Both Monoclonal and Polyclonal Immunoglobulin Contingents Mediate Complement Activation in Monoclonal Gammopathy Associated-C3 Glomerulopathy

C3 glomerulopathy (C3G) results from acquired or genetic abnormalities in the complement alternative pathway (AP). C3G with monoclonal immunoglobulin (MIg-C3G) was recently included in the spectrum of “monoclonal gammopathy of renal significance.” However, mechanisms of complement dysregulation in MIg-C3G are not described and the pathogenic effect of the monoclonal immunoglobulin is not understood. The purpose of this study was to investigate the mechanisms of complement dysregulation in a cohort of 41 patients with MIg-C3G. Low C3 level and elevated sC5b-9, both biomarkers of C3 and C5 convertase activation, were present in 44 and 78% of patients, respectively. Rare pathogenic variants were identified in 2/28 (7%) tested patients suggesting that the disease is acquired in a large majority of patients. Anti-complement auto-antibodies were found in 20/41 (49%) patients, including anti-FH (17%), anti-CR1 (27%), anti-FI (5%) auto-antibodies, and C3 Nephritic Factor (7%) and were polyclonal in 77% of patients. Using cofactor assay, the regulation of the AP was altered in presence of purified IgG from 3/9 and 4/7 patients with anti-FH or anti-CR1 antibodies respectively. By using fluid and solid phase AP activation, we showed that total purified IgG of 22/34 (65%) MIg-C3G patients were able to enhance C3 convertase activity. In five documented cases, we showed that the C3 convertase enhancement was mostly due to the monoclonal immunoglobulin, thus paving the way for a new mechanism of complement dysregulation in C3G. All together the results highlight the contribution of both polyclonal and monoclonal Ig in MIg-C3G. They provide direct insights to treatment approaches and opened up a potential way to a personalized therapeutic strategy based on chemotherapy adapted to the B cell clone or immunosuppressive therapy

Consequence of chronic activation of TGFβ signaling on muscle metabolism during atrophy

La perte de masse musculaire, appelée atrophie musculaire, est associée à de nombreuses pathologies chroniques telles que le cancer, les pathologies neuromusculaires et constitue une des altérations majeures intervenant au cours du vieillissement. Cette fonte musculaire diminue grandement la qualité de vie, pouvant conduire à une perte d’autonomie. Elle représente également un facteur de comorbidité dans les maladies chroniques qui altère la tolérance et l’efficacité des traitements des patients et augmente la mortalité. Une des voies de signalisation identifiées dans l’induction du processus d’atrophie musculaire est la signalisation des ligands TGFβ (Transforming Growth Factor β). Elle est activée dans le muscle dans la plupart des conditions d’atrophie musculaire. Les conséquences de l’activation chronique de cette signalisation dans le muscle n’ont pas été étudiées. La compréhension des conséquences de l’activation chronique de la signalisation TGFβ sur l’homéostasie musculaire et les mécanismes moléculaires associés est essentielle pour le développement de nouvelles approches diagnostiques ou thérapeutiques. Cette thèse porte sur l’élaboration d’un nouveau modèle murin avec une activation chronique de la signalisation TGFβ au sein du muscle squelettique, grâce à l’expression inductible d’un récepteur de type I constitutivement activé spécifiquement dans les fibres musculaires adultes.Nous avons alors déterminé que l’activation chronique de la signalisation du TGFβ au sein du muscle conduit à la mise en place d’une atrophie progressive importante. L’atrophie musculaire est liée à une baisse de la synthèse protéique et à l’augmentation du catabolisme avec une activation séquentielle des atrogènes, liée à l’activation de la signalisation Smad2/3. De plus, nous avons pu déterminer que l’activation chronique de la signalisation TGFβ engendre une altération du contrôle de la qualité mitochondriale déterminée notamment par une altération de la biogenèse mitochondriale, de la fonction mitochondriale et de leur élimination conduisant à la mise en place d’un stress oxydant à long terme au sein du muscle. La mise en place de ces défauts métaboliques contribue à l’entretien de l’atrophie musculaire.Loss of muscle mass, called muscular atrophy is associated to several chronical pathologies as cancer, muscular pathology and is one of the major alterations during ageing. This muscle wasting causes a decrease of quality of life, which could lead to loss of autonomy. It’s also a comorbidity factor in the chronical diseases altering efficiency and safety of treatments that increases patients mortality. One of signalling pathways activated in the muscular atrophy process is TGFβ (Transforming Growth Factor β) ligands pathway. However, consequences of chronical activation of TGFβ pathway in muscle have not yet been studied. Understanding of chronical activation of TGFβ signalling outcome on the muscular homeostasis and molecular mechanisms is necessary for the development of new diagnostic and therapeutic approaches. This thesis is about the development and characterisation of new mouse model with chronical activation of TGFβ pathway in skeletal muscle through inductible expression of TGFβ type I receptor constitutively activated restricted to adult muscle fiber. It has been shown that the chronical activation of TGFβ pathway in muscle leads to an important progressive atrophy establishment. Moreover, this atrophy is due to a decrease in protein synthesis and increase of catabolism with sequential activation of atrogenes, linked to Smad2/3 activation pathway. Chronical activation of TGFβ pathway generates degradation of mitochondrial quality control determined by deterioration of mitochondrial biogenesis, function and removal leading to the establishment of long-term oxidative stress in muscle. These metabolic defects contribute to maintain the muscular atrophy

