Bactrocera carambolae is one of the approximately 100 sibling species of the Bactrocera dorsalis complex and considered to be very closely related to B. dorsalis. Due to their high morphological similarity and overlapping distribution, as well as to their economic impact and quarantine status, the development of reliable markers for species delimitation between the two taxa is of great importance. Here we present the complete mitochondrial genome of B. carambolae sourced from its native range in Malaysia and its invaded territory in Suriname. The mitogenome of B. carambolae presents the typical organization of an insect mitochondrion. Comparisons of the analyzed B. carambolae sequences to all available complete mitochondrial sequences of B. dorsalis revealed several species-specific polymorphic sites. Phylogenetic analysis based on Bactrocera mitogenomes supports that B. carambolae is a differentiated taxon though closely related to B. dorsalis. The present complete mitochondrial sequences of B. carambolae could be used, in the frame of Integrative Taxonomy, for species discrimination and resolution of the phylogenetic relationships within this taxonomically challenging complex, which would facilitate the application of species-specific population suppression strategies, such as the sterile insect technique.

Rheumatoid arthritis (RA) is characterized by autoimmune joint destruction with debilitating consequences. Despite treatment advancements with biologic therapies, a significant proportion of RA patients show an inadequate clinical response, and restoration of immune self-tolerance represents an unmet therapeutic need. We have previously described a tolerogenic phenotype of plasmacytoid dendritic cells (pDCs) in RA patients responding to anti–TNF-α agents. However, the molecular mechanisms involved in tolerogenic reprogramming of pDCs in RA remain elusive. In this study, guided by transcriptomic analysis of CD303+CD123+ pDCs from RA patients in remission, we revealed enhanced expression of IL-6R and its downstream signaling compared with healthy pDCs. Functional assessment demonstrated that IL-6R engagement resulted in marked reduction of TNF-α secretion by pDCs whereas intracellular TNF-α was significantly increased. Accordingly, pharmacologic inhibition of IL-6R signaling restored TNF-α secretion levels by pDCs. Mechanistic analysis demonstrated impaired activity and decreased lysosomal degradation of ADAM17 (a disintegrin and metalloproteinase 17) sheddase in pDCs, which is essential for TNF-α cleavage. Importantly, reduction of TNF-α secretion by IL-6–treated pDCs attenuated the inflammatory potential of RA patient–derived synovial fibroblasts. Collectively, these findings position pDCs as an important source of TNF-α in RA pathogenesis and unravel an anti-inflammatory mechanism of IL-6 by limiting the pDC-derived TNF-α secretion.

Background Rheumatoid arthritis (RA) is a chronic autoimmune disease for which prediction of long-term prognosis from disease’s outset is not clinically feasible. The importance of immunoglobulin G (IgG) and its Fc N-glycosylation in inflammation is well-known and studies described its relevance for several autoimmune diseases, including RA. Herein we assessed the association between IgG N-glycoforms and disease prognosis at 2 years in an early inflammatory arthritis cohort. Methods Sera from 118 patients with early inflammatory arthritis naïve to treatment sampled at baseline were used to obtain IgG Fc glycopeptides, which were then analyzed in a subclass-specific manner by liquid chromatography coupled to mass spectrometry (LC-MS). Patients were prospectively followed and a favorable prognosis at 2 years was assessed by a combined index as remission or low disease activity (DAS28 < 3.2) and normal functionality (HAQ ≤ 0.25) while on treatment with conventional synthetic DMARDs and never used biologic DMARDs. Results We observed a significant association between high levels of IgG2/3 Fc galactosylation (effect 0.627 and adjusted p value 0.036 for the fully galactosylated glycoform H5N4F1; effect −0.551 and adjusted p value 0.04963 for the agalactosylated H3N4F1) and favorable outcome after 2 years of treatment. The inclusion of IgG glycoprofiling in a multivariate analysis to predict the outcome (with HAQ, DAS28, RF, and ACPA included in the model) did not improve the prognostic performance of the model. Conclusion Pending confirmation of these findings in larger cohorts, IgG glycosylation levels could be used as a prognostic marker in early arthritis, to overcome the limitations of the current prognostic tools.

BackgroundReestablishing immune tolerance and long term remission represent major therapeutic goals in rheumatoid arthritis (RA). Our laboratory previously demonstrated that plasmacytoid dendritic cells (pDCs) from RA patients in remission have the ability to induce IL-10 producing regulatory T cells (Tregs) in vitro.1 However, the molecular pathway of RA pDC-mediated Treg induction remains elusive.ObjectivesHerein, we sought to identify the molecular mechanism through which pDCs contribute to restoration of tolerance in RA.MethodspDCs were isolated from peripheral blood of RA patients responding to anti-TNF therapy (remission based on disease activity score DAS28 <5.1) and healthy control subjects and DNA microarrays were performed. Flow cytometry and real time PCR were used to verify the expression of de-regulated genes in RA pDCs. Finally, in vitro cultures of pDCs activated with CpG A in the presence or absence of recombinant IL-6 (rIL-6) were performed to assess the functional importance of these gene signatures.ResultspDCs from RA patients (n=5) exhibited a differential gene signature (6741 deregulated genes) compared to pDCs from healthy controls (n=5). Notably, IL-6 receptor (IL-6R) gene, exhibited increased expression levels in pDCs isolated from RA patients compared to healthy pDCs and the surface expression levels of IL-6 receptor were verified in a subsequent cohort of patients responding to therapy (n=9) versus active patients or healthy donors. Moreover, assessment of IL-6 signalling pathway in RA patients versus healthy donors revealed a significant increase of pSTAT1 expression levels in RA patients (n=9) compared with healthy donors (n=6) (mean fluorescence intensity ±SEM, 7.98±0.8 versus 12.65±1.18, p value=0.0076). Importantly, IL-6-treated pDCs exhibited a vast decrease in TNF-α production (p value=0.0002) whereas no differences were found in the production of IFN-α and in their antigen presenting capacity between CpG-treated pDCs in the presence or absence of rIL-6. Moreover, confocal experiments in progress will assess the expression levels of TNF-α in pDCs isolated from RA patients in remission versus active or healthy donors. The functional importance of the previous findings will be addressed in coculture experiments of IL-6 stimulated pDCs with monocytes isolated from healthy donors and monitor their activation and maturation status.ConclusionsWe found that pDCs from RA patients in remission display increased IL-6R expression levels and an activated IL-6 signalling pathway. Activation of IL-6 signalling on pDCs in vitro significantly decreases the production of TNF-α whereas it does not alter IFN-α production and their antigen presenting capacity. This novel finding and the underlying mechanism that may drive pDCs towards a previously described tolerogenic phenotype, need to be further addressed.Reference[1] Kavousanaki, et al. Arthritis Rheum2010.AcknowledgementsProject funded by “Pancretia” health organisation.Disclosure of InterestNone declared