Abatacept to treat chronic intestinal pseudo-obstruction in five systemic sclerosis patients with a description of the index case:

Chronic intestinal pseudo-obstruction is a severe complication of systemic sclerosis. Inflammatory neuropathy and immunological alterations have a prominent role in the development of systemic scle..

Expression of CD4 on human peripheral blood neutrophils

AbstractCD4, the primary receptor for entry of HIV, is known to be expressed on T cells and monocytes/macrophages; healthy natural killer (NK) lymphocytes; in vitro human herpesvirus 6 (HHV6)–infected CD8+, NK, and γδ T lymphocytes; CD34+ progenitor cells; and a subset of eosinophils and basophils. We here report the unconventional expression of CD4 at the surface of peripheral blood neutrophils derived from 4 of 51 (7.8%) HIV-1–infected and 3 of 25 (12%) uninfected donors, with similar frequency within the 2 groups. The percentage of CD4+ neutrophils ranged from 39% to 97% of the total neutrophil population. Both surface and cytoplasmic forms of CD4 were present in neutrophils. Quantitative RNA polymerase chain reaction (PCR) revealed that neutrophils contain levels of CD4 mRNA comparable to those of peripheral blood mononuclear cells derived from the same donor. The conformation of CD4 expressed at the surface of neutrophils was similar to that of CD4 expressed on T lymphocytes as determined by the binding of monoclonal antibodies specific for conformational epitopes and the binding of recombinant HIV-1 gp120. Thus, our data provide evidence that neutrophils express endogenous CD4 and bind HIV. Owing to their abundance in peripheral blood, CD4+ neutrophils may influence significantly the biodistribution of HIV delivering it to sites of inflammation or to additional tissue reservoirs

Neuropsychological and psychological functioning aspects in myotonic dystrophy type 1 patients in Italy

Introduction: Myotonic Dystrophy Type 1 (DM1) is an autosomal dominant genetic illness, characterized by a progressive loss of strength. Important deficits in cognitive functioning and a significant prevalence of psychiatric disorders have been previously reported. Methods: A neuropsychological and psychological assessment was carried out in 31 DM1 patients (61% males) in order to measure the cognitive functioning and explore their personality profiles. The MMSE Mini-Mental State Examination, Frontal Assessment Battery (FAB), ENB-2 Battery assessing memory (short term, long term and working memory), integration capacities, visual-spatial ability, attention (selective, divided, shifting/switching) executive functions, praxis, discrimination and logic capabilities and psychopathology Symptom Check List 90-R (SCL-90-R) were administered. The neuropsychological and psychological evaluation of DM1 patients was carried out taking into consideration the clinical parameters (CTG repeat, age at onset, disease duration, Muscular Impairment Rate Scale (MIRS), Medical Research Council Scale (MRC) and the Epworth Sleepiness Scales (EPS)). Results: Regarding psychopathology 19.4% of patients scored a moderate or high level of symptoms intensity index (GSI), 12.9% reported a high number of symptoms (PST) and 16.1% reported a high intensity level of the perceived symptoms (PSDI). Fatigue and daytime sleepiness resulted as being associated with higher levels of psychoticism (PSY). Only 1 patient reported a severe impairment in the spatial and temporal orientation, memory, language, praxis, attention and calculation. Longer disease duration was also associated with cognitive impairment evaluated through ENB-2 (p < 0.05). Discussions and Conclusions: There are indications of the utility of neuropsychological and psychological screening and support for these patients and their families due to the link between disease duration and cognitive performances. A proposal of a clinical protocol, with an illustration of a clinical case report of a family is presented

Serum microRNA screening and functional studies reveal miR-483-5p as a potential driver of fibrosis in systemic sclerosis

Abstract Objective MicroRNAs (miRNAs) are regulatory molecules, which have been addressed as potential biomarkers and therapeutic targets in rheumatic diseases. Here, we investigated the miRNA signature in the serum of systemic sclerosis (SSc) patients and we further assessed their expression in early stages of the disease. Methods The levels of 758 miRNAs were evaluated in the serum of 26 SSc patients as compared to 9 healthy controls by using an Openarray platform. Three miRNAs were examined in an additional cohort of 107 SSc patients and 24 healthy donors by single qPCR. MiR-483-5p expression was further analysed in the serum of patients with localized scleroderma (LoS) (n = 22), systemic lupus erythematosus (SLE) (n = 33) and primary Sjogren's syndrome (pSS) (n = 23). The function of miR-483-5p was examined by transfecting miR-483-5p into primary human dermal fibroblasts and pulmonary endothelial cells. Results 30 miRNAs were significantly increased in patients with SSc. Of these, miR-483-5p showed reproducibly higher levels in an independent SSc cohort and was also elevated in patients with preclinical-SSc symptoms (early SSc). Notably, miR-483-5p was not differentially expressed in patients with SLE or pSS, whereas it was up-regulated in LoS, indicating that this miRNA could be involved in the development of skin fibrosis. Consistently, miR-483-5p overexpression in fibroblasts and endothelial cells modulated the expression of fibrosis-related genes. Conclusions Our findings showed that miR-483-5p is up-regulated in the serum of SSc patients, from the early stages of the disease onwards, and indicated its potential function as a fine regulator of fibrosis in SSc

