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Systemic sclerosis (SSc) is a connective tissue disease characterized by extensive fibrosis of the skin and internal organs, associated with vasculopathy and autoimmune features. Antinuclear antibodies (ANA) are found in almost all SSc patients and constitute strong diagnosis and prognosis biomarkers. However, it remains unclear whether ANA are simple bystanders or if they can have a role in the pathophysiology of the disease. One might think that the nuclear nature of their targets prevents any accessibility to autoantibodies. Nevertheless, recent data suggest that ANA could be pathogenic or at least contribute to the perennation of the disease. We review here first the indirect clues of the contribution of ANA to SSc: they are associated to the disease subtypes, they may precede disease onset, their titer correlates with disease activity and severity, there is an association between molecular subsets, and some patients can respond to B-cell targeting therapy. Then, we describe in a second part the mechanisms of ANA production in SSc from individual genetic background to post-transcriptional modifications of neoantigens. Finally, we elaborate on the potential mechanisms of pathogenicity: ANA could be pathogenic through immune-complex-mediated mechanisms; other processes potentially involve molecular mimicry and ANA penetration into the target cell, with a focus on anti-topoisomerase-I antibodies, which are the most probable candidate to play a role in the pathophysiology of SSc. Finally, we outline some technical and conceptual ways to improve our understanding in this field.

Background:A differential diagnosis between angiotensin-converting enzyme inhibitor (ACEi) angioedema (AE) and histaminergic AE (hAE) might be challenging. Follow-up data may help discriminate these conditions but are scarcely reported.Objective:To report on the follow-up of patients with suspected ACEi-AE and to describe the baseline characteristics of AE attacks in patients with a diagnosis of ACEi-AE after follow-up.Methods:Sixty-four patients with suspected ACEi-AE (i.e., with exposure to ACEi before the first attack, no urticaria associated, and normal C1-inhibitor levels) and at least one follow-up visit were included. Data were retrospectively collected at baseline and during the follow-up.Results:After the follow-up, the diagnosis of ACEi-AE was probable in only 30 patients. The remaining patients were reclassified as having probable hAE (21 patients) or undetermined-mechanism AE (13 patients). Patients with ACEi-AE were mostly men (61%), with a median age of 64 years (interquartile range [IQR] ±17 years), with a highly variable delay from ACEi introduction (median: 23 months; interquartile range: 103 months). Attacks preferentially involved lips (50%), tongue (47%), and throat (30%). Interestingly, patients with probable ACEi-AE after a follow-up also frequently presented with a history of allergy and atopic conditions (20%), attacks with preferential evening onset (25%), and spontaneous resolution in < 24 hours (26%), which are usually considered as suggestive of hAE. ACEi-AE attacks responded to icatibant in 79% of the patients.Conclusion:Patients with probable ACEi-AE were mostly men with facial involvement. A third of the patients with an initial suspected diagnosis of ACEi-AE had a final diagnosis of probable hAE. Although a follow-up of all patients should be a standard of care, it is critical to the correct diagnosis in the case of suspected bradykinin-associated AE, which may actually be due to histamine.

