Publications by authors named "Nadine Cerf-Bensussan"

128 Publications

Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.

Am J Hum Genet 2021 Jun 18;108(6):1126-1137. Epub 2021 May 18.

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville 3052, Melbourne, VIC, Australia; Department of Paediatrics, The University of Melbourne, 3010 Parkville, Melbourne, VIC, Australia.

Dysregulated transforming growth factor TGF-β signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-β-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-β signaling, ipo8 zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8 zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-β signaling during development and reinforces the existing link between TGF-β signaling and connective tissue defects.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.020DOI Listing
June 2021

The Promise of Novel Therapies to Abolish Gluten Immunogenicity in Celiac Disease.

Gastroenterology 2021 Apr 20. Epub 2021 Apr 20.

Institute of Translational Immunology, Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2021.04.031DOI Listing
April 2021

Intestinal immunoregulation: lessons from human mendelian diseases.

Mucosal Immunol 2021 Apr 15. Epub 2021 Apr 15.

Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM UMR 1163, Paris, France.

The mechanisms that maintain intestinal homeostasis despite constant exposure of the gut surface to multiple environmental antigens and to billions of microbes have been scrutinized over the past 20 years with the goals to gain basic knowledge, but also to elucidate the pathogenesis of inflammatory bowel diseases (IBD) and to identify therapeutic targets for these severe diseases. Considerable insight has been obtained from studies based on gene inactivation in mice as well as from genome wide screens for genetic variants predisposing to human IBD. These studies are, however, not sufficient to delineate which pathways play key nonredundant role in the human intestinal barrier and to hierarchize their respective contribution. Here, we intend to illustrate how such insight can be derived from the study of human Mendelian diseases, in which severe intestinal pathology results from single gene defects that impair epithelial and or hematopoietic immune cell functions. We suggest that these diseases offer the unique opportunity to study in depth the pathogenic mechanisms leading to perturbation of intestinal homeostasis in humans. Furthermore, molecular dissection of monogenic intestinal diseases highlights key pathways that might be druggable and therapeutically targeted in common forms of IBD.
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http://dx.doi.org/10.1038/s41385-021-00398-3DOI Listing
April 2021

Single-cell analysis of FOXP3 deficiencies in humans and mice unmasks intrinsic and extrinsic CD4 T cell perturbations.

Nat Immunol 2021 May 8;22(5):607-619. Epub 2021 Apr 8.

Department of Immunology, Harvard Medical School, Boston, MA, USA.

FOXP3 deficiency in mice and in patients with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome results in fatal autoimmunity by altering regulatory T (T) cells. CD4 T cells in patients with IPEX syndrome and Foxp3-deficient mice were analyzed by single-cell cytometry and RNA-sequencing, revealing heterogeneous T-like cells, some very similar to normal T cells, others more distant. Conventional T cells showed no widespread activation or helper T cell bias, but a monomorphic disease signature affected all CD4 T cells. This signature proved to be cell extrinsic since it was extinguished in mixed bone marrow chimeric mice and heterozygous mothers of patients with IPEX syndrome. Normal T cells exerted dominant suppression, quenching the disease signature and revealing in mutant T-like cells a small cluster of genes regulated cell-intrinsically by FOXP3, including key homeostatic regulators. We propose a two-step pathogenesis model: cell-intrinsic downregulation of core FOXP3-dependent genes destabilizes T cells, de-repressing systemic mediators that imprint the disease signature on all T cells, furthering T cell dysfunction. Accordingly, interleukin-2 treatment improved the T-like compartment and survival.
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http://dx.doi.org/10.1038/s41590-021-00910-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173714PMC
May 2021

Feline low-grade intestinal T cell lymphoma: a unique natural model of human indolent T cell lymphoproliferative disorder of the gastrointestinal tract.

Lab Invest 2021 Jun 10;101(6):794-804. Epub 2021 Mar 10.

Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM U1163, Imagine Institute, Paris, France.

