherapeutic

A novel two-score system for interferon status segregates autoimmune diseases and correlates with clinical features

Measurement of type I interferon (IFN-I) has potential to diagnose and stratify autoimmune diseases, but existing results have been inconsistent. Interferon-stimulated-gene (ISG) based methods may be afected by the modularity of the ISG transcriptome, cell-specifc expression, response to IFN-subtypes and bimodality of expression. We developed and clinically validated a 2-score system (IFN-Score-A and -B) using Factor Analysis of 31 ISGs measured by TaqMan selected from 3-IFN-annotated modules. We evaluated these scores using in-vitro IFN stimulation as well as in sorted cells then clinically validated in a cohort of 328 autoimmune disease patients and healthy controls. ISGs varied in response to IFNsubtypes and both scores varied between cell subsets. IFN-Score-A diferentiated Systemic Lupus Erythematosus (SLE) from both Rheumatoid Arthritis (RA) and Healthy Controls (HC) (both p<0.001), while IFN-Score-B diferentiated SLE and RA from HC (both p<0.001). In SLE, both scores were associated with cutaneous and hematological (all p<0.05) but not musculoskeletal disease activity. Comparing with bimodal (IFN-high/low) classifcation, signifcant diferences in IFN-scores were found between diagnostic groups within the IFN-high group. Our continuous 2-score system is more clinically relevant than a simple bimodal classifcation of IFN status. This system should allow improvement in diagnosis, stratifcation, and therapy in IFN-mediated autoimmunity

Antinuclear antibodies directed against proliferating cell nuclear antigen are not specifically associated with systemic lupus erythematosus

status: publishe

Overexpression of ubiquitin-specific peptidase 15 in systemic sclerosis fibroblasts increases response to transforming growth factor β

Objective Ubiquitination of proteins leads to their degradation by the proteasome, and is regulated by ubiquitin ligases and substrate-specific ubiquitin-specific peptidases (USPs). The ubiquitination process also plays important roles in the regulation of cell metabolism and cell cycle. Here, we found that the expression of several USPs is increased in SSc tenosynovial and skin biopsies, and we demonstrated that USP inhibition decreases TGF-β signalling in primary fibroblast cell lines. Methods High-density transcriptomic studies were performed using total RNA obtained from SSc tenosynovial samples. Confirmatory immunostaining experiments were performed on tenosynovial and skin samples. In vitro experiments were conducted in order to study the influence of USP modulation on responses to TGF-β stimulation. Results Tenosynovial biopsies from SSc patients overexpressed known disease-associated gene pathways: fibrosis, cytokines and chemokines, and Wnt/TGF-β signalling, but also several USPs. Immunohistochemistry experiments confirmed the detection of USPs in the same samples, and in SSc skin biopsies. Exposure of primary fibroblast cell lines to TGF-β induced USP gene expression. The use of a pan-USP inhibitor decreased SMAD3 phosphorylation, and expression of COL1A1, COL3A1 and fibronectin gene expression in TGF-β-stimulated fibroblasts. The effect of the USP inhibitor resulted in increased SMAD3 ubiquitination, and was blocked by a proteasome inhibitor, thereby confirming the specificity of its action. Conclusion Overexpression of several USPs, including USP15, amplifies fibrotic responses induced by TGF-β, and is a potential therapeutic target in SSc

Overexpression of ubiquitin-specific peptidase 15 in systemic sclerosis fibroblasts increases response to transforming growth factor β

Objective Ubiquitination of proteins leads to their degradation by the proteasome, and is regulated by ubiquitin ligases and substrate-specific ubiquitin-specific peptidases (USPs). The ubiquitination process also plays important roles in the regulation of cell metabolism and cell cycle. Here, we found that the expression of several USPs is increased in SSc tenosynovial and skin biopsies, and we demonstrated that USP inhibition decreases TGF-β signalling in primary fibroblast cell lines. Methods High-density transcriptomic studies were performed using total RNA obtained from SSc tenosynovial samples. Confirmatory immunostaining experiments were performed on tenosynovial and skin samples. In vitro experiments were conducted in order to study the influence of USP modulation on responses to TGF-β stimulation. Results Tenosynovial biopsies from SSc patients overexpressed known disease-associated gene pathways: fibrosis, cytokines and chemokines, and Wnt/TGF-β signalling, but also several USPs. Immunohistochemistry experiments confirmed the detection of USPs in the same samples, and in SSc skin biopsies. Exposure of primary fibroblast cell lines to TGF-β induced USP gene expression. The use of a pan-USP inhibitor decreased SMAD3 phosphorylation, and expression of COL1A1, COL3A1 and fibronectin gene expression in TGF-β-stimulated fibroblasts. The effect of the USP inhibitor resulted in increased SMAD3 ubiquitination, and was blocked by a proteasome inhibitor, thereby confirming the specificity of its action. Conclusion Overexpression of several USPs, including USP15, amplifies fibrotic responses induced by TGF-β, and is a potential therapeutic target in SSc