An immunogenomic exome landscape of triple positive primary antiphospholipid patients.

Primary antiphospholipid syndrome is characterized by thrombosis and autoantibodies directed against phospholipids or associated proteins. The genetic etiology of PAPS remains unknown. We enrolled 21 patients with thromboembolic events associated to lupus anticoagulant, anticardiolipin and anti ß2 glycoprotein1 autoantibodies. We performed whole exome sequencing and a systematic variant-based analysis in genes associated with thrombosis, in candidate genes previously associated with APS or inborn errors of immunity. Data were compared to public databases and to a control cohort of 873 non-autoimmune patients. Variants were identified following a state-of-the-art pipeline. Enrichment analysis was performed by comparing with the control cohort. We found an absence of significant HLA bias and genetic heterogeneity in these patients, including when testing combinations of rare variants in genes encoding for proteins involved in thrombosis and of variants in genes linked with inborn errors of immunity. These results provide evidence of genetic heterogeneity in PAPS, even in a homogenous series of triple positive patients. At the individual scale, a combination of variants may participate to the breakdown of B cell tolerance and to the vessel damage.

The course of non-infectious uveitis in pregnancy: a retrospective study of 79 pregnancies.

PURPOSE: The study aims to describe the course and management of non-infectious uveitis during pregnancy and postpartum period in European populations. METHODS: A retrospective observational study in two tertiary centers in France was performed. Pregnant patients during the follow-up of a non-infectious uveitis as well as those with new-onset uveitis were included. The medical records were analyzed with a systematic collection of the characteristics of the uveitis, the treatment and evolution of the uveitis, and the course of the pregnancy including obstetric complications. RESULTS: Seventy-nine pregnancies in 59 women were included: 48 patients (68 pregnancies) were followed for uveitis and 11 had a new-onset uveitis diagnosis. Most patients had idiopathic uveitis (32.2%) or sarcoid uveitis (27.1%). Among the patients followed for uveitis at the time of conception, there were 18 relapses (26.5%) requiring treatment escalation. Relapses occurred mainly in the two first trimester (n = 12) or during the postpartum period (n = 5) and were significantly associated with an active uveitis at the time of conception (OR = 9.2, 95% CI [1.57-48.4], p = 0.01). The characteristics of the new-onset uveitis were similar to those already existing before pregnancy. Obstetric complications occurred in 25 pregnancies (31.6%), mainly gestational hypertension and gestational diabetes. CONCLUSION: The frequency of non-infectious uveitis relapses decreases as pregnancy progresses, in agreement with data from other non-European studies. However, multidisciplinary monitoring should be advised, especially to uncontrolled patients at the time of conception.

Severe pulmonary arterial hypertension and massive ascites in a patient with systemic lupus erythematosus and secondary Sjogren's syndrome.

BACKGROUND: Pulmonary arterial hypertension (PAH), is a rare manifestation of systemic lupus erythematosus (SLE), characterized by pulmonary arterial remodeling leading to right ventricular failure and death. To date, optimal management of SLE-associated PAH should be clarified, especially regarding the respective places of immunosuppressants and PAH vasodilator treatments. CASE REPORT: We report the case of a 48-year-old woman with SLE and secondary Sjogren syndrome, associated with severe PAH and lupus peritonitis with massive ascites, who showed a remarkable response, both for SLE flare and PAH, to a treatment combining immunosuppressants and pulmonary arterial vasodilator treatment. CONCLUSION: This observation highlights the interest of combining immunosuppressive therapy in SLE-PAH, whose modalities in association with PAH treatments should be clarified.

[EBV and immunodeficiency]. / EBV et immunodépression.

Epstein-Barr virus (EBV), discovered in 1964, is a double-stranded DNA virus belonging to the Herpesviridae family. EBV has a lymphoid tropism with transforming capacities using different oncogenic viral proteins. This virus has two replication cycles: a lytic cycle mainly occuring during primary infection and a latent cycle allowing viral persistence into host memory B cells. More than 90% of adults are seropositive for EBV worldwide, with a past history of asymptomatic or mild primary infection. EBV infection can sometimes cause life-threatening complications such as hemophagocytic lymphohistiocytosis, and lead to the development of lymphoproliferative disorders or cancers. Risk factors associated with these phenotypes have been recently described through the study of monogenic primary immune deficiencies with EBV susceptibility. We here review the virological and immunological aspects of EBV infection and EBV-related complications with an overview of current available treatments.

[Hughes-Stovin syndrome: About one case in a young man with recurrent thrombosis and pulmonary artery aneurysm and literature review]. / Syndrome de Hughes-Stovin : à propos d'un cas chez un jeune patient avec thromboses récurrentes et anévrysme de l'artère pulmonaire et revue de la littérature.