Indolent T cell lymphoproliferative disorder (LPD) of the gastrointestinal tract (GI-TLPD) is a rare human primary gastrointestinal T cell lymphoma that was recently included in the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Low-grade intestinal T cell lymphoma (LGITL), an emerging disease in the domestic cat, shares a number of features with human GI-TLPD. In this prospective study, we determined whether feline LGITL might serve as a model of human GI-TLPD. We analyzed clinical, laboratory, and radiological data and performed histopathological and molecular studies on small intestinal biopsies from 22 domestic cats diagnosed with LGITL. This cancer mostly affects aging cats, is associated with nonspecific gastrointestinal tract signs, and is usually characterized by an indolent course. A histopathological analysis indicated that LGITL was mainly located in the jejunum. The small intestinal lamina propria was infiltrated by large numbers of small CD3+ T cell lymphocytes with various CD4 and CD8 expression profiles (CD4+ CD8- (4 out of 11, 36%), CD4- CD8+ (3 out of 11, 27%), and CD4- CD8- (4 out of 11, 36%)). Intraepithelial lymphocyte (IEL) counts were elevated in all cases. Ki67 was expressed in lamina propria lymphocytes and IELs at a low level (<30%). Most LGITLs were labelled by antibodies against phosphorylated STAT5, but were negative for CD56 and phosphorylated STAT3. T cell receptor gamma chain gene monoclonality was found in 86% of cases. These findings confirmed that feline LGITL shares clinical and histopathological features with human GI-TLPD. Feline LGITL may therefore constitute a relevant model of the human disease.
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http://dx.doi.org/10.1038/s41374-021-00581-xDOI Listing
June 2021

A novel mutation of PCSK1 responsible for PC1/3 deficiency in two siblings.

Clin Res Hepatol Gastroenterol 2021 Mar 1;45(6):101640. Epub 2021 Mar 1.

Service de Pédiatrie Multidisciplinaire, Hôpital de la Timone Enfants, APHM, 13385 Marseille, France.

Proprotein convertase 1 (PCSK1, PC1/3) deficiency is an uncommon cause of neonatal malabsorptive diarrhoea associated with endocrinopathies that are due to the disrupted processing of a large number of prohormones, including proinsulin. To date, only 26 cases have been reported. Herein, we describe two siblings with typical features including severe congenital diarrhoea, central diabetes insipidus, growth hormone deficiency, and hypoadrenalism. Next generation sequencing found a homozygous missense mutation in exon 5 of PCSK1 gene, c.500A>C (p.Asp167Ala), located within the catalytic domain. Both patients presented a high level of proinsulin. In the first years of life they required parenteral nutrition and hormone replacement therapy. The patients, aged 3 and 1.5 years, experienced several infectious episodes associated with septic shocks. While the mechanism underlying intestinal failure remains poorly investigated, parenteral nutrition is essential in order to ensure normal growth in early childhood.
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http://dx.doi.org/10.1016/j.clinre.2021.101640DOI Listing
March 2021

Oncogenetic landscape of lymphomagenesis in coeliac disease.

Gut 2021 Feb 12. Epub 2021 Feb 12.

Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM UMR 1163, Paris, France

Objective: Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of coeliac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis.

Design: Pure populations of RCDII-cells derived from intestinal biopsies (n=9) or sorted from blood (n=2) were analysed by whole exome sequencing, comparative genomic hybridisation and RNA sequencing. Biopsies from RCDII (n=50), EATL (n=19), type I refractory CeD (n=7) and uncomplicated CeD (n=18) were analysed by targeted next-generation sequencing. Moreover, functional in vitro studies and drug testing were performed in RCDII-derived cell lines.

Results: 80% of RCDII and 90% of EATL displayed somatic gain-of-functions mutations in the JAK1-STAT3 pathway, including a remarkable p.G1097 hotspot mutation in the JAK1 kinase domain in approximately 50% of cases. Other recurrent somatic events were deleterious mutations in nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) regulators TNFAIP3 and TNIP3 and potentially oncogenic mutations in TET2, KMT2D and DDX3X. JAK1 inhibitors, and the proteasome inhibitor bortezomib could block survival and proliferation of malignant RCDII-cell lines.

Conclusion: Mutations activating the JAK1-STAT3 pathway appear to be the main drivers of CeD-associated lymphomagenesis. In concert with mutations in negative regulators of NF-κB, they may favour the clonal emergence of malignant lymphocytes in the cytokine-rich coeliac intestine. The identified mutations are attractive therapeutic targets to treat RCDII and block progression towards EATL.
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http://dx.doi.org/10.1136/gutjnl-2020-322935DOI Listing
February 2021

Loss-of-Function Mutation in PTPN2 Causes Aberrant Activation of JAK Signaling Via STAT and Very Early Onset Intestinal Inflammation.

Gastroenterology 2020 11 25;159(5):1968-1971.e4. Epub 2020 Jul 25.

Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, Inserm, UMR1163, F-75015, Paris, France. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.07.040DOI Listing
November 2020

Intracellular offspring released from SFB filaments are flagellated.

Nat Microbiol 2020 01 9;5(1):34-39. Epub 2019 Dec 9.

Institut Imagine, Laboratory of Intestinal Immunity, Inserm UMR1163, Paris, France.

The gut commensal segmented filamentous bacterium (SFB) attaches to the ileal epithelium and potently stimulates the host immune system. Using transmission electron microscopy (TEM), we show that mouse and rat SFB are flagellated above the concave tip at the unicellular intracellular offspring (IO) stage and that flagellation occurs prior to full IO differentiation and release of IOs from SFB filaments. This finding adds a missing link to the SFB life cycle.
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http://dx.doi.org/10.1038/s41564-019-0608-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927800PMC
January 2020

Nod2 Protects the Gut From Experimental Colitis Spreading to Small Intestine.

J Crohns Colitis 2020 Jun;14(5):669-679

Centre de recherche sur l'inflammation, INSERM et Université de Paris, Paris, France.

Background And Aims: Nucleotide oligomerization domain 2 [NOD2] mutations are key risk factors for Crohn's disease [CD]. NOD2 contributes to intestinal homeostasis by regulating innate and adaptive immunity together with intestinal epithelial function. However, the exact roles of NOD2 in CD and other NOD2-associated disorders remain poorly known.

Methods: We initially observed that NOD2 expression was increased in epithelial cells away from inflamed areas in CD patients. To explore this finding, Nod2 mRNA expression, inflammation, and cytokines expression were examined in the small bowel of wild-type [WT], Nod2 knockout and Nod2 mutant mice after rectal instillation of 2,4,6-trinitrobenzene sulphonic acid [TNBS].

Results: In WT mice, Nod2 upregulation upstream to rectal injury was associated with pro-inflammatory cytokine expression but no overt histological inflammatory lesions. Conversely, in Nod2-deficient mice the inflammation spread from colitis to ileum and duodenum.

Conclusions: Nod2 protects the gut from colitis spreading to small intestine.
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http://dx.doi.org/10.1093/ecco-jcc/jjz196DOI Listing
June 2020

Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: a phase 2a, randomised, double-blind, placebo-controlled, parallel-group study.

Lancet Gastroenterol Hepatol 2019 12 4;4(12):960-970. Epub 2019 Sep 4.

Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Medical Centre, Amsterdam, Netherlands.

Background: Refractory coeliac disease type 2 is a rare subtype of coeliac disease with high mortality rates; interleukin 15 (IL-15) is strongly implicated in its pathophysiology. This trial aimed to investigate the effects of AMG 714, an anti-IL-15 monoclonal antibody, on the activity and symptoms of refractory coeliac disease type 2.

Methods: This was a randomised, double-blind, placebo-controlled, phase 2a study of adults with a confirmed diagnosis of refractory coeliac disease type 2. Patients were randomly assigned at a 2:1 ratio to receive seven intravenous doses over 10 weeks of AMG 714 (8 mg/kg) or matching placebo. Biopsy samples were obtained at baseline and week 12 for cellular analysis and histology. The change in the proportion of aberrant intraepithelial lymphocytes from baseline to week 12 with respect to all intraepithelial lymphocytes was the primary endpoint and was quantified using flow cytometry. Secondary endpoints were the change in aberrant intraepithelial lymphocytes with respect to intestinal epithelial cells; intestinal histological scores (villous height-to-crypt depth ratio; VHCD); intraepithelial lymphocyte counts; Marsh score; and patient-reported symptom measures, including the Bristol stool form scale (BSFS) and gastrointestinal symptom rating scale (GSRS). Main analyses were done in the per-protocol population of patients who received their assigned treatment, provided evaluable biopsy samples, and did not have major protocol deviations; only patients with non-atypical disease were included in the analyses of aberrant intraepithelial lymphocytes, including the primary analysis. Safety was assessed in all patients who received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02633020) and EudraCT (2015-004063-36).

