[GATA2 gene mutations: 3 cases]. / Mutations du gène GATA2 : à propos de 3 cas.

INTRODUCTION: Heterozygous germline mutations of GATA2 gene (guanine-adenine-thymine-adenine binding protein 2) are hereditary mutations that can be pathogenic, sometimes occurring sporadically, responsible for a florid clinical-biological picture, sometimes serious and quickly leading to the death. CASE REPORTS: We reported two women and one man with germline mutations in the GATA2 gene. The first patient, aged 19, initially presented with monocytopenia and chronic lymphedema of the four limbs, suggestive of Emberger syndrome. The second patient, 28-years-old, presented with a disseminated atypical mycobacterium (Mycobacterium kansasii) infection, raising suspicion of an immune deficiency such as MonoMAC syndrome (deficiency syndrome of dendritic cells, monocytes, B lymphocytes and NK cells). The last patient, 30-years-old, presented with pancytopenia, leading to the diagnosis of a family form of myelodysplastic syndromes and acute myeloid leukemia characterized by a mutation of the GATA2 gene. CONCLUSIONS: Each case illustrates a typical clinical presentation of GATA2 deficiency, although the evolution of these syndromes ultimately reveals a complex, heterogeneous and intricate picture of hematological, dermatological, infectious, pulmonary, ENT or oncological symptoms. Mutations in the GATA2 gene remain a diagnostic and therapeutic challenge for the internist, and require multidisciplinary management given the florid picture that can be of interest to all specialties. The clinical spectrum of these GATA2 mutations as well as the latest management recommendations from the recent litterature and the "GATA2 club" are described in this article.

Treatment of Eosinophilic Annular Erythema: Retrospective multicenter study and literature review.

BACKGROUND: Eosinophilic annular erythema (EAE) is a rare eosinophil-related skin disease which typically manifests with annular erythematous plaques and severe pruritus. Besides the diagnosis, the treatment of EAE is challenging since relevant published data are sparse. METHODS: The aim of this study was to assess the underlying diseases, treatments and outcomes of patients with EAE. To this end, we conducted a retrospective multicenter study and a systematic review of the MEDLINE database. RESULTS: We included 18 patients with EAE followed in 8 centers. The MEDLINE database search yielded 37 relevant publications reporting 55 cases of EAE with 106 treatment sequences. The most common and efficient treatments included topical or systemic corticosteroids, hydroxychloroquine and dapsone. In refractory patients, a combination of systemic corticosteroids with hydroxychloroquine was associated with 88% of complete clinical response. DISCUSSION: To improve the management of EAE patients, we discuss the following treatment strategy: in topical steroid-resistant patients, hydroxychloroquine can be given as first-line systemic treatment. Dapsone, hydroxychloroquine or systemic corticosteroids are second-line options to consider. Last, monoclonal antibodies or JAK inhibitors targeting type 2 inflammation could represent promising last-resort options in refractory patients.

[Telomeropathies: A study of 15 cases]. / Téloméropathies de recrutement hématologique : étude de 15 cas.

INTRODUCTION: Telomeres are composed of a repeated sequence of double-stranded nucleotides TTAGGG and numerous proteins including the Shelterin complex. Their main role is to maintain the stability of the genome during cell replication through a mechanism of copying the repeted sequence by the telomerase complexe. All the diseases involving a deregulation of this complex are now grouped together under the term telomeropathies. They are difficult to diagnose and manage. Our objective was to describe the clinico-biological characteristics and treatments used, in patients affected by telomeropathies previously seen by an hematologist followed at the Lille University Hospital Center. METHODS: This is a retrospective, single-center study carried out within the department of internal medicine-clinical immunology, Reference center for rare autoimmune and systemic diseases at Lille University Hospital Center between 2005 and 2020 including all patients followed for telomeropathy. RESULTS: Probands and relatives were included. Fifteen patients were studied from 10 independant families. Sixty percent had an heterozygous TERC gene mutation. Sixty seven percent had haematological diseases including macrocytosis, anemia and/or thrombocytopenia, 20 % had a fibrotic hepatic disease, 27 % had a fibrotic pulmonary disease. Lymphocyte immunophenotyping showed a double negative T lymphocyte population with γδ TCR expression in 5 (33 %) patients. Forty-seven percent of the patients had not received any treatment. Twenty-seven percent were on androgen therapy. Twenty percent had received cyclosporine and 13 % anti-lymphocyte serum in the context of initial misdiagnosis. CONCLUSION: It is important to be aware of the complexity of telomeropathies, a differential diagnosis of immune aplastic anemia, in order to optimize management and avoid inappropriate treatments. Allografting of hematopoietic stem cells is the only potentially curative treatment. Our analysis found particularities in immunophenotyping lymphocyte not previously described to our knowledge, whose physiopathological imputability remains to be demonstrated.