INTRODUCTION: First described in 1959, Hughes-Stovin syndrome is a very rare disorder combining vascular aneurysms, especially from pulmonary arteries, and thrombosis. The disease affects mostly the young male and is sometime associated with Behçet' disease. CASE REPORT: Here, we report the case of a 19-year-old man with hemoptysis and dyspnea revealing recurrent pulmonary embolisms despite efficient anticoagulant therapy. The patient subsequently developed fever and an inflammatory syndrome. Physical examination showed ulcers of the tongue. Angio-CT revealed recent pulmonary embolism, femoral vein thrombosis, and a unique threatening aneurysm of a left pulmonary artery segment. The aneurysm was embolized and simultaneously a vena cava filter was inserted. CONCLUSION: Hughes-Stovin syndrome requires immediate therapeutic decision, with an important risk of the anticoagulation. High dose steroids and in most cases, intensive immunosuppressive therapies are required such as cyclophosphamide.

[Sinusoidal obstruction syndrome after BeAM conditioning regiment for autologous stem cell transplantation: Imputability of bendamustine? Report of two cases and literature review]. / Syndrome obstructif sinusoïdal après conditionnement par BeEAM pour autogreffe de cellules souches hématopoïétiques : imputabilité de la bendamustine ? À propos de deux cas et revue de la littérature.

INTRODUCTION: Sinusoidal obstruction syndrome is a rare complication of autologous hematopoietic stem cell transplantation. This syndrome is mainly described following conditioning regiment with busulfan, cyclophosphamide and/or total body irradiation. CASE REPORTS: We report for the first time two cases of sinusoidal obstruction syndrome occurring lately after BeAM conditioning regiment (bendamustine, etoposide, aracytine, melphalan) for autologous stem cell transplantation in patients treated for malignant lymphoma. CONCLUSION: Our observations highlight the difficulty to diagnose this complication with often non-specific clinical presentation and possible delayed occurrence after to transplantation, but also the therapeutic challenges, defibrotide being the only agent currently efficient. Physiopathology and potential responsibility of bendamustine in the sinusoidal obstruction syndrome occurrence will be discussed.

[Primary immunodeficiency and autoimmunity]. / Déficit immunitaire primitif de l'adulte et auto-immunité.

Many evidences highlight that immunodeficiency and autoimmunity are two sides of a same coin. Primary immune deficiencies (PIDs), which are rare mono- or multigenic defects of innate or adaptative immunity, frequently associate with autoimmunity. Analyses of single-gene defects in immune pathways of families with PIDs, by new tools of molecular biology (next genome sequencing technologies), allowed a better understanding of the ways that could both drive immune defect with immune deficiency and autoimmunity. Moreover, genes implicated in rare single-gene defects are now known to be also involved in polygenic conventional autoimmune diseases. Here, we describe the main autoimmune symptoms occurring in PIDs and the underlying mechanisms that lead to autoimmunity in immunodeficiency. We review the links between autoimmunity and immunodeficiency and purpose some principles of care for patients with PIDs and autoimmunity.

[Prevention of infections in adults and adolescents with systemic lupus erythematosus: Guidelines for the clinical practice based on the literature and expert opinion]. / Prévention des infections au cours du lupus systémique chez l'adulte et l'adolescent : élaboration de recommandations pour la pratique clinique, à partir d'une analyse de la littérature et de l'avis d'experts.

PURPOSE: To develop French recommendations about the management of vaccinations, the screening of cervical cancer and the prevention of pneumocystis pneumonia in systemic lupus erythematosus (SLE). METHODS: Thirty-seven experts qualified in internal medicine, rheumatology, dermatology, nephrology and pediatrics have selected recommendations from a list of proposition based on available data from the literature. For each recommendation, the level of evidence and the level of agreement among the experts were specified. RESULTS: Inactivated vaccines do not cause significant harm in SLE patients. Experts recommend that lupus patient should receive vaccinations accordingly to the recommendations and the schedules for the general public. Pneumococcal vaccination is recommended for all SLE patients. Influenza vaccination is recommended for immunosuppressed SLE patients. Live attenuated vaccines should be avoided in immunosuppressed patients. Yet, recent works suggest that they can be considered in mildly immunosuppressed patients. Experts have recommended a cervical cytology every year for immunosuppressed patients. No consensus was obtained for the prevention of pneumocystis pneumonia. CONCLUSION: These recommendations can be expected to improve clinical practice uniformity and, in the longer term, to optimize the management of SLE patients.

[Screening and management of cardiovascular risk factors in systemic lupus erythematosus: Recommendations for clinical practice based on the literature and expert opinion]. / Dépistage et prise en charge du risque cardiovasculaire au cours du lupus systémique : élaboration de recommandations pour la pratique clinique, à partir d'une analyse de la littérature et de l'avis d'experts.