Findings: From April 13, 2016, to Jan 19, 2017, 28 patients were enrolled and randomly assigned to AMG 714 (n=19) and placebo (n=9). Six patients were not included in the primary analysis because of protocol deviation (one in the AMG 714 group), insufficient biopsy samples (one in the AMG 714 group), and atypical intraepithelial lymphocytes (three in the AMG 714 group and one in the placebo group). At 12 weeks, the least square mean difference between AMG 714 and placebo in the relative change from baseline in aberrant intraepithelial lymphocyte percentage was -4·85% (90% CI -30·26 to 20·56; p=0·75). The difference between the AMG 714 and placebo groups in aberrant intraepithelial lymphocytes with respect to epithelial cells at 12 weeks was -38·22% (90% CI -95·73 to 19·29; nominal p=0·18); the difference in change in Marsh score from baseline was 0·09% (95% CI -1·60-1·90; nominal p=0·92); the difference in VHCD ratio was 10·67% (95% CI -38·97 to 60·31; nominal p=0·66); and the difference in change in total intraepithelial lymphocyte count was -12·73% (95% CI -77·57-52·12); nominal p=0·69). Regarding symptoms, the proportion of patients with diarrhoea per the BSFS score decreased from ten (53%) of 19 at baseline to seven (37%) of 19 at week 12 in the AMG 714 group and increased from two (22%) of nine at baseline to four (44%) of nine at week 12 in the placebo group (nominal p=0·0008); and the difference between the groups in change in GSRS score was -0·14 (SE 0·19; nominal p=0·48). Eight (89%) patients in the placebo group and 17 (89%) in the AMG 714 group had treatment-emergent adverse events, including one (11%) patient in the placebo group and five (26%) in the AMG 714 group who had serious adverse events. The most common adverse event in the AMG 714 group was nasopharyngitis (eight [42%] patients vs one [11%] in the placebo group).

Interpretation: In patients with refractory coeliac disease type 2 who were treated with AMG 714 or placebo for 10 weeks, there was no difference between the groups in terms of the primary endpoint of aberrant intraepithelial lymphocyte reduction from baseline. Effects on symptoms and other endpoints suggest that further research of AMG 714 may be warranted in patients with refractory coeliac disease type 2.

Funding: Celimmune and Amgen.
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http://dx.doi.org/10.1016/S2468-1253(19)30265-1DOI Listing
December 2019

Microbiology and immunology: An ideal partnership for a tango at the gut surface-A tribute to Philippe Sansonetti.

Cell Microbiol 2019 11 26;21(11):e13097. Epub 2019 Aug 26.

Laboratory of Intestinal Immunity, INSERM UMR 1163, Institut Imagine, Paris, France.

Over the past 20 years, the highly dynamic interactions that take place between hosts and the gut microbiota have emerged as a major determinant in health and disease. The complexity of the gut microbiota represents, however, a considerable challenge, and reductionist approaches are indispensable to define the contribution of individual bacteria to host responses and to dissect molecular mechanisms. In this tribute to Philippe Sansonetti, I would like to show how rewarding collaborations with microbiologists have guided our team of immunologists in the study of host-microbiota interactions and, thanks to the use of controlled colonisation experiments in gnotobiotic mice, toward the demonstration that segmented filamentous bacteria (SFB) are indispensable to drive the post-natal maturation of the gut immune barrier in mice. The work led with Philippe Sansonetti to set up in vitro culture conditions has been one important milestone that laid the ground for in-depth characterization of the molecular attributes of this unusual symbiont. Recent suggestions that SFB may be present in the human microbiota encourage further cross-fertilising interactions between microbiologists and immunologists to define whether results from mice can be translated to humans and, if so, how SFB may be used to promote human intestinal defences against enteropathogens. Nurturing the competences to pursue this inspiring project is one legacy of Philippe Sansonetti.
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http://dx.doi.org/10.1111/cmi.13097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027583PMC
November 2019

Recent advances in celiac disease and refractory celiac disease.

F1000Res 2019 26;8. Epub 2019 Jun 26.

Université Paris Descartes, Paris, France.

Celiac disease (CeD), defined as gluten-induced enteropathy, is a frequent and largely underdiagnosed disease. Diagnosis relies on the detection of highly specific serum IgA anti-transglutaminase auto-antibodies and on the demonstration of duodenal villous atrophy. Treatment necessitates a strict gluten-free diet, which resolves symptoms and enables histological recovery. However, regular follow-up is necessary to assess mucosal healing, which emerges as an important prognostic factor. Recent work on CeD pathogenesis has highlighted how the cross-talk between gluten-specific CD4 T cells and interleukin-15 can activate cytotoxic intraepithelial lymphocytes and trigger epithelial lesions. Moreover, acquisition by a subset of intraepithelial lymphocytes of somatic gain-of-function mutations in the JAK-STAT pathway was shown to be a decisive step in the progression toward lymphomas complicating CeD, thus opening new therapeutic perspectives for these rare but life-threatening complications.
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http://dx.doi.org/10.12688/f1000research.18701.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600866PMC
June 2020

Scratching Beneath the Surface: Linking Skin Pathology with Food Allergy.