Poor performance of albumin or protein-adjusted plasma calcium to diagnose dyscalcemia in hospitalized patients: A confirmatory study in a general internal medicine department.

INTRODUCTION: Hypo- and hypercalcemia are common and some causes require urgent diagnosis and treatment. Measurement of ionized calcium is the reference test to diagnose calcium disorders but total calcium adjusted for protein or albumin concentration is more often used. METHODS: Patients hospitalised in a general internal medicine department from September 2013 to December 2015 who had a total plasma calcium concentration and a serum albumin or protein concentration measured within 24h of a ionized calcium blood measurement were included. Total calcium was adjusted for protein or albumin concentration using widely used formulas and compared to ionized calcium as the gold standard. RESULTS: Among 210 included patients, 46 (22%) had hypocalcemia, 124 (59%) normocalcemia and 40 (19%) hypercalcemia according to ionized calcium concentration. Total calcium had 50% sensitivity and 95% specificity to diagnose hypocalcemia and a 93% sensitivity and 89% specificity to diagnose hypercalcemia. Adjusting total calcium for protein or albumin concentrations did not increase and sometimes decreased diagnostic accuracy. CONCLUSION: Total calcium, with or without albumin/protein adjustment, is poorly sensitive to screen for hypocalcemia. Unadjusted total calcium is as sensitive as protein- or albumin-adjusted total calcium to screen for hypercalcemia. These data argue against the use of albumin- or protein-adjusted calcium. Ionized calcium measurement should be performed to confirm dyscalcemia in patients with abnormal total calcium concentration and to rule out hypocalcemia in patients with total calcium concentration in the lower range of normal values.

Raising rare disease awareness using red flags, role play simulation and patient educators: results of a novel educational workshop on Raynaud phenomenon and systemic sclerosis.

BACKGROUND: As lack of awareness of rare diseases (RDs) among healthcare professionals results in delayed diagnoses, there is a need for a more efficient approach to RD training during academic education. We designed an experimental workshop that used role-play simulation with patient educators and focused on teaching "red flags" that should raise the suspicion of an RD when faced with a patient with frequently encountered symptoms. Our objective was to report our experience, and to assess the improvement in learners' knowledge and the satisfaction levels of the participants. RESULTS: The workshop consisted of 2 simulated consultations that both started with the same frequent symptom (Raynaud phenomenon, RP) but led to different diagnoses: a frequent condition (idiopathic RP) and an RD (systemic sclerosis, SSc). In the second simulated consultation, the role of the patient was played by a patient educator with SSc. By juxtaposing 2 seemingly similar situations, the training particularly highlighted the elements that help differentiate SSc from idiopathic RP. When answering a clinical case exam about RP and SSc, students that had participated in the workshop had a higher mean mark than those who had not (14 ± 3.7 vs 9.6 ± 5.5 points out of 20, p = 0.001). Participants mostly felt "very satisfied" with this training (94%), and "more comfortable" about managing idiopathic RP and SSc (100%). They considered the workshop "not very stressful" and "very formative" (both 71%). When asked about the strengths of this training, they mentioned the benefits of being put in an immersive situation, allowing a better acquisition of practical skills and a more interactive exchange with teachers, as well as the confrontation with a real patient, leading to a better retention of semiological findings and associating a relational component with this experience. CONCLUSIONS: Through the use of innovative educational methods, such as role-play simulation and patient educators, and by focusing on teaching "red flags", our workshop successfully improved RP and SSc learning in a way that satisfied students. By modifying the workshop's scenarios, its template can readily be applied to other clinical situations, making it an interesting tool to teach other RDs.

T helper 2 inflammatory markers are associated with recurrence in chronic rhinosinusitis with nasal polyps after endoscopic sinus surgery.

