Phénotype clinique et réponses humorales intestinales de patients déficitaires en IgA

Selective IgA deficiency (sIgAd) and common variable immunodeficiency (CVID) lead to lack of seric IgA in all cases for the former and half cases for the latter. Complications associated with these conditions are mucosal infections, auto-immunity and unexplained entheropathy. IgA responses are mainly triggered in intestinal mucosal associated lymphoïd tissues and contribute to host/intestinal flora (gut microbiota) homeostasis. Symbiosis disruption, also called dysbiosis, can induce inflammatory bowel disease, inappropriate local and systemic humoral responses, and metabolic troubles. The aim of this study is to describe clinical phenotype of patients lacking seric IgA (sIgAd and CVID, n=26) and to study their intestinal humoral responses. Our results showed that 100% CVID and 85% sIgAd patients had recurrent respiratory tract and/or digestive and/or vaginal infections, leading to antibiotics abuse. Moreover, 63% sIgAd patients had at least one autoimmune condition and 33% CVID patients had an autoimmune cytopenia; Polyclonal lymphoproliferation was found in 66% CVID patients. Interestingly, 46% dIgAs patients and 75% CVID patients had a chronic diarrhea with inflammatory histological features in all cases. Intestinal humoral responses were altered since IgA responses were indeed abolished. In cases of sIgAd, intestinal IgM responses were systematically observed. Our results suggest that all patients have at least one complication, and half of them present with gastrointestinal troubles, suggesting intestinal dysbiosis possibly related to secretory IgA deficiency and despite IgM secretion.L’absence d’IgA sérique définit le défaut sélectif en IgA (dIgAs) et est retrouvé chez ½ patient au cours du déficit immunitaire commun variable (DICV). Ces deux déficits humoraux primitifs s’accompagnent d’infections muqueuses, de manifestations auto-immunes, d’entéropathie. Les réponses IgA sont majoritairement induites dans les muqueuses digestives et contribuent au maintien de la symbiose entre l’hôte et sa flore digestive (microbiote intestinal). La rupture de cette symbiose peut induire colite inflammatoire, réponses humorales locales et systémiques inappropriées, et troubles métaboliques. Le but de notre étude est de décrire le phénotype clinique des patients déficitaires en IgA (dIgAs et DICV, n=26) et d’étudier leurs réponses humorales intestinales. Nos résultats montrent que 100% des patients DICV et 85% des patients dIgAs ont des infections ORL ou respiratoires récurrentes et/ou digestives et/ou vaginales entraînant une surconsommation d’antibiotiques. De plus, 63% des patients dIgAs ont au moins une maladie auto-immune, et 33% des patients DICV ont une cytopénie auto-immune ; 66% des patients DICV ont une lymphoprolifération polyclonale. Par ailleurs, 46% des patients dIgAs et 75% des patients DICV ont une diarrhée chronique avec des anomalies inflammatoires de la muqueuse dans 100% des cas. Les réponses humorales intestinales sont altérées avec absence d’IgA sécrétoire, associée à la présence d’IgM sécrétoire dans 100% des cas de dIgAs. Ces résultats suggèrent que les patients qui ont une absence d’IgA sérique ont tous au moins une complication, et que 50% d’entre eux ont des symptômes évocateurs de dysbiose intestinale possiblement liés à l’absence d’IgA sécrétoire et malgré la sécrétion d’IgM