Immunity 2019 05;50(5):1124-1126

INSERM U1163 and Institut Imagine, Laboratory of Intestinal Immunity, 75015 Paris, France; Université de Paris, 75006 Paris, France. Electronic address:

A link between atopic dermatitis and food allergy has long been suspected but remains elusive. In this issue, Leyva-Castillo et al. (2019) show how mechanical injury of the skin initiates a cascade of events that stimulate the expansion of mucosal mast cells and promote food anaphylaxis.
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http://dx.doi.org/10.1016/j.immuni.2019.04.013DOI Listing
May 2019

A Weaning Reaction to Microbiota Is Required for Resistance to Immunopathologies in the Adult.

Immunity 2019 05 19;50(5):1276-1288.e5. Epub 2019 Mar 19.

Microenvironment & Immunity Unit, Institut Pasteur, 75724 Paris, France; INSERM U1224, 75724 Paris, France. Electronic address:

Microbes colonize all body surfaces at birth and participate in the development of the immune system. In newborn mammals, the intestinal microbiota is first shaped by the dietary and immunological components of milk and then changes upon the introduction of solid food during weaning. Here, we explored the reactivity of the mouse intestinal immune system during the first weeks after birth and into adulthood. At weaning, the intestinal microbiota induced a vigorous immune response-a "weaning reaction"-that was programmed in time. Inhibition of the weaning reaction led to pathological imprinting and increased susceptibility to colitis, allergic inflammation, and cancer later in life. Prevention of this pathological imprinting was associated with the generation of RORγt regulatory T cells, which required bacterial and dietary metabolites-short-chain fatty acids and retinoic acid. Thus, the weaning reaction to microbiota is required for immune ontogeny, the perturbation of which leads to increased susceptibility to immunopathologies later in life.
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http://dx.doi.org/10.1016/j.immuni.2019.02.014DOI Listing
May 2019

Microbiota Sensing by Mincle-Syk Axis in Dendritic Cells Regulates Interleukin-17 and -22 Production and Promotes Intestinal Barrier Integrity.

Immunity 2019 02 29;50(2):446-461.e9. Epub 2019 Jan 29.

Immunobiology Laboratory, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, Madrid 28029, Spain. Electronic address:

Production of interleukin-17 (IL-17) and IL-22 by T helper 17 (Th17) cells and group 3 innate lymphoid cells (ILC3s) in response to the gut microbiota ensures maintenance of intestinal barrier function. Here, we examined the mechanisms whereby the immune system detects microbiota in the steady state. A Syk-kinase-coupled signaling pathway in dendritic cells (DCs) was critical for commensal-dependent production of IL-17 and IL-22 by CD4 T cells. The Syk-coupled C-type lectin receptor Mincle detected mucosal-resident commensals in the Peyer's patches (PPs), triggered IL-6 and IL-23p19 expression, and thereby regulated function of intestinal Th17- and IL-17-secreting ILCs. Mice deficient in Mincle or with selective depletion of Syk in CD11c cells had impaired production of intestinal RegIIIγ and IgA and increased systemic translocation of gut microbiota. Consequently, Mincle deficiency led to liver inflammation and deregulated lipid metabolism. Thus, sensing of commensals by Mincle and Syk signaling in CD11c cells reinforces intestinal immune barrier and promotes host-microbiota mutualism, preventing systemic inflammation.
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http://dx.doi.org/10.1016/j.immuni.2018.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382412PMC
February 2019

Efficacy of Ruxolitinib Therapy in a Patient With Severe Enterocolitis Associated With a STAT3 Gain-of-Function Mutation.

Gastroenterology 2019 03 15;156(4):1206-1210.e1. Epub 2018 Dec 15.

Inserm UMR1163, Intestinal Immunity, Institut Imagine, Paris, France; Université Paris Descartes Sorbonne Paris Cité, Paris, France; AP-HP, Gastroenterology, Hôpital Cochin, Paris, France. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2018.11.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433619PMC
March 2019

NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study.

