Comparing astroglial reactivity in two transgenic mouse models of tauopathy

Astrocytes are becoming crucial players in the pathology of neurodegenerative disorders, such as Alzheimer’s disease (AD). Astrocyte responses have been mainly analyzed in the context of amyloid-beta (Abeta) pathology, highlighting their role in the development/progression of amyloidosis and their relationship with the microglial response. Regarding tau pathology, some studies have reported that astrocytes respond to hyperphosphorylated tau (phospho-tau) and suggested their implication on tau transmission/elimination. Here, we aimed to analyze the astroglial reactivity to tau pathology in the hippocampus of two transgenic mouse models of tauopathy, ThyTau22 and P301S. Proteinopathy was assessed by western-blotting and immunohistochemistry using phospho-tau antibodies (AT8). Inflammatory markers (GFAP, Iba-1, CD45, TREM2) were analyzed by qPCR and immunohistochemistry for bright-field microscopy; glial-phospho-tau relationship was analyzed under confocal and transmission electron microscopy. P301S mice exhibited an intense reactive astrogliosis, increasing with aging in parallel to a strong phospho-tau pathology. ThyTau22 model showed a slighter astrocyte reactivity accompanied by a lesser accumulation of phospho-tau. Astrogliosis in P301S mice closely correlated with an acute DAM-like microglial activation, not observed in ThyTau22 hippocampus. Confocal and ultrastructural studies revealed that, in both models, astrocytic processes contained phospho-tau, especially those surrounding blood vessels. Our results support that astrocytes respond to tau pathology in the absence of Abeta. This reactivity highly correlates with phospho-tau pathology and markedly depends on microglial activation. Moreover, astrocytes may play a role in the elimination/spreading of phospho-tau species through the brain. Deciphering the mechanisms underlying these processes might help to develop therapies to slow down the progression of AD.Supported by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union through grants PI18/01557 (to AG), PI18/01556 (to JV), and by Junta de Andalucia through Consejería de Economía y Conocimiento grants UMA18-FEDERJA-211 (AG), P18-RT-2233 (AG) and US-1262734 (JV) co-financed by Programa Operativo FEDER2014-2020. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

The major environmental risk factor for rheumatoid arthritis (RA) is smoking, which according to a widely accepted model induces protein citrullination in the lungs, triggering the production of anticitrullinated protein antibodies (ACPA) and RA development. Nevertheless, some research findings do not fit this model. Therefore, we obtained six independent cohorts with 2253 RA patients for a detailed analysis of the association between smoking and RA autoantibodies. Our results showed a predominant association of smoking with the concurrent presence of the three antibodies: rheumatoid factor (RF), ACPA and anti-carbamylated protein antibodies (ACarPA) (3 Ab vs. 0 Ab: OR = 1.99, p = 2.5 × 10?8). Meta-analysis with previous data (4491 patients) confirmed the predominant association with the concurrent presence of the three antibodies (3 Ab vs. 0 Ab: OR = 2.00, p = 4.4 ×10?16) and revealed that smoking was exclusively associated with the presence of RF in patients with one or two antibodies (RF+ 1+2 vs. RF? 0+1+2: OR = 1.32, p = 0.0002). In contrast, no specific association with ACPA or ACarPA was found. Therefore, these results showed the need to understand how smoking favors the concordance of RA specific antibodies and RF triggering, perhaps involving smoking-induced epitope spreading and other hypothesized mechanisms

Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum TimeCourse

Introduction: Increased cardiovascular (CV) morbidity and mortality is observed in inflammatory joint diseases (IJDs) such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. However, the management of CV disease in these conditions is far from being well established.Areas covered: This review summarizes the main epidemiologic, pathophysiological, and clinical risk factors of CV disease associated with IJDs. Less common aspects on early diagnosis and risk stratification of the CV disease in these conditions are also discussed. In Europe, the most commonly used risk algorithm in patients with IJDs is the modified SCORE index based on the revised recommendations proposed by the EULAR task force in 2017.Expert opinion: Early identification of IJD patients at high risk of CV disease is essential. It should include the use of complementary noninvasive imaging techniques. A multidisciplinary approach aimed to improve heart-healthy habits, including strict control of classic CV risk factors is crucial. Adequate management of the underlying IJD is also of main importance since the reduction of disease activity decreases the risk of CV events. Non-steroidal anti-inflammatory drugs may have a lesser harmful effect in IJD than in the general population, due to their anti-inflammatory effects along with other potential beneficial effects.This research was partially funded by FOREUM—Foundation for Research in Rheumatolog