BACKGROUND: Despite maximum medical treatment and endoscopic sinus surgery (ESS), chronic rhinosinusitis with nasal polyps (CRSwNP) can require revision surgery. With a growing literature on the diversity of cytokine inflammation patterns in CRSwNP, an endotype-driven approach could lead to the identification of cytokine profiles that predict recurrence. METHODS: A monocentric longitudinal study was carried out until June 2019 following CRSwNP patients who underwent surgery for the first time between December 2010 and January 2012. The biomarker profiles were established on blood and nasal secretions at the time of the first surgery (Interleukin (IL)-5, IgE, IgA, eosinophilic cationic protein (ECP) and eosinophilic- derived neurotoxin (EDN)). Profiles were compared between the patients still controlled by medical treatment and the patients requiring revision surgery during the course of the follow-up period. RESULTS: Among the 48 patients initially enrolled in our study, 8 required revision surgery (16,7%). Clinical features (asthma, allergy, aspirin intolerance, active smoking) and levels of blood markers measured at the time of the first surgery were comparable between the 2 groups of patients. Levels of IL-5, IgE and ECP in nasal secretions were significantly increased in the group of patients needing revision surgery. CONCLUSIONS: Based on simple approach of nasal secretions sampling, we showed that a predominant T helper 2 proteins expression profile can be associated with recurrent CRSwNP after ESS. Initial immunoprofiling in CRSwNP disease may contribute to better predict the therapeutic response to optimal medical and surgical treatment, and help define the role of innovative targeted treatment, beside corticosteroids and ESS.

A fibered laser system for the MIGA large scale atom interferometer.

We describe the realization and characterization of a compact, autonomous fiber laser system that produces the optical frequencies required for laser cooling, trapping, manipulation, and detection of 87Rb atoms - a typical atomic species for emerging quantum technologies. This device, a customized laser system from the Muquans company, is designed for use in the challenging operating environment of the Laboratoire Souterrain à Bas Bruit (LSBB) in France, where a new large scale atom interferometer is being constructed underground - the MIGA antenna. The mobile bench comprises four frequency-agile C-band Telecom diode lasers that are frequency doubled to 780 nm after passing through high-power fiber amplifiers. The first laser is frequency stabilized on a saturated absorption signal via lock-in amplification, which serves as an optical frequency reference for the other three lasers via optical phase-locked loops. Power and polarization stability are maintained through a series of custom, flexible micro-optic splitter/combiners that contain polarization optics, acousto-optic modulators, and shutters. Here, we show how the laser system is designed, showcasing qualities such as reliability, stability, remote control, and flexibility, while maintaining the qualities of laboratory equipment. We characterize the laser system by measuring the power, polarization, and frequency stability. We conclude with a demonstration using a cold atom source from the MIGA project and show that this laser system fulfills all requirements for the realization of the antenna.

[Isolated right ventricular acute myocardial infarction mimicking anterior infarction]. / Infarctus isolé du ventricule droit mimant un infarctus antérieur.

Isolated right ventricular acute myocardial infarction is rare and its presentation can sometimes mimic an anterior ST-segment elevation myocardial infarction. We reported two cases of isolated right ventricular acute myocardial infarction presenting with a ST-elevation in anterior leads. The first case was admitted for an out-of-hospital cardiac arrest due to ventricular fibrillation. The patient died from neurologic consequences of the cardiac arrest, despite a successful prehospital thrombolysis, followed by a percutaneous angioplasty of the right coronary artery. The second case occurred after a complex percutaneous angioplasty of the right coronary artery, complicated by a total occlusion of a right marginal branch. These two cases illustrate the limits of the ECG for the diagnosis of isolated right ventricular acute infarction, and the difficulties of the differential diagnosis with anterior infarction, which may determine the treatment and the prognosis.

Intrauterine growth restriction, soluble fms-like tyrosine kinase-1 to placental growth factor ratio increase and preeclampsia.

BACKGROUND: Intrauterine growth restriction (IUGR) and preeclampsia (PE) share common features such as ischemic placental disease but also differ in their clinical expression regarding maternal diseases. The reason why IUGRremains isolated in some cases yet is followed by clinical manifestations of PE in other cases remains unexplained. CASE REPORT: A 40-year old woman, gravida two, para one, experienced early-onset IUGR with a significant increase in the ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) but, surprisingly, without any maternal clinical manifestations of PE. CONCLUSION: IUGR and a significant increase in sFlt-1/PlGF ratio without PE raise the issue of a missing factor enabling IUGR, a significant increase in sFlt-1/PlGF ratio, and PE to be linked. TEACHING POINTS: (1) Early-onset IUGR and a significant increase in sFlt-1/PlGF ratio do not necessarily mean the onset of PE. (2) Combining early-onset IUGR and a significant increase in sFlt-1/PlGF ratio without PE raises the question of an additional factor responsible for the onset of PE.