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci

Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients

Objectives The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations. Methods Samples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated. Results Overall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples. Conclusions We discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc.EU/EFPIA/Innovative Medicines Initiative Joint Undertaking PRECISESADS 115 56

COVID-19-associated Guillain-Barré syndrome in the early pandemic experience in Lombardia (Italy)

Objective To estimate the incidence and describe clinical characteristics and outcome of GBS in COVID-19 patients (COVID19-GBS) in one of the most hit regions during the frst pandemic wave, Lombardia. Methods Adult patients admitted to 20 Neurological Units between 1/3–30/4/2020 with COVID19-GBS were included as part of a multi-center study organized by the Italian society of Hospital Neuroscience (SNO). Results Thirty-eight COVID19-GBS patients had a mean age of 60.7 years and male frequency of 86.8%. CSF albuminocytological dissociation was detected in 71.4%, and PCR for SARS-CoV-2 was negative in 19 tested patients. Based on neurophysiology, 81.8% of patients had a diagnosis of AIDP, 12.1% of AMSAN, and 6.1% of AMAN. The course was favorable in 76.3% of patients, stable in 10.5%, while 13.2% worsened, of which 3 died. The estimated occurrence rate in Lombardia ranges from 0.5 to 0.05 GBS cases per 1000 COVID-19 infections depending on whether you consider positive cases or estimated seropositive cases. When we compared GBS cases with the pre-pandemic period, we found a reduction of cases from 165 to 135 cases in the 2-month study period in Lombardia. Conclusions We detected an increased incidence of GBS in COVID-19 patients which can refect a higher risk of GBS in COVID-19 patients and a reduction of GBS events during the pandemic period possibly due to a lower spread of more common respiratory infectious diseases determined by an increased use of preventive measures

The Long Non-coding RNA NRIR Drives IFN-Response in Monocytes: Implication for Systemic Sclerosis

TLR4 activation initiates a signaling cascade leading to the production of type I IFNs and of the downstream IFN-stimulated genes (ISGs). Recently, a number of IFN-induced long non-coding RNAs (lncRNAs) that feed-back regulate the IFN response have been identified. Dysregulation of this process, collectively known as the “Interferon (IFN) Response,” represents a common molecular basis in the development of autoimmune and autoinflammatory disorders. Concurrently, alteration of lncRNA profile has been described in several type I IFN-driven autoimmune diseases. In particular, both TLR activation and the upregulation of ISGs in peripheral blood mononuclear cells have been identified as possible contributors to the pathogenesis of systemic sclerosis (SSc), a connective tissue disease characterized by vascular abnormalities, immune activation, and fibrosis. However, hitherto, a potential link between specific lncRNA and the presence of a type I IFN signature remains unclear in SSc. In this study, we identified, by RNA sequencing, a group of lncRNAs related to the IFN and anti-viral response consistently modulated in a type I IFN-dependent manner in human monocytes in response to TLR4 activation by LPS. Remarkably, these lncRNAs were concurrently upregulated in a total of 46 SSc patients in different stages of their disease as compared to 18 healthy controls enrolled in this study. Among these lncRNAs, Negative Regulator of the IFN Response (NRIR) was found significantly upregulated in vivo in SSc monocytes, strongly correlating with the IFN score of SSc patients. Weighted Gene Co-expression Network Analysis showed that NRIR-specific modules, identified in the two datasets, were enriched in “type I IFN” and “viral response” biological processes. Protein coding genes common to the two distinct NRIR modules were selected as putative NRIR target genes. Fifteen in silico-predicted NRIR target genes were experimentally validated in NRIR-silenced monocytes. Remarkably, induction of CXCL10 and CXCL11, two IFN-related chemokines associated with SSc pathogenesis, was reduced in NRIR-knockdown monocytes, while their plasmatic level was increased in SSc patients. Collectively, our data show that NRIR affects the expression of ISGs and that dysregulation of NRIR in SSc monocytes may account, at least in part, for the type I IFN signature present in SSc patients

Implementation and performances of the IPbus protocol for the JUNO Large-PMT readout electronics

The Jiangmen Underground Neutrino Observatory (JUNO) is a large neutrino detector currently under construction in China. Thanks to the tight requirements on its optical and radio-purity properties, it will be able to perform leading measurements detecting terrestrial and astrophysical neutrinos in a wide energy range from tens of keV to hundreds of MeV. A key requirement for the success of the experiment is an unprecedented 3% energy resolution, guaranteed by its large active mass (20 kton) and the use of more than 20,000 20-inch photo-multiplier tubes (PMTs) acquired by high-speed, high-resolution sampling electronics located very close to the PMTs. As the Front-End and Read-Out electronics is expected to continuously run underwater for 30 years, a reliable readout acquisition system capable of handling the timestamped data stream coming from the Large-PMTs and permitting to simultaneously monitor and operate remotely the inaccessible electronics had to be developed. In this contribution, the firmware and hardware implementation of the IPbus based readout protocol will be presented, together with the performances measured on final modules during the mass production of the electronics