Background and Aims Immunosuppressive treatments have improved the prognosis of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), transforming these formerly fatal diseases into chronic conditions, with periods of remission and relapse. Relapse prevention is based on remission-maintenance immunosuppressive treatment with a usual duration of 18 to 24 months. Recent studies demonstrated that a prolonged - 48 to 54 months - maintenance treatment reduced the risk of relapse and could reduce end-stage renal disease (Karras A 2017, Charles P 2020). However, prolonged maintenance treatment may not be necessary for all patients. On the one hand, MPO-ANCA (vs PR3-ANCA) and decreased estimated glomerular filtration rate (eGFR) have been associated with a low risk of relapse (Walsh 2012). On the other hand, treatment of AAV is not devoid of risk. Flossman et al showed that mortality after the first year of treatment was mainly related to cardiovascular, infectious and neoplastic complications (Flossman 2011). Thus, it has been well demonstrated that patients with renal AAV without PR3 ANCA have the lowest risk of relapse and the highest mortality rate (Mahr A 2013). This study aimed to determine: first, the risk of late relapse in AAV patients with renal involvement and without PR3-ANCA after end of remission-maintenance treatment, and second, risk factors for relapse in this population. Method Patients with renal involvement without PR3-ANCA recruited to prospective, randomized trials of the European Vasculitis Study group (EUVAS): CYCAZAREM, CYCLOPS, MEPEX, IMPROVE and the French Vasculitis Study Group (FVSG): WEGENT were included in the analysis if their disease was in remission at the end of relapse-prevention therapy. This consisted in azathioprine, methotrexate or mycophenolate mofetil and was stopped after 18-24 months (around 24-27 months after diagnosis). Cumulative incidence of relapse was estimated using the Kalbfleich and Prentice method, considering death as a competing event. Risk factors for relapse were assessed using the Fine and Gray competing risk regression model. Results 108 patients were included, 64 of whom (59.3%) were male, 79 were MPO-ANCA positive (73.1%) and 29 ANCA negative (26.9%). Average age at diagnosis was 59.6 +/- 12.4 years. Relapse rate was 25.5% 60 months after cessation of maintenance treatment (figure 1) of which 46.2% were renal relapses (figure 2). Lower GFR at diagnosis was correlated with a lower risk of relapse. For every 15-point decrease in GFR at diagnosis, the risk of relapse decreased by a factor of 0.72 (HR 95% CI: 0.59 to 0.88). Figure 3 represents the cumulative incidence of relapse by eGFR level. Relapse risk did not appear to be impacted by the presence at diagnosis of systemic/constitutional (HR: 0.70; CI 95%: 0.30-1.65; p: 0.47), lung (HR: 0.87; CI 95%: 0.40-1.86; p: 0.71), skin involvement (HR: 0.84; CI 95%: 0.29-2.39; p: 0.74), ear, nose and throat (HR: 1.53; CI 95%: 0.74-3.27; p: 0.28) or eye disease (HR: 1.58; CI 95%: 0.62-4.10; p: 0.34). Presence of MPO-ANCA at diagnosis did not influence relapse-risk. Conclusion Even in this population of renal AAV without PR3-ANCA, there remains a risk of late relapse, after the end of a two-year conventional maintenance regimen. Using additional criteria (such as eGFR at diagnosis < or > 45 ml/min/1.73m2) could help select a group of patients who are at lower risk of relapse. Factors that potentially increase (ENT or eye disease) risk of relapse need to be explored further. If these data are confirmed, sub-groups could be identified who could receive only a short maintenance treatment, or perhaps none. These findings also need to be to be analysed following rituximab maintenance.

International audience; Fibroblasts (Fb) are key effector cells in systemic sclerosis (SSc). Fb stimulation with transforming growth factor beta 1 (TGF-β1) is considered as a positive control in studies assessing fibrogenesis. The lack of standardization of TGF-β1 stimulation might be responsible for discrepancies in experiments performed in different conditions. Using quantitative proteomics analysis, we evaluated the impact of changes in experimental conditions on proteomic profiles of primary Fb. Principal component analysis (PCA) identified several groups of differentially expressed proteins influenced by cell passage, culture medium, and both concentration and duration of exposure to TGF-β1 stimulation. Bioinformatics analysis revealed that late passages expressed proteins involved in senescence. TGF-β1 concentration and time of stimulation were correlated with the expression of proteins involved in the fibrogenesis and inflammatory processes. These data underline the need for standardization of culture conditions to allow inter-data comparisons in future in vitro studies, especially when using “omics” approaches.