An unexpected asymptomatic epiglottal site of Kimura disease.

INTRODUCTION: Kimura disease (KD) is a chronic lymphoproliferative disorder of unknown etiology that affects the skin and lymph nodes, mostly observed in males of Asian descent. The natural history of asymptomatic epiglottal KD remains unknown. This rare site of KD is often only diagnosed when tumor growth starts to obstruct the upper airways. OBSERVATION: A 34-year-old North African male presented with fatigue and multiple, slowly progressive, fluctuating skin nodules in the right mandibular and retroauricular regions. Computed tomography of the head and neck revealed a large soft tissue tumor close to the right mandibular body and unexpected thickening of the epiglottis. Transnasal laryngoscopy confirmed the CT findings and showed thickening of the epiglottis. The diagnosis of KD was based on histological examination of biopsy specimens taken from the right mandibular tumor, a cervical lymph node, and the epiglottis. DISCUSSION: Most cases of KD with epiglottal involvement present with dysphonia and dysphagia. No consensus guidelines are available concerning the complementary investigations that should be performed. This case report raises the question of whether patients with suspected KD should be systematically screened for lesions in unusual and potentially dangerous anatomic sites.

Comparison of the novel ARCHITECT procalcitonin assay with established procalcitonin assay systems.

AIMS: This study assessed the performance of a new fully automated immunoassay, ARCHITECT B.R.A.H.M.S procalcitonin (PCT), comparing the results with other commercial assays on routine clinical specimens. METHODS: At nine sites from eight countries, precision analysis was carried out on controls by ANOVA. Threshold and linearity were verified according to standard procedures. Comparison of ARCHITECT B.R.A.H.M.S PCT with the Cobas®, LIAISON®, VIDAS® and Kryptor® PCT assays was evaluated using Passing-Bablok and Deming regression analyses. RESULTS: The within-laboratory standard deviation and %CV across all sites ranged from 0.005 to 0.008 and 2.7 to 4.1; 0.040 to 0.212 and 2.1 to 11.7; 1.628 to 4.191 and 2.5-6.3 for the three control levels, respectively. The mean slope (linearity analysis) across all sites ranged from 0.85 to 1.03, with a mean y-intercept ranging from -6.15 to + 1.71 and a correlation coefficient ranging from 0.94 to 1.00. The LoB, LoD, and LoQ claims were verified. Deming regression analysis of 1116 plasma or serum samples with PCT results detected across a dynamic assay range of 0.02-100 µg/l using the ARCHITECT B.R.A.H.M.S PCT assay yielded results of r = 0.989 vs. Roche Cobas®, r = 0.986 vs Kryptor® B.R.A.H.M.S, r = 0.987 vs BioMèrieux VIDAS® and r = 0.972 vs. Diasorin LIAISON®, respectively. Concordance at cut-offs of 0.25 µg/l and 0.50 µg/l were 96.9% and 98.1% with Roche Cobas®, 95.4% and 96.1% with B.R.A.H.M.S Kryptor®, 93.8% and 98.4% with BioMèrieux VIDAS®, and 92.7% and 93.9% with Diasorin LIAISON®. CONCLUSIONS: Compared with other assays, ARCHITECT B.R.A.H.M.S PCT offers excellent precision and low-end sensitivity.

Diffusion of organic anions in clay-rich media: Retardation and effect of anion exclusion.

The transport of emerging organic contaminants through the geosphere is often an environmental issue. The sorption of organic compounds slows their transport in soils and porous rocks and retardation is often assessed by extrapolation of batch experiments. However, transport experiments are preferable to strengthen migration data and modelling. In this context, we evaluated the adsorption of various organic acids by means of through-diffusion experiments in a sedimentary clay-rich rock (Callovo-Oxfordian, East of Paris Basin, France). A low diffusivity of organic anions was quantified with effective diffusion coefficients, De, ranged between 0.5 and 7 10-12 m2 s-1. These values indicated an organic anion exclusion. As for chloride, the porosity accessible to organic anions was lower than that of water: εa(organic anions) < ε(water). The partial exclusion of organic anions from rock porosity was linked to both charge and size effects. A significant retardation was observed for organic anions such as oxalate, citrate or α-isosaccharinate. Yet, retardation measured by diffusion experiments was significantly lower than expected from batch experiments on crushed samples. An empirical correction factor is proposed to account for a possible decrease of retardation with accessible porosity of diffusing solute. This feature has significant implications for the estimation of migration parameters of organic compounds in the environment.

