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Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTK pos TREM2 high and MerTK pos LYVE1 pos ) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTK pos STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTK pos STM subpopulations could therefore be a potential treatment strategy for RA. Multiple subpopulations of synovial tissue macrophages with varied transcriptional, phenotypic and functional features may contribute to disease flare and tissue repair in patients with active rheumatoid arthritis and patients in clinical remission.

MicroRNA-155 (miR-155) is an important regulator of B cells in mice. B cells have a critical role in the pathogenesis of rheumatoid arthritis (RA). Here we show that miR-155 is highly expressed in peripheral blood B cells from RA patients compared with healthy individuals, particularly in the IgD - CD27 - memory B-cell population in ACPA + RA. MiR-155 is highly expressed in RA B cells from patients with synovial tissue containing ectopic germinal centres compared with diffuse synovial tissue. MiR-155 expression is associated reciprocally with lower expression of PU.1 at B-cell level in the synovial compartment. Stimulation of healthy donor B cells with CD40L, anti-IgM, IL-21, CpG, IFN-α, IL-6 or BAFF induces miR-155 and decreases PU.1 expression. Finally, inhibition of endogenous miR-155 in B cells of RA patients restores PU.1 and reduces production of antibodies. Our data suggest that miR-155 is an important regulator of B-cell activation in RA. MiR-155 is thought to inhibit PU.1 and thereby drive antigen-induced B-cell maturation. Here the authors show that patients with rheumatoid arthritis have high B-cell miR-155 expression and that an antagomir can rescue PU.1 expression, suggesting potential therapeutic avenues to treat rheumatoid arthritis.

Background Prognostic biomarkers of treatment response to distinct biologic disease-modifying anti-rheumatic drugs (b-DMARDs) are still lacking within the management of rheumatoid arthritis (RA). Methods Thirty-four b-DMARDs naive RA patients, divided by disease duration into early (cohort 1) and long standing (cohort 2), received CTLA4-Ig. At study entry, and every 3 months for 1 year, each patient underwent peripheral blood (PB)-derived CD4 pos cell subpopulation assessment by flow cytometry, STAT3 and STAT5 expression by RT-PCR and IL-6, IL-12p70, TGFβ, and IL-10 serum levels by ELISA. The DAS and CDAI remission was assessed at 6 and 12 months. Results DAS- and CDAI-defined remission within 12 months was achieved by 16 (47.1%) and 8 (23.5%) RA patients, respectively. Considering the whole RA cohort, CTLA4-Ig induced a significant decrease of IL-6 serum levels from baseline to 6 and 12 months, as well as of PB CD4 pos CD25 pos FoxP3 pos cells at 6 and 12 months, and of CD4 pos IL17 pos cells after 12 months. PB CD4 pos cells of RA patients showed higher STAT3 and STAT5 expression than healthy controls, which remained unchanged within 12 months of treatment. At study entry, RA patients achieving DAS remission had significantly lower IL-6 serum levels than RA patients not achieving this outcome. In particular, having baseline IL-6 serum levels ≤ 8.4 pg/ml, significantly identified naïve to b-DMARDs RA patients more likely to achieve DAS-remission under CTLA4-Ig at 6 months (66.7%) compared to RA patients with baseline IL-6 serum levels > 8.4 pg/ml [15.4%, OR (95%Cis) 11.00 (1.75–55.82)]. Moreover, having CD4 pos CD25 pos FoxP3 pos cells rate ≥ 6.0% significantly identifies naïve to b-DMARDs early RA patients more likely to achieve DAS remission at 6 months (83.3%) compared to RA patients with baseline CD4 pos CD25 pos FoxP3 pos cells < 6.0% [16.7%, OR (95% Cis) 25.00 (1.00–336.81)]. Conclusions Baseline IL-6 serum levels and peripheral blood-derived CD4 pos subpopulations are putative novel prognostic biomarkers of CTLA4-Ig response in RA patients.