Gut 2019 08 17;68(8):1396-1405. Epub 2018 Nov 17.

Clinical Haematology, Necker-Enfants Malades University Hospital, AP-HP, Paris, France.

Objectives: Primary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs).

Design: NKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested in human primary tumour cells isolated from fresh duodenal biopsies.

Results: NKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of >25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL .

Conclusion: NKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.
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http://dx.doi.org/10.1136/gutjnl-2018-317371DOI Listing
August 2019

Copy number variations and founder effect underlying complete IL-10Rβ deficiency in Portuguese kindreds.

PLoS One 2018 26;13(10):e0205826. Epub 2018 Oct 26.

INSERM, UMR1163 and Institut Imagine, Laboratory of Intestinal Immunity, Paris, France.

Mutations in interleukin-10 receptor (IL-10R) genes are one cause of very early-onset inflammatory bowel disease with perianal lesions, which can be cured by hematopoietic stem cell transplantation. Using a functional test, which assesses responsiveness of peripheral monocytes to IL-10, we identified three unrelated Portuguese patients carrying two novel IL-10RB mutations. In the three patients, sequencing of genomic DNA identified the same large deletion of exon 3 which precluded protein expression. This mutation was homozygous in two patients born from consanguineous families and heterozygous in the third patient born from unrelated parents. Microsatellite analysis of the IL10RB genomic region revealed a common haplotype in the three Portuguese families pointing to a founder deletion inherited from a common ancestor 400 years ago. In the third patient, surface expression of IL-10R was normal but signaling in response to IL-10 was impaired. Complementary DNA sequencing and next-generation sequencing of IL10RB locus with custom-made probes revealed a ≈ 6 Kb duplication encompassing the exon 6 which leads to a frameshift mutation and a loss of the TYK2-interacting Box 2 motif. Altogether, we describe two novel copy number variations in IL10RB, one with founder effect and one preserving cell surface expression but abolishing signaling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205826PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203366PMC
April 2019

Feline low-grade alimentary lymphoma: an emerging entity and a potential animal model for human disease.

BMC Vet Res 2018 Oct 11;14(1):306. Epub 2018 Oct 11.

Internal Medicine Department, Université Paris-Est, École Nationale Vétérinaire d'Alfort, 7 Avenue du Général de Gaulle, 94700, Maisons-Alfort, France.

Background: Low-grade alimentary lymphoma (LGAL) is characterised by the infiltration of neoplastic T-lymphocytes, typically in the small intestine. The incidence of LGAL has increased over the last ten years and it is now the most frequent digestive neoplasia in cats and comprises 60 to 75% of gastrointestinal lymphoma cases. Given that LGAL shares common clinical, paraclinical and ultrasonographic features with inflammatory bowel diseases, establishing a diagnosis is challenging. A review was designed to summarise current knowledge of the pathogenesis, diagnosis, prognosis and treatment of feline LGAL. Electronic searches of PubMed and Science Direct were carried out without date or language restrictions.

Results: A total of 176 peer-reviewed documents were identified and most of which were published in the last twenty years. 130 studies were found from the veterinary literature and 46 from the human medicine literature. Heterogeneity of study designs and outcome measures made meta-analysis inappropriate. The pathophysiology of feline LGAL still needs to be elucidated, not least the putative roles of infectious agents, environmental factors as well as genetic events. The most common therapeutic strategy is combination treatment with prednisolone and chlorambucil, and prolonged remission can often be achieved. Developments in immunohistochemical analysis and clonality testing have improved the confidence of clinicians in obtaining a correct diagnosis between LGAL and IBD. The condition shares similarities with some diseases in humans, especially human indolent T-cell lymphoproliferative disorder of the gastrointestinal tract.

Conclusions: The pathophysiology of feline LGAL still needs to be elucidated and prospective studies as well as standardisation of therapeutic strategies are needed. A combination of conventional histopathology and immunohistochemistry remains the current gold-standard test, but clinicians should be cautious about reclassifying cats previously diagnosed with IBD to lymphoma on the basis of clonality testing. Importantly, feline LGAL could be considered to be a potential animal model for indolent digestive T-cell lymphoproliferative disorder, a rare condition in human medicine.
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http://dx.doi.org/10.1186/s12917-018-1635-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180644PMC
October 2018

A Single-Tube, EuroClonality-Inspired, TRG Clonality Multiplex PCR Aids Management of Patients with Enteropathic Diseases, including from Formaldehyde-Fixed, Paraffin-Embedded Tissues.