Exploring gravity with the MIGA large scale atom interferometer.

We present the MIGA experiment, an underground long baseline atom interferometer to study gravity at large scale. The hybrid atom-laser antenna will use several atom interferometers simultaneously interrogated by the resonant mode of an optical cavity. The instrument will be a demonstrator for gravitational wave detection in a frequency band (100 mHz-1 Hz) not explored by classical ground and space-based observatories, and interesting for potential astrophysical sources. In the initial instrument configuration, standard atom interferometry techniques will be adopted, which will bring to a peak strain sensitivity of [Formula: see text] at 2 Hz. This demonstrator will enable to study the techniques to push further the sensitivity for the future development of gravitational wave detectors based on large scale atom interferometers. The experiment will be realized at the underground facility of the Laboratoire Souterrain à Bas Bruit (LSBB) in Rustrel-France, an exceptional site located away from major anthropogenic disturbances and showing very low background noise. In the following, we present the measurement principle of an in-cavity atom interferometer, derive the method for Gravitational Wave signal extraction from the antenna and determine the expected strain sensitivity. We then detail the functioning of the different systems of the antenna and describe the properties of the installation site.

Impact of allergy on phenotypic and endotypic profiles of nasal polyposis.

OBJECTIVES: To assess the impact of allergy on clinical presentations (phenotypes) and inflammatory patterns (endotypes) of chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: A single-center prospective study was conducted over an 18-month period. Fifty-seven patients with refractory CRSwNP were included. The diagnosis of allergy was based on concordant skin prick tests and symptoms. Phenotypes were determined on symptom severity score, polyp size classification and Lund-Mackay CT staging. Inflammatory endotypes were determined on biomarker analysis (IgE, IgA, IL-5, IL-9, ECP, EDN) in blood and nasal secretions. Eosinophil counts were obtained in blood, nasal secretions and polyps. RESULTS: Phenotype and endotype profiles were comparable in patients with (n=15) or without (n=42) allergy. Only asthma with high total IgE blood concentration showed association with allergy. CONCLUSIONS: The present results suggest that allergy is not directly involved in the clinical expression and specific inflammatory pathways of CRSwNP. New therapies target inflammation signaling pathways, and identifying accurate blood and tissue biomarkers will be the line of research most likely to improve treatment of CRSwNP.

Adsorption of polar organic molecules on sediments: Case-study on Callovian-Oxfordian claystone.

The release and transport of anthropogenic organic matter through the geosphere is often an environmental criterion of safety. Sedimentary rocks are widely studied in this context as geological barriers for waste management. It is the case of Callovian-Oxfordian claystone (COx), for which several studies report adsorption of anthropogenic organic molecules. In this study, we evaluated and reviewed adsorption data of polar organic molecules on COx claystone. Experiments were performed on raw claystone, decarbonated and clay fractions. Adsorption isotherms were measured with adsorbates of various polarities: adipate, benzoate, ortho-phthalate, succinate, gluconate, oxalate, EDTA, citrate. A significant adsorption was observed for multidentate polycarboxylic acids as evidenced with phthalate, succinate, oxalate, gluconate, EDTA and citrate (Rd = 1.53, 3.52, 8.4, 8.8, 12.4, 54.7 L kg-1 respectively). Multiple linear regression were performed as a statistical analysis to determine the predictors from these adsorption data. A linear correlation between adsorption data (Rd) and dipole moment (µ) of adsorbates was evidenced (R2 = 0.91). Molecules with a high dipole moment, µ(D) > 2.5, displayed a significant adsorption, Rd≫1 L kg-1. A qualitative correlation can be easily estimated using the water/octanol partition coefficient, Pow, of adsorbates (R2 = 0.77). In this case, two opposite trends were distinguished for polar and apolar molecules. The use of organic carbon content in sediments is relevant for predicting adsorption of apolar compounds, log (Pow)>+1. The oxides/clays contents may be relevant regarding polar molecules, log (apparentPow)<-1. The proposed scheme offers a general methodology for investigation of geo-barriers towards heterogeneous organic plumes.