BackgroundAutoantibodies (Aab) are frequent in systemic sclerosis (SSc) [1]. Recently, it has been showed that immunoglobulins G (IgG) from SSc promoted proinflammatory and profibrotic phenotype in monocyte secretome [2]. Fibroblasts (FB) are key effectors cells in SSc and data on FB proteins secretion in the presence of IgG from SSc patients are lacking. While recognized as potent biomarkers, the pathogenic role of Aab is much more debated.ObjectivesTo explore the FB secretome in the presence of purified IgG from SSc patientsMethodsNormal dermal FB were cultured in the presence of purified IgG from patients with diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc) or healthy controls (HC). After 72 h of culture, the cell supernatants were collected, centrifuged and passed through a filter to remove the cells. After proteins digestion, secretome was explored using mass spectrometry coupled with liquid chromatography (LC-MS/MS). Analysis of variance (ANOVA) and hierarchical clustering were used to identify proteins responses patterns.ResultsProteomic identified and quantified 1268 proteins, among them 377 were significant after ANOVA. SSc and HC secretome appeared distinct. Hierarchical clustering on significant proteins after ANOVA showed 3 distinct groups of patients secretome: a first group including mostly dcSSc anti-topoisomerase-I (ATA) positive (dcSSc ATA+) patients, a second group including mostly dcSSc ATA negative (dcSSc ATA-) patients, a third group more heterogeneous including the majority of HC, lcSSc anti-centromere positive (lcSSc ACA+) patients and dcSSc ATA- patients (Figure 1.A). The comparison of FB secretome in the presence of purified IgG from dcSSc ATA+ vs IgG HC revealed 203 differentially expressed proteins (DEP) (Figure 1.B). The enriched Gene Ontology (GO) terms upregulated in IgG dcSSc ATA+ were involved in endocytic vesicle lumen, vesicle lumen, extracellular matrix or glycosaminoglycan binding. The comparisons of IgG dcSSc ATA- vs IgG HC and IgG lcSSc ACA+ vs IgG HC revealed 85 and 15 DEP, respectively. Follistatin, amyloid beta A4 protein, myosin-9 and calreticulin were commonly overexpressed in the 3 subtypes of SSc. 40 proteins were exclusively overexpressed in the condition dcSSc ATA+. Among them, collagen alpha-1(VII) chain, galectin-3-binding protein, desintegrin and metalloproteinase domain-containing 10, low affinity immunoglobulin gamma Fc region receptor III-A, CD59 glycoprotein, growth arrest-arrest specific protein and clusterin were overexpressed in the condition dcSSc ATA+ (Figure 1.C).Figure 1.Heatmap representing the 377 differentially expressed proteins after ANOVA in all samples. Cluster analysis identified 3 group of patients and 2 different clusters of protein expression (A). Volcanoplot represented the comparison IgG dcSSc ATA+ vs IgG HC (B). Venn diagram representing the proteins in common and exclusive of the following comparison: IgG dcSSc ATA+ vs HC, IgG dcSSc ATA- vs IgG HC and IgG dcSSc ATA- vs IgG HC (C). IgG HC: purified IgG from healthy controls; IgG dcSSc ATA+: purified IgG from diffuse systemic sclerosis anti-topoisomerase-I positive patients; IgG dcSSc ATA-: purified IgG from diffuse systemic sclerosis anti-topoisomerase-I negative patients; IgG lcSSc ACA+: purified IgG from limited systemic sclerosis anti-centromere positive patients. ANOVA: analysis of variance.ConclusionUsing sensitive proteomic approach, we identified that purified IgG from SSc patients modified FB secretome in a serotype dependent manner. The data support the pathogenic role of Aab in SSc.References[1]Denton CP, Khanna D. Systemic sclerosis. The Lancet 2017; 390:1685–99. doi:10.1016/S0140-6736(17)30933-9[2]Murthy S, Wannick M, Eleftheriadis G, et al. Immunoglobulin G of systemic sclerosis patients programs a pro-inflammatory and profibrotic phenotype in monocyte-like THP-1 cells. Rheumatology (Oxford) 2021; 60:3012–22. doi:10.1093/rheumatology/keaa747Disclosure of InterestsNone declared.

Resume Introduction La maladie de Gaucher est une maladie de surcharge lysosomale due a un deficit enzymatique de la glucocerebrosidase. Le type 3, avec atteinte neurologique, peut presenter dans le cadre de la mutation D409H, un phenotype particulier. Observation Nous rapportons le cas d’une femme de 22 ans presentant une maladie de Gaucher. Malgre une amelioration sous enzymotherapie substitutive, il persistait des difficultes de communication, initialement attribuees a une barriere linguistique. Apres bilan complementaire, on evoquait une maladie de Gaucher de type 3 et le genotypage de la glucocerebrosidase mettait en evidence une mutation D409H a l’etat homozygote. Conclusion Le phenotype clinique de cette mutation comprend une calcification des valves cardiaques, des opacites corneennes, une atteinte de l’oculomotricite et une hydrocephalie. De par sa severite initiale moindre et la survenue tardive des troubles neurologiques rendant son diagnostic plus difficile, cette forme de la maladie merite a etre connue dans les services de medecine adulte.