J Mol Diagn 2019 01 28;21(1):111-122. Epub 2018 Sep 28.

Hematology Laboratory, Necker-Enfants Malades Hosptial and Paris Descartes, Sorbonne Paris Cité University, Paris, France; Hematology Laboratory, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, France; INSERM UMR1151 and Institut Necker-Enfants Malades, Paris, France; Centre national Expert des Lymphomes Associés à la maladie Coeliaque, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, France. Electronic address:

Celiac disease is a chronic inflammation of the small intestine with villous atrophy that can become refractory to a gluten-free diet. Two categories of refractory celiac disease can be distinguished by the phenotype of intraepithelial lymphocytes and the status of TRG genes. Their distinction is important because 30% to 50% of type II but only 0% to 14% of type I evolve to an aggressive enteropathy-associated T-cell lymphoma and therefore require intensive treatment. Currently, differential diagnosis integrates immunohistochemistry, immunophenotyping, and TRG clonality analyses, but each has limitations. A single-tube multiplex TRG PCR (ECN) was prospectively compared to an in-house two-tube TRG PCR (N2T) in 73 samples, including 67 cryopreserved intestine tissues. Thirteen formalin-fixed, paraffin-embedded (FFPE) samples were also analyzed retrospectively. The ECN PCR had comparable efficiency to detect major clonal rearrangements in highly infiltrated tissues from T-cell lymphoproliferative disorders and type II refractory celiac disease and to detect the persistence of minor clones in type II refractory celiac disease follow-up samples. The ECN PCR abolished the risk of amplification of false-positive weak clonal rearrangements in cryopreserved specimens and allowed improved detection of clonal rearrangements in DNA from FFPE samples. The ECN PCR allows robust assessment of cryopreserved and FFPE digestive tissues at diagnosis and follow-up of enteropathies with villous atrophy, thus guiding therapeutic management.
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http://dx.doi.org/10.1016/j.jmoldx.2018.08.006DOI Listing
January 2019

Modulation of the gut microbiota to improve innate resistance.

Curr Opin Immunol 2018 10 8;54:137-144. Epub 2018 Sep 8.

INSERM UMR 1163, Institut Imagine, Laboratory of Intestinal Immunity, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75006 Paris, France. Electronic address:

One major benefit from the association of hosts with the complex microbial communities that establish at body surfaces is the resistance to pathogen infection. This protective role of symbiotic microbes is becoming ever more relevant, given the alarming rise of multidrug-resistant pathogens and severe infections in patients following extensive antibiotic treatment. Herein, we highlight some recent mechanistic studies that have provided insights into how the highly dynamic dialogue amongst intestinal bacteria and between intestinal bacteria and their host can contribute to protect the host against pathogens in and outside the gut. We then discuss how delineating the rules of this dialogue can help design strategies to modulate the microbiota and improve host resistance to infections.
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http://dx.doi.org/10.1016/j.coi.2018.08.003DOI Listing
October 2018

Inherited p40phox deficiency differs from classic chronic granulomatous disease.

J Clin Invest 2018 08 6;128(9):3957-3975. Epub 2018 Aug 6.

Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, and.

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.
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http://dx.doi.org/10.1172/JCI97116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118590PMC
August 2018

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study.

J Crohns Colitis 2018 Aug;12(9):1104-1112

GENIUS Group [GENetically ImmUne-mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN].

Background And Aims: An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment.

Methods: A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally.

Results: Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES.

Conclusions: Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.
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http://dx.doi.org/10.1093/ecco-jcc/jjy068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113703PMC
August 2018

Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis.

EMBO Mol Med 2018 04;10(4)

INSERM, UMR1163, Laboratory of Intestinal Immunity and Institut Imagine, Paris, France

Herein, we report the first identification of biallelic-inherited mutations in as a Mendelian cause of inflammatory bowel disease in two unrelated patients. encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all mutations were loss of function. mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate that mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.
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http://dx.doi.org/10.15252/emmm.201708483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887907PMC
April 2018

Human Gut Symbiont Promotes and Regulates Innate Immunity.

Front Immunol 2017 26;8:1166. Epub 2017 Sep 26.

Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom.

Objective: is a flagellated gut anaerobic bacterium belonging to the family within the Firmicutes phylum. A significant decrease of colonization in the gut of ulcerative colitis patients has recently been demonstrated. In this work, we have investigated the mechanisms of -host cross talk using both murine and models.