PURPOSE: To develop French recommendations about screening and management of cardiovascular risk factors in systemic lupus erythematosus (SLE). METHODS: Thirty-nine experts qualified in internal medicine, rheumatology and nephrology have selected recommendations from a list developed based on evidence from the literature. For each recommendation, the level of evidence and the level of agreement among the experts were specified. RESULTS: Experts recommended an annual screening of cardiovascular risk factors in SLE. Statins should be prescribed for primary prevention in SLE patients based on the level of LDL-cholesterol and the number of cardiovascular risk factors, considering SLE as an additional risk factor. For secondary prevention, experts have agreed on an LDL-cholesterol target of <0.7 g/L. Hypertension should be managed according to the 2013 European guidelines, using renin-angiotensin system blockers as first line agents in case of renal involvement. Aspirin can be prescribed in patients with high cardiovascular risk or with antiphospholipid antibodies. CONCLUSION: These recommendations about the screening and management of cardiovascular risk factors in SLE can be expected to improve clinical practice uniformity and, in the longer term, to optimize the management of SLE patients.

Molecular analysis of rearranged VH genes during B cell chronic lymphocytic leukemia: intraclonal stability is frequent but not constant.

Several genetic mechanisms have been shown to diversify the expressed antibody repertoire of committed B lymphocytes. These include V gene replacement, ongoing gene rearrangement and somatic hypermutation. These mechanisms may be operational at discrete points in the B cell differentiation pathway and generate idiotype diversity in various malignant B cell tumors. In particular, V region mutations have been established as a major mechanism of tumor escape from anti-idiotype immunotherapy in some lymphoma. On the other hand, previous studies on a few selected cases have shown that this mutation process does not affect the B cell clone during chronic lymphocytic leukemia. However, to what extent this intraclonal stability is a general phenomenon during B cell CLL is not clear. Therefore, we randomly selected 6 patients suffering from classical B cell CLL (sIgM (+), CD5 (+), CD19 (+)) at different stages of the disease and analysed the intraclonal variability of the expressed variable region of the heavy chain (VH). After PCR amplification of the cDNA corresponding to the rearranged VDJ regions, the products were cloned and sequenced. In five cases, multiple clone analysis did not show any intraclonal variability whatever the stage of the disease. Furthermore, in a single case, this intraclonal stability was confirmed during a three year period of time when the disease progressed. The sixth case behaved differently since we found multiple nucleotide substitutions, apparently accumulating as the malignant clone expanded. Besides the theoretical difficulties that these changes can induce during immunotherapy, two findings merit further discussion: 1) the distribution of the ongoing mutations affecting the VH region was not suggestive of an antigen driven selection, 2) this intraclonal variability was specific for the VH region, since the VL region showed no intraclonal variation.

[Lipomatosis induced by corticosteroid therapy]. / Les lipomatoses induites par la corticothérapie.

Steroid-induced lipomatosis usually presents as a localized hypertrophy of the adipose tissue and seems more common than previously thought. Most patients develop this phenomenon after prolonged administration of moderate to high doses of oral corticosteroids. The localizations are numerous and determine the clinical presentation. Often asymptomatic, they can also be revealed by worrying symptoms usually due to a compressive syndrome. The most frequently reported localizations (spinal epidural, retro-orbital, mediastinal) are also the most clinically apparent. The cessation or reduction of steroid therapy, when medically possible, inconsistently results in the decrease or disappearance of the lipomatosis deposits. Computerized tomography or magnetic resonance imaging are the most helpful diagnostic means. Interestingly, these lipomatoses have rarely been reported in patients with Cushing disease. Their pathophysiology remains poorly elucidated and may imply an inhibition of the brown adipose tissue lipolysis.

[Rhabdomyolysis caused by simvastatinin a patient following heart transplantation and cyclosporine therapy]. / Rhabdomyolyse causée par la simvastatine chez un transplanté cardiaque sous ciclosporine.

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are cholesterol-lowering agents which may induce rhabdomyolysis. The authors present a case of rhabdomyolysis attributed to simvastatin in a heart-transplant recipient. They stress the probability of a dose-dependent muscular toxicity and the risk of overdosage in patients already under treatment with drugs that interfere with the pharmacokinetics of HMG-CoA reductase inhibitors, notably ciclosporine.

[Pulmonary histiocytosis, then bronchiolo-alveolar cancer in HIV-1 infection]. / Histiocytose pulmonaire, puis cancer bronchiolo-alvéolaire au cours d'une infection par VIH-1.