Effects of IgA deficiency on Host/Intestinal microbiota symbiosis in humans

Le système immunitaire muqueux, et plus particulièrement les réponses intestinales IgA sont essentielles non seulement à la défense contre les agents pathogènes, mais aussi au façonnement de la flore intestinale commensale. Dans les modèles murins de déficit en IgA, on observe une dysbiose intestinale majeure associée à une inflammation muqueuse, réversibles après restauration des IgA. Le but de ce travail est de décrire l'impact de l'absence d'IgA chez l'homme sur la composition du microbiote intestinal ainsi que ses conséquences locales et systémiques. L'étude comparative par analyse métagénomique des selles de 17 sujets déficitaires en IgA et de 34 donneurs sains retrouve l'absence de différence majeure en termes de répartition des phyla dominants, de diversité et de richesse génique bactériennes entre les deux groupes. En revanche, en analysant à l'échelon des espèces, on observe dans le déficit en IgA une surreprésentation d'espèces pro-inflammatoires et une sous-représentation d'espèces anti-inflammatoires. En outre, en l'absence d'IgA, nous observons la présence de réponses IgM qui opsonisent partiellement les genres ciblés par l'IgA, mais semblent maintenir la diversité au sein des Actinobactéries. Les patients présentent un biais phénotypique lymphocytaire T circulant (TH17) associé à des stigmates de translocation bactérienne. Enfin, l'absence d'IgA s'associe à une perturbation du réseau bactérien minimal "obligatoire". Ces résultats suggèrent que le déficit en IgA humain s'accompagne d'une dysbiose modérée associée à une altération de l'architecture du réseau bactérien induisant une hyperactivation du système immunitaire, malgré la présence de réponses IgM.IgA responses play a key role in gut mucosa, defending host against pathogens but also shaping the commensal flora. In order to get insights into the specific contributions of IgA to host/microbial symbiosis in humans, we explored patients that lack only IgA, using gut microbial metagenomics and systems immunology. Microbiota composition was compared between 34 healthy controls and 17 selective IgA deficiency (sIgAd) patients. Contrary to what was observed in murine models of IgA deficiency, we show that human sIgAd is not associated with massive perturbations of gut microbial ecology, regarding phyla distribution, bacterial diversity and gene richness. A clear gut microbial signature is however associated to sIgAd: we found 19 over-represented MGS mainly described to be pro-inflammatory, but also 14 under-represented MGS, mainly known to be beneficial. We also explored local consequences of IgA deficiency, particularly whether IgM could replace IgA at host/bacterial interface. Using a combination of bacterial flow sorting and DNA sequencing, we therefore analysed the composition of IgM-coated microbiomes observed in sIgAd. We show that IgM only partially supply IgA deficiency, as not all typical IgA targets can also be opsonized by IgM, but nevertheless contribute to maintain Actinobacteria diversity. IgA deficiency is associated with a skewed circulating CD4+ T cell profile towards TH17, as well as markers of bacterial translocation. Finally, sIgAd is associated with a perturbation of the minimal bacterial network. Altogether our results suggest that human IgA deficiency is associated with a mild dysbiosis associated to systemic inflammation despite the presence of Ig

Impact du déficit en IgA sur la symbiose hôte/microbiote intestinal chez l'homme

IgA responses play a key role in gut mucosa, defending host against pathogens but also shaping the commensal flora. In order to get insights into the specific contributions of IgA to host/microbial symbiosis in humans, we explored patients that lack only IgA, using gut microbial metagenomics and systems immunology. Microbiota composition was compared between 34 healthy controls and 17 selective IgA deficiency (sIgAd) patients. Contrary to what was observed in murine models of IgA deficiency, we show that human sIgAd is not associated with massive perturbations of gut microbial ecology, regarding phyla distribution, bacterial diversity and gene richness. A clear gut microbial signature is however associated to sIgAd: we found 19 over-represented MGS mainly described to be pro-inflammatory, but also 14 under-represented MGS, mainly known to be beneficial. We also explored local consequences of IgA deficiency, particularly whether IgM could replace IgA at host/bacterial interface. Using a combination of bacterial flow sorting and DNA sequencing, we therefore analysed the composition of IgM-coated microbiomes observed in sIgAd. We show that IgM only partially supply IgA deficiency, as not all typical IgA targets can also be opsonized by IgM, but nevertheless contribute to maintain Actinobacteria diversity. IgA deficiency is associated with a skewed circulating CD4+ T cell profile towards TH17, as well as markers of bacterial translocation. Finally, sIgAd is associated with a perturbation of the minimal bacterial network. Altogether our results suggest that human IgA deficiency is associated with a mild dysbiosis associated to systemic inflammation despite the presence of IgMLe système immunitaire muqueux, et plus particulièrement les réponses intestinales IgA sont essentielles non seulement à la défense contre les agents pathogènes, mais aussi au façonnement de la flore intestinale commensale. Dans les modèles murins de déficit en IgA, on observe une dysbiose intestinale majeure associée à une inflammation muqueuse, réversibles après restauration des IgA. Le but de ce travail est de décrire l'impact de l'absence d'IgA chez l'homme sur la composition du microbiote intestinal ainsi que ses conséquences locales et systémiques. L'étude comparative par analyse métagénomique des selles de 17 sujets déficitaires en IgA et de 34 donneurs sains retrouve l'absence de différence majeure en termes de répartition des phyla dominants, de diversité et de richesse génique bactériennes entre les deux groupes. En revanche, en analysant à l'échelon des espèces, on observe dans le déficit en IgA une surreprésentation d'espèces pro-inflammatoires et une sous-représentation d'espèces anti-inflammatoires. En outre, en l'absence d'IgA, nous observons la présence de réponses IgM qui opsonisent partiellement les genres ciblés par l'IgA, mais semblent maintenir la diversité au sein des Actinobactéries. Les patients présentent un biais phénotypique lymphocytaire T circulant (TH17) associé à des stigmates de translocation bactérienne. Enfin, l'absence d'IgA s'associe à une perturbation du réseau bactérien minimal "obligatoire". Ces résultats suggèrent que le déficit en IgA humain s'accompagne d'une dysbiose modérée associée à une altération de l'architecture du réseau bactérien induisant une hyperactivation du système immunitaire, malgré la présence de réponses IgM