Diagnosis of primary antibody and complement deficiencies in young adults after a first invasive bacterial infection.

OBJECTIVES: Screening for primary immunodeficiencies (PIDs) in adults is recommended after two severe bacterial infections. We aimed to evaluate if screening should be performed after the first invasive infection in young adults. METHODS: Eligible patients were retrospectively identified using hospital discharge and bacteriology databases in three centres during a 3-year period. Eighteen to 40-year-old patients were included if they had experienced an invasive infection with encapsulated bacteria commonly encountered in PIDs (Streptococcus pneumoniae (SP), Neisseria meningitidis (NM), Neisseria gonorrhoeae (NG), Haemophilus influenzae (HI), or group A Streptococcus (GAS)). They were excluded in case of general or local predisposing factors. Immunological explorations and PIDs diagnoses were retrieved from medical records. Serum complement and IgG/A/M testings were systematically proposed at the time of study to patients with previously incomplete PID screening. RESULTS: The study population comprised 38 patients. Thirty-six had experienced a first invasive episode and a PID was diagnosed in seven (19%): two cases of common variable immunodeficiency revealed by SP bacteraemia, one case of idiopathic primary hypogammaglobulinaemia, and two cases of complement (C6 and C7) deficiency revealed by NM meningitis, one case of IgG2/IgG4 subclasses deficiency revealed by GAS bacteraemia, and one case of specific polysaccharide antibody deficiency revealed by HI meningitis. Two patients had previously experienced an invasive infection before the study period: in both cases, a complement deficiency was diagnosed after a second NM meningitis and a second NG bacteraemia, respectively. CONCLUSION: PID screening should be considered after a first unexplained invasive encapsulated-bacterial infection in young adults.

Long term use of metformin in idiopathic cyclic edema, report of thirteen cases and review of the literature.

INTRODUCTION: Idiopathic cyclic edema (ICE) is a rare cause of edema. To date, there is no standard of care. The physiopathology of ICE could be explained by an impairment of capillary permeability. In 1995, a study demonstrated the efficacy of metformin on symptoms and capillary permeability. We evaluated ICE-patients who were treated with metformin in our department. METHODS: We retrospectively included patients diagnosed for ICE between January 1997 and October 2013. ICE was diagnosed in the presence of edema after excluding other etiologies. LANDIS test was used to support ICE diagnosis in all patients. The absence of edema at follow-up was considered as complete response (CR), partial decreased was considered as partial response (PR). Adverse events were recorded. RESULTS: Thirteen patients have accepted to use metformin. The median treatment duration was 28.5 months [8-167] and the median follow-up of treated patients was 40.5 months [14-167]. CR was reached in 10 patients (77%), and PR in 2 patients (15%). Two patients reported side-effects as diarrheas and one of them stopped the treatment due to mild diarrhea. CONCLUSION: We report the interest and tolerance of the long-term use of metformin in ICE. No severe adverse events were noticed. A prospective study is needed to confirm the efficacy of metformin in ICE-patients.

Role of B cells in the pathogenesis of systemic sclerosis.

Systemic sclerosis (SSc) is an orphan disease characterized by progressive fibrosis of the skin and internal organs. Aside from vasculopathy and fibrotic processes, its pathogenesis involves an aberrant activation of immune cells, among which B cells seem to play a significant role. Indeed, B cell homeostasis is disturbed during SSc: the memory subset is activated and displays an increased susceptibility to apoptosis, which is responsible for their decreased number. This chronic loss of B cells enhances bone marrow production of the naïve subset that accounts for their increased number in peripheral blood. This permanent activation state can be explained mainly by two mechanisms: a dysregulation of B cell receptor (BCR) signaling, and an overproduction of B cell survival signals, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). These disturbances of B cell homeostasis induce several functional anomalies that participate in the inflammatory and fibrotic events observed during SSc: autoantibody production (some being directly pathogenic); secretion of pro-inflammatory and pro-fibrotic cytokines (interleukin-6); direct cooperation with other SSc-involved cells [fibroblasts, through transforming growth factor-ß (TGF-ß) signaling, and T cells]. These data justify the evaluation of anti-B cell strategies as therapeutic options for SSc, such as B cell depletion or blockage of B cell survival signaling.