RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models

Preeclampsia, with the hallmark features of new-onset hypertension and proteinuria after 20 weeks of gestation, is a major cause of fetal and maternal morbidity and mortality. Studies have demonstrated a role for the renin-angiotensin system (RAS) in its pathogenesis; however, small-molecule RAS blockers are contraindicated because of fetal toxicity. We evaluated whether siRNA targeting maternal hepatic angiotensinogen (Agt) could ameliorate symptoms of preeclampsia without adverse placental or fetal effects in 2 rodent models. The first model used a cross of females expressing human Agt with males expressing human renin, resulting in upregulation of the circulating and uteroplacental RAS. The second model induced ischemia/reperfusion injury and subsequent local and systemic inflammation by surgically reducing placental blood flow midgestation (reduced uterine perfusion pressure [RUPP]). These models featured hypertension, proteinuria, and fetal growth restriction, with altered biomarkers. siRNA treatment ameliorated the preeclamptic phenotype in both models, reduced blood pressure, and improved intrauterine growth restriction, with no observed deleterious effects on the fetus. Treatment also improved the angiogenic balance and proteinuria in the transgenic model, and it reduced angiotensin receptor activating antibodies in both. Thus, an RNAi therapeutic targeting Agt ameliorated the clinical sequelae and improved fetal outcomes in 2 rodent models of preeclampsia

The BAFF Receptor Transduces Survival Signals by Co-opting the B Cell Receptor Signaling Pathway

SummaryFollicular B cell survival requires signaling from BAFFR, a receptor for BAFF and the B cell antigen receptor (BCR). This “tonic” BCR survival signal is distinct from that induced by antigen binding and may be ligand-independent. We show that inducible inactivation of the Syk tyrosine kinase, a key signal transducer from the BCR following antigen binding, resulted in the death of most follicular B cells because Syk-deficient cells were unable to survive in response to BAFF. Genetic rescue studies demonstrated that Syk transduces BAFFR survival signals via ERK and PI3 kinase. Surprisingly, BAFFR signaling directly induced phosphorylation of both Syk and the BCR-associated Igα signaling subunit, and this Syk phosphorylation required the BCR. We conclude that the BCR and Igα may be required for B cell survival because they function as adaptor proteins in a BAFFR signaling pathway leading to activation of Syk, demonstrating previously unrecognized crosstalk between the two receptors

The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain

Peer reviewe

B Cell Activating Factor (BAFF) and T Cells Cooperate to Breach B Cell Tolerance in Lupus-Prone New Zealand Black (NZB) Mice

The presence of autoantibodies in New Zealand Black (NZB) mice suggests a B cell tolerance defect however the nature of this defect is unknown. To determine whether defects in B cell anergy contribute to the autoimmune phenotype in NZB mice, soluble hen egg lysozyme (sHEL) and anti-HEL Ig transgenes were bred onto the NZB background to generate double transgenic (dTg) mice. NZB dTg mice had elevated levels of anti-HEL antibodies, despite apparently normal B cell functional anergy in-vitro. NZB dTg B cells also demonstrated increased survival and abnormal entry into the follicular compartment following transfer into sHEL mice. Since this process is dependent on BAFF, BAFF serum and mRNA levels were assessed and were found to be significantly elevated in NZB dTg mice. Treatment of NZB sHEL recipient mice with TACI-Ig reduced NZB dTg B cell survival following adoptive transfer, confirming the role of BAFF in this process. Although NZB mice had modestly elevated BAFF, the enhanced NZB B cell survival response appeared to result from an altered response to BAFF. In contrast, T cell blockade had a minimal effect on B cell survival, but inhibited anti-HEL antibody production. The findings suggest that the modest BAFF elevations in NZB mice are sufficient to perturb B cell tolerance, particularly when acting in concert with B cell functional abnormalities and T cell help

Crucial Role for BAFF-BAFF-R Signaling in the Survival and Maintenance of Mature B Cells

Defects in the expression of either BAFF (B cell activating factor) or BAFF-R impairs B cell development beyond the immature, transitional type-1 stage and thus, prevents the formation of follicular and marginal zone B cells, whereas B-1 B cells remain unaffected. The expression of BAFF-R on all mature B cells might suggest a role for BAFF-R signaling also for their in vivo maintenance. Here, we show that, 14 days following a single injection of an anti-BAFF-R mAb that prevents BAFF binding, both follicular and marginal zone B cell numbers are drastically reduced, whereas B-1 cells are not affected. Injection of control, isotype-matched but non-blocking anti-BAFF-R mAbs does not result in B cell depletion. We also show that this depletion is neither due to antibody-dependent cellular cytotoxicity nor to complement-mediated lysis. Moreover, prevention of BAFF binding leads to a decrease in the size of the B cell follicles, an impairment of a T cell dependent humoral immune response and a reduction in the formation of memory B cells. Collectively, these results establish a central role for BAFF-BAFF-R signaling in the in vivo survival and maintenance of both follicular and marginal zone B cell pools

Cracking the BAFF code.