Polarimetric Properties of Event Horizon Telescope Targets from ALMA

We present the results from a full polarization study carried out with the Atacama Large Millimeter/submillimeter Array (ALMA) during the first Very Long Baseline Interferometry (VLBI) campaign, which was conducted in 2017 April in the λ3 mm and λ1.3 mm bands, in concert with the Global mm-VLBI Array (GMVA) and the Event Horizon Telescope (EHT), respectively. We determine the polarization and Faraday properties of all VLBI targets, including Sgr A*, M87, and a dozen radio-loud active galactic nuclei (AGNs), in the two bands at several epochs in a time window of 10 days. We detect high linear polarization fractions (2%–15%) and large rotation measures (RM > 103.3–105.5 rad m−2), confirming the trends of previous AGN studies at millimeter wavelengths. We find that blazars are more strongly polarized than other AGNs in the sample, while exhibiting (on average) order-of-magnitude lower RM values, consistent with the AGN viewing angle unification scheme. For Sgr A* we report a mean RM of (−4.2 ± 0.3) × 105 rad m−2 at 1.3 mm, consistent with measurements over the past decade and, for the first time, an RM of (–2.1 ± 0.1) × 105 rad m−2 at 3 mm, suggesting that about half of the Faraday rotation at 1.3 mm may occur between the 3 mm photosphere and the 1.3 mm source. We also report the first unambiguous measurement of RM toward the M87 nucleus at millimeter wavelengths, which undergoes significant changes in magnitude and sign reversals on a one year timescale, spanning the range from −1.2 to 0.3 × 105 rad m−2 at 3 mm and −4.1 to 1.5 × 105 rad m−2 at 1.3 mm. Given this time variability, we argue that, unlike the case of Sgr A*, the RM in M87 does not provide an accurate estimate of the mass accretion rate onto the black hole. We put forward a two-component model, comprised of a variable compact region and a static extended region, that can simultaneously explain the polarimetric properties observed by both the EHT (on horizon scales) and ALMA (which observes the combined emission from both components). These measurements provide critical constraints for the calibration, analysis, and interpretation of simultaneously obtained VLBI data with the EHT and GMVA

Differences in antibody responses between trivalent inactivated influenza vaccine and live attenuated influenza vaccine correlate with the kinetics and magnitude of interferon signaling in children.

BACKGROUND: Live attenuated influenza vaccine (LAIV) and trivalent inactivated influenza vaccine (TIV) are effective for prevention of influenza virus infection in children, but the mechanisms associated with protection are not well defined. METHODS: We analyzed the differences in B-cell responses and transcriptional profiles in children aged 6 months to 14 years immunized with these 2 vaccines. RESULTS: LAIV elicited a significant increase in naive, memory, and transitional B cells on day 30 after vaccination, whereas TIV elicited an increased number of plasmablasts on day 7. Antibody titers against the 3 vaccine strains (H1N1, H3N2, and B) were significantly higher in the TIV group and correlated with number of antibody-secreting cells. Both vaccines induced overexpression of interferon (IFN)-signaling genes but with different kinetics. TIV induced expression of IFN genes on day 1 after vaccination in all age groups, and LAIV induced expression of IFN genes on day 7 after vaccination but only in childrentiters. CONCLUSIONS: These results suggest that LAIV and TIV induced significantly different B-cell responses in vaccinated children. Early induction of IFN appears to be important for development of antibody responses. J Infect Dis 2014 Jul 15; 210(2):224-33

HLA-B*08 Identified as the Most Prominently Associated Major Histocompatibility Complex Locus for Anti-Carbamylated Protein Antibody-Positive/Anti-Cyclic Citrullinated Peptide-Negative Rheumatoid Arthritis

Objective. Previously, only the HLA-DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti-carbamylated protein antibody-positive (anti-CarP+) RA.Methods. Analyses were restricted to RA patients who were anti-cyclic citrullinated peptide antibody negative (anti-CCP), because the anti-CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti-CCP- RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for similar to 8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti-CarP status in RA patients was tested with logistic regression and combined with inverse-variance meta-analysis. Significance of the associations was assessed according to a study-specific threshold of P < 2.0 x 10(-5).Results. The HLA-B*08 allele and its correlated amino acid variant Asp-9 showed a significant association with anti-CarP+/anti-CCP- RA (P < 3.78 x 10(-7); I-2 = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti-CarP-/anti-CCP- RA patients, and anti-CCP- RA patients who were positive for other anti-citrullinated protein antibodies. Based on these findings, anti-CarP+/anti-CCP- RA patients could be separated from other antibody-defined subsets of RA patients in whom an association with the HLA-B*08 allele has been previously demonstrated. No other MHC variant remained associated with anti-CarP+/anti-CCP- RA after accounting for the presence of the HLA-B*08 allele. Specifically, the reported association of HLA-DRB1*03 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium.Conclusion. These results identify HLA-B*08 carrying Asp-9 as the MHC locus showing the strongest association with anti-CarP+/anti-CCP- RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies.Pathophysiology and treatment of rheumatic disease

Timing of onset affects arthritis presentation pattern in antisyntethase syndrome