Kegiatan Pengabdian Kepada Masyarakat ini bertujuan untuk memberikan Pelatihan kepada Para Peserta Didik atau Siswa SMPN 13 Tangerang Selatan dalam memberi Pengetahuan tentang Perkembangan Teknologi Dalam Dunia Pendidikan meliputi Sejarah Perkembangan Teknologi, dan Dampak Dari PerkembanganTeknologi. Adapun metode yang dilakukan dengan penyampaian materi dan SimulasiAplikasi-aplikasi pembelajaran. Adapun hasil kegiatan pengabdian masyarakat memberikan pengetahuan tentang sejarah perkembangan teknologi, pengaruh yang diberikan dalam dunia Pendidikan serta dampak negative dari perkembangan teknologi, sehingga peserta didik khususnya Siswa SMPN 13 Tangerang Selatan langsung dapat merasakan dari pelatihan ini. Metode yang dilakukan dalam pengabdian Masyarakat yang dilaksanakandengan SMPN 13 Tangeran Selatan, didahului dengan tatap muka dengan Kepala Sekolah SMPN13 Tangerang Selatan untuk membicarakan permasalahan yang dihadapi dalam pelaksanaan pembelajaran jarak jauh di masa pandemi ini, agar pembelajaran tetap optimal walau dilaksanakan tanpa tatap muka, dengan memberikan materi pembelajaran dengan mensimulasikan aplikasi-aplikasi dan memanfaatkan media sosial agar pembelajaran menjadi menarik serta menumbuhkan kreatifitas Peserta Didik khususnya Siswa SMPN 13 Tangerang Selatan.Kata Kunci : PKM, Pengetahuan, Perkembangan Teknologi.

Background Fibroblasts (Fb) are key effectors cells in systemic sclerosis (SSc).1 Fb stimulation with TGF-β1 is usually considered as the positive control in studies assessing the fibrogenesis in SSc.2 Yet, the lack of standardisation of TGF-β1 stimulation might be responsible for discrepancies in experiments performed in different conditions. Proteomic approach allows the analysis of differential expression of the whole proteins (proteome) in Fb, and appears an interesting approach to compare different culture conditions. Objectives We designed this study to compare the whole protein expression in Fb stimulated by TGF-β1 in different conditions. Methods At fifth passage, primary culture of human Fb from healthy subjects (ATCC; PCS-201–012) were stimulated or not with different concentrations of recombinant human active TGF-β1 (0.04, 1, and 5 ng/mL) (R and D Systems; 240-B-002) during 24, 48 and 72 hours. Proteins were extracted and analysed using an eFASP LC-MS/MS approach on an Orbitrap mass spectrometer (Thermo Scientific; Q Exactive +). Proteins quantitation was performed by Maxquant and statistical analysis by Perseus using ANOVA and principal component analysis (PCA). Results A total of 3267 proteins were identified, of which 1957 showed differential expression using ANOVA analysis. PCA revealed several clusters of differential proteins expression (figure 1). There were clear clusters of protein expression related to (i) unstimulated and stimulated conditions, (ii) between the three different times of stimulation and (iii) to TGF-β1 concentrations used. Although the expression of proteins in Fb exposed to 0.04 and 1 ng/mL of TGF-β1 during 72 hour were rather close, there was a unique proteins profile related to the condition with 5 ng/mL of TGF-β1 during 72 hour. Figure 1: PCA representation of differential proteins expression in different conditions. [TGF-β1]=0.04 ng/mL: square; [TGF-β1]=1 ng/mL: circle; [TGF-β1]=5 ng/mL: diamond. The more the points appear distanced, the more different is the protein expression. Conclusions This study highlights a variation of proteins expression depending on both stimulation time and TGF-β1 concentrations in Fb culture. The identification of protein differentially expressed will provide insights in the impact of TGF-β1 on Fb physiology under stimulation conditions. These data underline the need of standardisation of culture conditions to allow inter-data comparisons using in sensitive “omic” approaches. References [1] Garret SM, Frost DB, Feghali-Bostwick C. The mighty fibroblast and its utility in scleroderma research. J Scleroderma Relat Disord2017;2(2):69–134. [2] Verrecchia F, Mauviel A. Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J Invest Dermatol2002Feb;118(2):211–5. Disclosure of Interest None declared

There are many factors that led to the occurrence of learning disability, namely impaired concentration, memory, dyslexia, dyscalculia, and the environment. The difficulty to determine solution and find out the cause of the learning disability occurrence is the problem of the research. Dempster-Shafer method is used to build an expert system in diagnosing learning disability. Interference engine used to calculate the value of belief function and the results of children diagnosis against symptoms. The result found that 15 of the 25 people inquired are known to experience learning disability while others are normal. Further development of the system which focuses on the characteristics of learning disability in more detail is needed.