The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting

Electronic democracy, a concept under construction

La démocratie représentative reste un régime essentiellement représentatif qui a été conçu précisément pour exclure la participation directe de l’universalité des citoyens à la prise de décisions politiques. L’introduction d’instruments de la participation directe, en forme de l’e-démocratie, crée un conflit au sein de ce régime, conflit qui ne sera résolu que par un aménagement de la notion de démocratie représentative, voire sa substitution par une autre notion, ayant vocation à concilier les exigences de la participation et de la représentation. Cette thèse se propose de réfléchir à un modèle de régime politique-type susceptible de permettre l'intégration de l'e-démocratie.Une telle intégration met en lumière l’interdépendance entre la démocratie et les droits fondamentaux qui sont menacés de manière inédite à l’ère numérique. La possibilité d’introduire l’e-démocratie est donc conditionnée à la protection renforcée des droits essentiels : la liberté d’expression, le droit au respect de la vie privée, ainsi qu’à la reconnaissance de nouveaux droits fondés sur l’autodétermination personnelle. L’introduction de l’e-démocratie peut également remettre en cause certains concepts bien établis, tels que le principe majoritaire, ou exiger leur reconsidération, comme dans le cas de la bonne gouvernance.Representative democracy remains essentially a representative government that was created precisely to avoid all the citizens to participate directly in political decision-making. Implementation of direct participation’s instruments in form of e-democracy creates a conflict within this government, a conflict which can be solved only by a renewal of representative democracy concept, even its substitution by another idea committed to reconciling representation and participation. This thesis aims a reflection on a concept of government capable of integrating e-democracy.Such an integration highlights the interdependent character of the link between democracy and human rights that are exposed to totally new threats in the digital era. The possibility to introduce e-democracy is conditional upon the reinforced protection of such essential rights and freedoms: as freedom of expression and right to respect for private and family life in the digital environment, as well as recognition of new rights based on personal self-determination. Implementation of e-democracy can also challenge well-established concepts such as majority principle or require their reconsideration, as in the case of good governance

Les « invisibilités » des campagnes électorales en ligne : quel encadrement juridique ?

International audienc

De l'annulation d'élections par Internet par le moyen des insuffisances du système de vote

National audience« La circonstance que des opérations électorales se déroulent par le truchement de machines à voter ne prive pas l'électeur de son droit de saisir le juge de l'élection de conclusions à fins d'annulation du scrutin, lorsque les irrégularités sont établies. Mais si le juge accueille les griefs relatifs au fonctionnement des machines à voter dans le cadre traditionnel de sa jurisprudence électorale, en assimilant la machine à voter à une urne, il n'a, jusqu'à présent, pas complètement adapté son office à la technicité particulière de ce procédé de vote et, pas conséquent, a échoué à en assurer un réel contrôle » 1. Ces propos du Maître Philippe Bluteau peuvent être appliqués de plein droit au vote par Internet. Le vote par Internet est une des modalités du vote électronique. En France, comme le note Gilles Guglielmi, le vote électronique prend aujourd'hui essentiellement deux formes : celle de machines à voter ou celle du vote à distance par Internet 2. Ce dernier est défini dans les textes officiels par les termes « vote par correspondance électronique » ou « vote électronique à distance ». L'électeur peut voter en utilisant un ordinateur connecté à internet depuis son domicile, son travail, etc. Comme tout vote, le vote par Internet n'est pas à l'abri des irrégularités qui peuvent donner lieu à l'annulation du scrutin. En effet, des manquements à un certain nombre de principes fondamentaux du droit électoral peuvent avoir pour conséquence que la volonté réelle des électeurs « ne peut pas être connue de manière certaine, et donc qu'il est impossible de connaître avec certitude le choix majoritaire des électeurs » 3. Dans ce cas, l'élection est annulée par le juge. Ces principes fondamentaux sont l'égalité, la liberté et le caractère secret du vote 4. Le respect de ce

Les « invisibilités » des campagnes électorales en ligne : quel encadrement juridique ?

International audienc