Background Differential diagnosis among psoriatic arthritis (PsA) and seronegative rheumatoid arthritis (Ab neg RA) can be challenging particularly in the clinical setting of peripheral phenotype and autoantibodies seronegativity. The aim of the study was to identify synovial tissue (ST) biomarkers differentially expressed in PsA and Ab neg RA and test their predictive value of therapeutic response. Methods Thirty-four PsA patients [12 DMARD naive and 22 non-responder to methotrexate (MTX-IR)] with peripheral joint involvement and 55 Ab neg RA (27 DMARD naive and 28 MTX-IR) underwent US-guided ST biopsy and immunohistochemistry (IHC) for CD68 + , CD3 + , CD20 + , CD21 + , CD117 + , and CD138 + cells. After study entry, each DMARD-naive patient started MTX therapy and was followed in an outpatient setting for at least 6 months to define the achievement of Minimal Disease Activity (PsA) and DAS remission (Ab neg RA) status respectively. Each IR-MTX patient was treated according to EULAR recommendations. Results At study entry, IHC analysis revealed that PsA patients had comparable levels of lining and sublining CD68 + and sublining CD21 + , CD20 + , and CD3 + cells than Ab neg RA, despite the therapeutic regimen. Moreover, regardless of the therapeutic scheme, PsA patients showed higher IHC score of CD117 + cells ( p  = 0.0004 and p  = 0.0005 for naive and MTX-IR patients respectively) compared to Ab neg RA patients. Conversely, Ab neg RA patients showed higher IHC score of CD138 + cells, irrespective to the therapeutic scheme ( p  = 0.04 and p  = 0.002 for naive and MTX-IR patients respectively). Analyzing the response rate to the therapeutic scheme, naive PsA patients reaching MDA status at 6 months follow-up, showed, at the study entry, lower IHC score of CD3 + cells compared to PsA patients not reaching this outcome ( p  = 0.02); conversely, naive Ab neg RA patients reaching DAS remission status at 6 months follow-up, showed, at the study entry, lower IHC score of sublining CD68 + cells compared to Ab neg RA patients not reaching this outcome ( p  < 0.001). Conclusions CD117 + and CD138 + cells are differentially distributed among PsA and Ab neg RA. Histological analysis of ST may help to solve the clinical overlap between the two diseases and provides prognostic data about the therapy success.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis. A third of psoriatic patients develop PsA unknown mechanisms. No reliable diagnostic markers are available for PsA, or prognostic biomarkers for PsA development in psoriasis. We previously uncovered a pro-inflammatory role for cathelicidin LL37 in lesional psoriasis skin. LL37 binds nucleic acids and stimulates plasmacytoid/myeloid dendritic cells (pDC, mDCs) to secrete type I interferon (IFN-I) and pro-inflammatory factors. LL37 becomes an autoantigen for psoriatic Th1-Th17/CD8 T cells. Anti-LL37 antibodies were detected in systemic lupus erythematosus, an autoimmune disease characterized by neutrophil-extracellular-traps release (NETosis) in target organs. LL37 can be substrate of irreversible post-translational modifications, citrullination or carbamylation, linked to neutrophil activity. Here we analyzed inflammatory factors, included LL37, in PsA and psoriasis plasma and PsA synovial fluids (SF)/biopsies. We show that LL37 (as a product of infiltrating neutrophils) and autoantibodies to LL37 are elevated in PsA, but not OA SF. Anti-LL37 antibodies correlate with clinical inflammatory markers. Anti-carbamylated/citrullinated-LL37 antibodies are present in PsA SF/plasma and, at lower extent, in psoriasis plasma, but not in controls. Plasma anti-carbamylated-LL37 antibodies correlate with PsA (DAS44) but not psoriasis (PASI) disease activity. Ectopic lymphoid structures, and deposition of immunoglobulin-(Ig)G-complexes (IC) co-localizing with infiltrating neutrophils, are observed in PsA and not OA synovial tissues (ST). Activated complement (C5a, C9), GM-CSF and IFN-I are up-regulated in PsA and not OA synovia and in PsA and psoriasis plasma but not in HD. C9 and GM-CSF levels in PsA SF correlate with clinical inflammatory markers and DAS44 (C9) and with anti-carbamylated/citrullinated-LL37 antibodies (GM-CSF and IFN-I). Thus, we uncover a role for LL37 as a novel PsA autoantibody target and correlation studies suggest participation of anti-LL37 antibodies to PsA pathogenesis. Notably, plasma antibodies to carbamylated-LL37, which correlate with DAS44, suggest their use as new disease activity markers. GM-CSF and complement C5a and C9 elevation may be responsible for autoantigens release by neutrophils and their modification, fueling inflammation and autoreactivity establishment. Finally, targeting GM-CSF, C5a, C9 can be beneficial in PsA.