Design: The complete genome sequence of A2-183 was determined. C3H/HeN germ-free mice were mono-colonized with , and the host-microbe interaction was studied using histology, transcriptome analyses and FACS. Further investigations were performed and using the TLR5KO and DSS-colitis murine models.

Results: In the bacterium, , host gut colonization upregulated genes involved in conjugation/mobilization, metabolism, motility, and chemotaxis. In the host cells, bacterial colonization upregulated genes related to antimicrobial peptides, gut barrier function, toll-like receptors (TLR) signaling, and T cell biology. CD4CD25FoxP3 T cell numbers increased in the of both mono-associated and conventional mice treated with . Treatment with the bacterium provided protection against DSS-induced colitis. The role of flagellin in host-bacterium interaction was also investigated.

Conclusion: Mono-association of mice with bacteria results in specific bidirectional gene expression patterns. A set of genes thought to be important for host colonization are induced in , while the host cells respond by strengthening gut barrier function and enhancing Treg population expansion, possibly TLR5-flagellin signaling. Our data reveal the immunomodulatory properties of that could be useful for the control and treatment of gut inflammation.
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http://dx.doi.org/10.3389/fimmu.2017.01166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622956PMC
September 2017

Lactobacillus paracasei feeding improves immune control of influenza infection in mice.

PLoS One 2017 20;12(9):e0184976. Epub 2017 Sep 20.

Bioaster, Paris, France.

Respiratory tract infections such as flu cause severe morbidity and mortality and are among the leading causes of death in children and adults worldwide. Commensal microbiota is critical for orchestrating tissue homeostasis and immunity in the intestine. Probiotics represent an interesting source of immune modulators and several clinical studies have addressed the potential beneficial effects of probiotics against respiratory infections. Therefore, we have investigated the mechanisms of protection conferred by L. paracasei CNCM I-1518 strain in a mouse model of influenza infection. Notably, local myeloid cells accumulation is generated in the lungs after seven days feeding with L. paracasei prior to viral infection. L. paracasei-fed mice showed reduced susceptibility to the influenza infection, associated with less accumulation of inflammatory cells in the lungs, faster viral clearance and general health improvement. Interestingly, Allobaculum was significantly increased in L. paracasei-fed mice 7 days after influenza infection, even if the gut microbiota composition was not altered overall. L. paracasei-purified peptidoglycan partially recapitulated the protective phenotype observed with the entire bacteria. Collectively, our results demonstrate that oral consumption of L. paracasei CNCM I-1518 modulates lung immunity was associated with an improved control of influenza infection. These results further extend the beneficial role for certain lactobacilli to alleviate the burden of respiratory tract infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184976PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607164PMC
October 2017

A New Case of Congenital Malabsorptive Diarrhea and Diabetes Secondary to Mutant .

Pediatrics 2017 08;140(2)

Divisions of Nutrition.

Congenital diarrheal disorders are a group of rare enteropathies that often present with life-threatening diarrhea in the first weeks of life. Enteric anendocrinosis, characterized by a lack of intestinal enteroendocrine cells due to recessively inherited mutations in the () gene, has been described as a cause of congenital malabsorptive diarrhea. Diabetes mellitus also is typically associated with mutations, be it early onset or a later presentation. Here we report a case of a 16-year-old male patient with severe malabsorptive diarrhea from birth, who was parenteral nutrition dependent and who developed diabetes mellitus at 11 years old. To the best of our knowledge, only 9 cases of recessively inherited mutations have been reported in the literature to date. Our patient presents with several remarkable differences compared with previously published cases. This report can contribute by deepening our knowledge on new aspects of such an extremely rare disease.
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http://dx.doi.org/10.1542/peds.2016-2210DOI Listing
August 2017

First Identification of Biallelic Inherited DUOX2 Inactivating Mutations as a Cause of Very Early Onset Inflammatory Bowel Disease.

Gastroenterology 2017 08 3;153(2):609-611.e3. Epub 2017 Jul 3.

INSERM, UMR1163, Laboratory of Intestinal Immunity and Institut Imagine, Paris, France and GENIUS group from ESPGHAN and Université Paris Descartes-Sorbonne Paris Cité, Paris, France.

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http://dx.doi.org/10.1053/j.gastro.2016.12.053DOI Listing
August 2017