Expression des produits des gènes PKD1 et PKD2 au cours de la néphrogènèse chez l' homme et localisations subcellulaires et fonctions de la polycystine

La polykystose rénale autosomique dominante est une des maladies monogéniques les plus fréquentes. Elle est caractérisée par le développement de kystes rénaux bilatéraux, conduisant progressivement à une insuffisance rénale terminale vers la sixième décade. La vaste majorité des cas est due à des mutations du gène PKD1 codant pour une large protéine transmembranaire dénommée polycystine-1. Plus rarement, la maladie est causée par des mutations situées sur le gène PKD2 codant pour la polycystine-2. La fonction précise des polycystines restent encore à établir. Leurs structures primaires suggèrent que la première puisse être un récepteur transmembranaire impliqué dans les interactions cellule-cellule et/ou cellule-matrice extracellulaire, alors que la seconde serait un canal calcique.PARIS5-BU-Necker : Fermée (751152101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Ridge optical waveguide curved in a KTiOPO4 single crystal for triple photon generation: preliminary characterization by birefringence phase-matched third-harmonic generation

International audienceRidge waveguides carved in bulk nonlinear crystals such as KTiOPO4 (KTP) are used to reach a strong confinement of electromagnetic waves with large second-order or third-order non-linearity. We report on our recent experiments where we show the possibility to shape the birefringence phase-matching (BPM) conditions for direct Third-Harmonic Generation (THG: ω + ω + ω → 3ω) in micrometric KTP ridge waveguides by acting on their transverse dimensions. The real goal of this preliminary study is to design quantum optical experiments based on Triple Photons Generation (TPG: 3ω → ω + ω + ω) that is the reverse process of THG, thus exhibiting the same BPM conditions

Ridge optical waveguide curved in a KTiOPO4 single crystal for triple photon generation: preliminary characterization by birefringence phase-matched third-harmonic generation

International audienceRidge waveguides carved in bulk nonlinear crystals such as KTiOPO4 (KTP) are used to reach a strong confinement of electromagnetic waves with large second-order or third-order non-linearity. We report on our recent experiments where we show the possibility to shape the birefringence phase-matching (BPM) conditions for direct Third-Harmonic Generation (THG: ω + ω + ω → 3ω) in micrometric KTP ridge waveguides by acting on their transverse dimensions. The real goal of this preliminary study is to design quantum optical experiments based on Triple Photons Generation (TPG: 3ω → ω + ω + ω) that is the reverse process of THG, thus exhibiting the same BPM conditions

Ex Vivo Test for Measuring Complement Attack on Endothelial Cells: From Research to Bedside

International audienceAs part of the innate immune system, the complement system plays a key role in defense against pathogens and in host cell homeostasis. This enzymatic cascade is rapidly triggered in the presence of activating surfaces. Physiologically, it is tightly regulated on host cells to avoid uncontrolled activation and self-damage. In cases of abnormal complement dysregulation/overactivation, the endothelium is one of the primary targets. Complement has gained momentum as a research interest in the last decade because its dysregulation has been implicated in the pathophysiology of many human diseases. Thus, it appears to be a promising candidate for therapeutic intervention. However, detecting abnormal complement activation is challenging. In many pathological conditions, complement activation occurs locally in tissues. Standard routine exploration of the plasma concentration of the complement components shows values in the normal range. The available tests to demonstrate such dysregulation with diagnostic, prognostic, and therapeutic implications are limited. There is a real need to develop tools to demonstrate the implications of complement in diseases and to explore the complex interplay between complement activation and regulation on human cells. The analysis of complement deposits on cultured endothelial cells incubated with pathologic human serum holds promise as a reference assay. This ex vivo assay most closely resembles the physiological context. It has been used to explore complement activation from sera of patients with atypical hemolytic uremic syndrome, malignant hypertension, elevated liver enzymes low platelet syndrome, sickle cell disease, pre-eclampsia, and others. In some cases, it is used to adjust the therapeutic regimen with a complement-blocking drug. Nevertheless, an international standard is lacking, and the mechanism by which complement is activated in this assay is not fully understood. Moreover, primary cell culture remains difficult to perform, which probably explains why no standardized or commercialized assay has been proposed. Here, we review the diseases for which endothelial assays have been applied. We also compare this test with others currently available to explore complement overactivation. Finally, we discuss the unanswered questions and challenges to overcome for validating the assays as a tool in routine clinical practice

Ridge optical waveguide curved in a KTiOPO4 single crystal for triple photon generation: preliminary characterization by birefringence phase-matched third-harmonic generation

International audienceRidge waveguides carved in bulk nonlinear crystals such as KTiOPO4 (KTP) are used to reach a strong confinement of electromagnetic waves with large second-order or third-order non-linearity. We report on our recent experiments where we show the possibility to shape the birefringence phase-matching (BPM) conditions for direct Third-Harmonic Generation (THG: ω + ω + ω → 3ω) in micrometric KTP ridge waveguides by acting on their transverse dimensions. The real goal of this preliminary study is to design quantum optical experiments based on Triple Photons Generation (TPG: 3ω → ω + ω + ω) that is the reverse process of THG, thus exhibiting the same BPM conditions

Guides d'onde en arête dans pour la génération de tierce harmonique

International audienc

Guides d'onde en arête dans pour la génération de tierce harmonique

International audienc