Current treatments for rheumatoid arthritis (RA) do not reverse underlying aberrant immune function. A genetic predisposition to RA, such as HLA-DR4 positivity, indicates that dendritic cells (DC) are of crucial importance to pathogenesis by activating auto-reactive lymphocytes. Here we show that microRNA-34a provides homoeostatic control of CD1c + DC activation via regulation of tyrosine kinase receptor AXL, an important inhibitory DC auto-regulator. This pathway is aberrant in CD1c + DCs from patients with RA, with upregulation of miR-34a and lower levels of AXL compared to DC from healthy donors. Production of pro-inflammatory cytokines is reduced by ex vivo gene-silencing of miR-34a. miR-34a-deficient mice are resistant to collagen-induced arthritis and interaction of DCs and T cells from these mice are reduced and do not support the development of Th17 cells in vivo . Our findings therefore show that miR-34a is an epigenetic regulator of DC function that may contribute to RA. Axl is a TAM receptor that can inhibit Toll-like receptor (TLR) -induced pro-inflammatory production by dendritic cells (DC). Here the authors show that miR-34a targets Axl to control CD1c+ DC activity in mice, and that miR-34a-deficient mice are resistant to collagen-induced arthritis, whereas DCs from patients with rheumatoid arthritis have high levels of miR- 34a.

Micro- and nano air vehicles are defined as “extremely small and ultra-lightweight air vehicle systems” with a maximum wingspan length of 15 cm and a weight less than 20 grams. Here, we provide a review of the current state of the art and identify the challenges of design and fabrication. Different configurations are evaluated, such as fixed wings, rotary wings, and flapping wings. The main advantages and drawbacks for each typology are identified and discussed. Special attention is given to rotary-wing vehicles (helicopter concept); including a review of their main structures, such as the airframe, energy storage, controls, and communications systems. In addition, a review of relevant sensors is also included. Examples of existing and future systems are also included. Micro- and nano-vehicles with rotary wings and rechargeable batteries are dominating. The flight times of current systems are typically around 1 hour or less due to the limited energy storage capabilities of the used rechargeable batteries. Fuel cells and ultra capacitors are promising alternative energy supply technologies for the future. Technology improvements, mainly based on micro- and nanotechnologies, are expected to continue in an evolutionary way to improve the capabilities of future micro- and nano air vehicles, giving improved flight times and payload capabilities.

We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1+ and FCN1+SPP1+ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48hiS100A12+ and CD48+SPP1+ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4+ predominant in healthy lung was transcriptionally related to STM cluster TREM2+ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post-COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1+ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14+ monocytes and development of PD-L1+ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post-COVID-19 pathology.

Background/Objectives: Juvenile idiopathic arthritis (JIA) is a chronic childhood disease that often persists into the reproductive years. JIA may impact long-term fertility due to the prolonged exposure to immunosuppressive therapies. Methods: A total of 35 adult JIA female patients of childbearing age and 20 age-matched healthy controls were studied to test their anti-Müllerian hormone (AMH) serum levels as a biomarker of ovarian reserve. Demographic characteristics, disease duration, previous and current treatments, disease activity (DAS44), and a health assessment questionnaire (HAQ) were recorded. Results: JIA patients had a mean age of 22.3 ± 2.9 years, a disease duration of 12.3 ± 6.1 years, and a DAS44 of 1.24 ± 0.61. No differences were found in AMH serum levels between JIA and controls (5.78 ± 2.37 ng/mL vs. 6.60 ± 2.68 ng/mL, respectively; p = 0.17). Among the patients, 22 (62.9%) were receiving a stable dose of methotrexate (MTX) and 19 (54.3%) a dose of TNFα inhibitors. No difference in AMH serum levels was observed between JIA patients who were or were not exposed to MTX (p = 0.29) or to TNFα inhibitors (p = 0.50). Conclusions: Ovarian reserve as assessed by AMH serum levels appears to be comparable between those with JIA and age-matched controls and does not appear to be influenced by disease characteristics or prior/concomitant exposure to immunosuppressive drugs.