79To evaluate if the timing of appearance with respect to disease onset may influence the arthritis presentation pattern in antisynthetase syndrome (ASSD).nonenoneGonzález-Gay, Miguel A; Montecucco, Carlomaurizio; Selva-O'Callaghan, Albert; Trallero-Araguas, Ernesto; Molberg, Ovynd; Andersson, Helena; Rojas-Serrano, Jorge; Perez-Roman, Diana Isabel; Bauhammer, Jutta; Fiehn, Christoph; Neri, Rossella; Barsotti, Simone; Lorenz, Hannes M; Doria, Andrea; Ghirardello, Anna; Iannone, Florenzo; Giannini, Margherita; Franceschini, Franco; Cavazzana, Ilaria; Triantafyllias, Konstantinos; Benucci, Maurizio; Infantino, Maria; Manfredi, Mariangela; Conti, Fabrizio; Schwarting, Andreas; Sebastiani, Giandomenico; Iuliano, Annamaria; Emmi, Giacomo; Silvestri, Elena; Govoni, Marcello; Scirè, Carlo Alberto; Furini, Federica; Lopez-Longo, Francisco Javier; Martínez-Barrio, Julia; Sebastiani, Marco; Manfredi, Andreina; Bachiller-Corral, Javier; Sifuentes Giraldo, Walter Alberto; Cimmino, Marco A; Cosso, Claudio; Belotti Masserini, Alessandro; Cagnotto, Giovanni; Codullo, Veronica; Romano, Mariaeva; Paolazzi, Giuseppe; Pellerito, Raffaele; Saketkoo, Lesley Ann; Ortego-Centeno, Norberto; Quartuccio, Luca; Batticciotto, Alberto; Bartoloni Bocci, Elena; Gerli, Roberto; Specker, Christof; Bravi, Elena; Selmi, Carlo; Parisi, Simone; Salaffi, Fausto; Meloni, Federica; Marchioni, Enrico; Pesci, Alberto; Dei, Giulia; Confalonieri, Marco; Tomietto, Paola; Nuno, Laura; Bonella, Francesco; Pipitone, Nicolò; Mera-Valera, Antonio; Perez-Gomez, Nair; Gerzeli, Simone; Lopez-Mejias, Raquel; Matos-Costa, Carlo Jorge; Pereira da Silva, Jose Antonio; Cifrian, José; Alpini, Claudia; Olivieri, Ignazio; Blázquez Cañamero, María Ángeles; Rodriguez Cambrón, Ana Belén; Castañeda, Santos; Cavagna, LorenzoGonzález-Gay, Miguel A; Montecucco, Carlomaurizio; Selva-O'Callaghan, Albert; Trallero-Araguas, Ernesto; Molberg, Ovynd; Andersson, Helena; Rojas-Serrano, Jorge; Perez-Roman, Diana Isabel; Bauhammer, Jutta; Fiehn, Christoph; Neri, Rossella; Barsotti, Simone; Lorenz, Hannes M; Doria, Andrea; Ghirardello, Anna; Iannone, Florenzo; Giannini, Margherita; Franceschini, Franco; Cavazzana, Ilaria; Triantafyllias, Konstantinos; Benucci, Maurizio; Infantino, Maria; Manfredi, Mariangela; Conti, Fabrizio; Schwarting, Andreas; Sebastiani, Giandomenico; Iuliano, Annamaria; Emmi, Giacomo; Silvestri, Elena; Govoni, Marcello; Scirè, Carlo Alberto; Furini, Federica; Lopez-Longo, Francisco Javier; Martínez-Barrio, Julia; Sebastiani, Marco; Manfredi, Andreina; Bachiller-Corral, Javier; Sifuentes Giraldo, Walter Alberto; Cimmino, Marco A; Cosso, Claudio; Belotti Masserini, Alessandro; Cagnotto, Giovanni; Codullo, Veronica; Romano, Mariaeva; Paolazzi, Giuseppe; Pellerito, Raffaele; Saketkoo, Lesley Ann; Ortego-Centeno, Norberto; Quartuccio, Luca; Batticciotto, Alberto; Bartoloni Bocci, Elena; Gerli, Roberto; Specker, Christof; Bravi, Elena; Selmi, Carlo; Parisi, Simone; Salaffi, Fausto; Meloni, Federica; Marchioni, Enrico; Pesci, Alberto; Dei, Giulia; Confalonieri, Marco; Tomietto, Paola; Nuno, Laura; Bonella, Francesco; Pipitone, Nicolò; Mera-Valera, Antonio; Perez-Gomez, Nair; Gerzeli, Simone; Lopez-Mejias, Raquel; Matos-Costa, Carlo Jorge; Pereira da Silva, Jose Antonio; Cifrian, José; Alpini, Claudia; Olivieri, Ignazio; Blázquez Cañamero, María Ángeles; Rodriguez Cambrón, Ana Belén; Castañeda, Santos; Cavagna, Lorenz