INTRODUCTION: Langerhans cell pulmonary histiocytosis is a rare disease, primarily enhanced by smoking, and of unclear mechanism. OBSERVATION: A 42 year-old man, smoking 25 packs-years, was infected by a type 1 human immunodeficiency virus (HIV-1). He successively developed pulmonary emphysema, Langerhans cell pulmonary histiocytosis and alveolar bronchial carcinoma of the lower right pulmonary lobe, which was fatal. DISCUSSION: We discuss the concomitance of pulmonary histiocytosis and alveolar bronchial carcinoma, exceptional in the literature, and the eventual enhancing role of HIV-1 infection. The principal incriminating factor in pulmonary histiocytosis probably remains smoking, but the HIV-1 infection may have participated in the emergence of the neoplastic pathology.

[Soluble tumor necrosis factor receptors in patients with systemic lupus erythematosus]. / Récepteurs solubles au tumor necrosis factor chez des malades ayant un lupus systémique.

OBJECTIVE: To study the variations of type II soluble receptors for tumor necrosis factor (sR-TNF) in patients with systemic lupus erythematosus and investigate their use in the clinical setting. PATIENTS AND METHODS: Twenty-six patients with systemic lupus were followed for a mean 3 years. sR-TNF and other immunological parameters (C reactive protein, anti-DNA antibodies, C3 and C4 complement fractions, soluble receptors for interleukin 2) were measured in sera at different points of the disease course. The systemic lupus activity measure (SLAM) was determined at each point, and confronted with the biology results. The study was cross sectional for the group and longitudinal for the patients. RESULTS: sR-TNF was the immunological parameter which correlated best with SLAM. It also correlated with sedimentation rate, C reactive protein, thrombopenia, anemia, creatinine level, anti-DNA antibodies and sR-IL2. The longitudinal study pointed out however that this finding is not consistent for each patient. CONCLUSION: A rise in sR-TNF related to systemic lupus activity but is of limited practical interest for individual patient follow-up.

[Immunological aspects of the antiphospholipid syndrome]. / Aspects immunologiques du syndrome des antiphospholipides.

Antiphospholipid antibodies constitute a group of heterogeneous antibodies, which mainly recognize complexes made of proteins and anionic phospholipids. The nature of these complexes is currently better defined, as well as known, the structure of the antiphospholipid antibodies owing to the analysis of the monoclonal forms of these antibodies which were also studied both in terms of their precise specificities and cross-reactivity. However, the origin of these autoantibodies is not clearly understood, as well as the possible link between antiphospholipid antibodies present in healthy individuals, and those observed in autoimmune diseases. Only a fraction of antiphospholipid antibodies are pathogenic and directly responsible for the clinical manifestations of the antiphospholipid syndrome, but there is, to date, no biological test able to accurately detect pathogenic antiphospholipid antibodies. The diverse mechanisms which link these autoantibodies to the occurrence of symptoms, mainly during obstetrical complications, are better understood, and suggest new therapeutic avenues.

Infectious agents and B cell tolerance breakdown.

The role of infectious agents in autoimmune diseases genesis is still a matter of debate. Several observations have suggested that autoimmune diseases may be initiated or worsened by infections (review by Kivity et al., 2009). However, there is no clear understanding of the underlying mechanisms. In particular, autoantibody production during infections could be the result of the non specific activation of "natural" autoreactive B cells that produce only low-affinity antibodies (Lacroix-Desmazes et al., 1998). A relevant hypothesis making the link between infections and autoimmune diseases could be the progressive genesis of more affine autoreactive B cells that could be involved in different pathogenic conditions. The major purpose of our work is therefore to study the breakdown of B cell tolerance and the ability for autoreactive B cells,especially low reactive B cells, to engage in an affinity maturation process during infections.We have created a new autoreactive B cell model allowing a relevant study of affinity maturation process. In this intermediate affinity SWHEL X HEL2x autoreactive model, knock-in B cells (Taki etal., 1993) express a B cell receptor highly specific for Hen-Egg Lysozyme (HEL) that recognizes HEL2x mutated auto-antigen with intermediate affinity (Phan et al., 2003; SWHEL model).Phenotypic analysis revealed that these autoreactive B cells are in a state of partial tolerance compared to the high affinity model (Phan et al., 2003; SWHEL X ML5 model) characterized by a strong anergy of HEL positive B cells.Experimental infections were performed with Borrelia burgdorferi, a Gram-negative spirochete,leading to sustained lymph nodes polyclonal B cell activation and hypergammaglobulinemia (Soulas et al., 2005). In SWHEL X HEL2x infected mice, in the presence of their auto-antigen,intermediate affinity autoreactive B cells are able to proliferate, to be activated, to enter into lymph nodes germinal centers and to produce IgM and IgG autoantibodies, although in low amounts.Moreover, IgG auto-antibodies in infected mice appear somatically mutated in the auto-antigen recognizing area. These data are consistent with a partial tolerance breakdown and the next experimental step will consist in checking the long-term survival of such activated autoreactive B cells and the impact of the observed mutations