The antibody/microbiota interface in health and disease

International audienceThe human intestine is densely colonized with commensal microbes that stimulate the immune system. While secretory Immunoglobulin (Ig) A is known to play a crucial role in gut microbiota compartmentalization, secretory IgM, and systemic IgG have recently been highlighted in host-microbiota interactions as well. In this review, we discuss important aspects of secretory IgA biology, but rather than focusing on mechanistic aspects of IgA impact on microbiota, we stress the current knowledge of systemic antibody responses to whole gut microbiota, in particular their generation, specificities, and function. We also provide a comprehensive picture of secretory IgM biology. Finally, therapeutic and diagnostic implications of these novel findings for the treatment of various diseases are outlined

Comment on “Diversification of the antigen-specific T cell receptor repertoire after varicella zoster vaccination”

International audienceAnalysis of antigen-specific T cells can be confounded by T cell activation in vitro

Immune/microbial interface perturbation in human IgA deficiency

International audienceIn a recently published article we report the metagenomic analysis of human gut microbiomes evolved in the absence of immunoglobulin A (IgA). We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. While our studyunderlines a rather expected pathobiont expansion, we at the same time highlight a less expected depletion in some typically beneficial symbionts. We also show that IgM partially supply IgA deficiency, explaining the relatively mild clinical phenotype associated with the early steps of thiscondition. Microbiome studies in patients should consider potential issues such as cohort size, human genetic polymorphism and treatments. In this commentary, we discuss how such issues were taken into account in our own stud

Analysis of bacterial-surface-specific antibodies in body fluids using bacterial flow cytometry.

Antibacterial antibody responses that target surfaces of live bacteria or secreted toxins are likely to be relevant in controlling bacterial pathogenesis. The ability to specifically quantify bacterial-surface-binding antibodies is therefore highly attractive as a quantitative correlate of immune protection. Here, binding of antibodies from various body fluids to pure-cultured live bacteria is made visible with fluorophore-conjugated secondary antibodies and measured by flow cytometry. We indicate the necessary controls for excluding nonspecific binding and also demonstrate a cross-adsorption technique for determining the extent of cross-reactivity. This technique has numerous advantages over standard ELISA and western blotting techniques because of its independence from scaffold binding, exclusion of cross-reactive elements from lysed bacteria and ability to visualize bacterial subpopulations. In addition, less than 10(5) bacteria and less than 10 μg of antibody are required per sample. The technique requires 3-4 h of hands-on experimentation and analysis. Moreover, it can be combined with automation and mutliplexing for high-throughput applications

Evolution of Nutritional Status after Early Nutritional Management in COVID-19 Hospitalized Patients

International audienceBackground & Aims: SARS-CoV2 infection is associated with an increased risk of malnutrition. Although there are numerous screening and nutritional management protocols for malnutrition, only few studies have reported nutritional evolution after COVID-19. The objectives of this study were to describe the evolution of nutritional parameters between admission and 30 days after hospital discharge, and to determine predictive factors of poor nutritional outcome after recovery in adult COVID-19 patients. Methods: In this observational longitudinal study, we report findings after discharge in 91 out of 114 patients initially admitted for COVID-19 who received early nutritional management. Nutritional status was defined using GLIM criteria and compared between admission and day 30 after discharge. Baseline predictors of nutritional status at day 30 were assessed using logistic regression. Results: Thirty days after discharge, 28.6% of patients hospitalized for COVID-19 were malnourished, compared to 42.3% at admission. Half of malnourished patients (53%) at admission recovered a normal nutritional status after discharge. Weight trajectories were heterogeneous and differed if patients had been transferred to an intensive care unit (ICU) during hospitalization (p = 0.025). High oxygen requirement during hospitalization (invasive ventilation p = 0.016 (OR 8.3 [1.6-61.2]) and/or oxygen therapy over 5 L/min p = 0.021 (OR 3.2 [1.2-8.9]) were strong predictors of malnutrition one month after discharge. Conclusions: With early nutritional management, most patients hospitalized for COVID-19 improved nutritional parameters after discharge. These findings emphasize the importance of nutritional care in COVID-19 patients hospitalized in medicine departments, especially in those transferred from ICU