Genetic Diagnosis Guides Treatment of Autoimmune Enteropathy

Fabienne Charbit-Henrion¹, Manon Haas², Stanislas Chaussade³, Christophe Cellier⁴, Nadine Cerf-Bensussan⁵, Georgia Malamut⁶; Contributors from the AUTOIMMUNE ENTEROPATHY WORKING GROUP; Sherine Khater⁷, Anis Khiat⁸, Sascha Cording⁸, Marianna Parlato⁸, Marie-Agnès Dragon-Durey⁷, Frédéric Beuvon⁹, Nicole Brousse¹⁰, Benoît Terris⁹, Capucine Picard¹¹, Mathieu Fusaro¹¹, Frédéric Rieux-Laucat¹², Marie-Claude Stolzenberg¹², Anne-Sophie Jannot¹³, Alexis Mathian, Matthieu Allez¹⁴, Marion Malphettes¹⁵, Claire Fieschi¹⁵, Alexandre Aubourg¹⁶, Camille Zallot¹⁷, Xavier Roblin¹⁸, Vered Abitbol¹⁹, Arthur Belle²⁰, Pauline Wils²¹, Morgane Cheminant²², Tamara Matysiak-Budnik²³, Lucine Vuitton²⁴, Philippe Pouderoux²⁵, Laurent Abramowitz²⁶, Martin Castelle²⁷, Felipe Suarez²⁸, Olivier Hermine²², Frank Ruemmele²⁹, Luc Mouthon³⁰

Affiliations

¹ Université Paris Cité, INSERM UMR 1163 and Imagine Institute, Laboratory of Intestinal Immunity, Paris, France; Department of Molecular Genetics, AP-HP, Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
² Université Paris Cité, INSERM UMR 1163 and Imagine Institute, Laboratory of Intestinal Immunity, Paris, France; Department of Gastroenterology, AP-HP, Centre-Université Paris Cité, Hôpital Cochin, Paris, France.
³ Department of Gastroenterology, AP-HP, Centre-Université Paris Cité, Hôpital Cochin, Paris, France.
⁴ Department of Gastroenterology, AP-HP, Centre-Université Paris Cité, Hôpital Européen Georges Pompidou, Paris, France.
⁵ Université Paris Cité, INSERM UMR 1163 and Imagine Institute, Laboratory of Intestinal Immunity, Paris, France. Electronic address: nadine.cerf-bensussan@inserm.fr.
⁶ Université Paris Cité, INSERM UMR 1163 and Imagine Institute, Laboratory of Intestinal Immunity, Paris, France; Department of Gastroenterology, AP-HP, Centre-Université Paris Cité, Hôpital Cochin, Paris, France. Electronic address: georgia.malamut@aphp.fr.
⁷ Department of Immunology, AP-HP, Centre-Université Paris Cité, Hôpital Européen Georges Pompidou, Paris, France.
⁸ Université de Paris Cité, INSERM UMR 1163 and Imagine Institute, Laboratory of Intestinal Immunity, Paris, France.
⁹ Department of Pathology, AP-HP, Centre-Université Paris Cité, Hôpital Cochin, Paris, France.
¹⁰ Department of Pathology AP-HP, Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
¹¹ Study Center of Primary Immunodeficiency, AP-HP, Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
¹² Université de Paris, INSERM UMR1163 and Imagine Institute, Immunogenetics of Pediatric Autoimmune Diseases, Paris, France.
¹³ Department of Clinical Investigation and Clinical Epidemiology, AP-HP-Centre-Université Paris Cité, Hôpital Européen Georges Pompidou, Paris, France.
¹⁴ Department of Gastroenterology, AP-HP, Nord-Université Paris Cité, Hôpital Saint Louis, Paris, France.
¹⁵ Department of Clinical Immunology, AP-HP, Nord-Université Paris Cité, Hôpital Saint Louis, Paris, France.
¹⁶ Department of Gastroenterology, CHRU de Tours, Tours, France.
¹⁷ Department of Gastroenterology, CHRU de Nancy, Hôpitaux de Brabois, Nancy, France.
¹⁸ Department of Gastroenterology, CHU de Saint Etienne, Saint Etienne, France.
¹⁹ Department of Gastroenterology, AP-HP. Centre- Université de Paris, Hôpital Cochin, Paris, France.
²⁰ Department of Gastroenterology, AP-HP, Centre- Université de Paris, Hôpital Cochin, Paris, France.
²¹ Department of Gastroenterology, CHRU de Lille, Lille, France.
²² Department of Haematology, AP-HP, Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
²³ Department of Gastroenterology, CHRU de Nantes, Hôpital Hôtel Dieu, Nantes, France.
²⁴ Department of Gastroenterology, CHRU de Besançon, Hôpital Jean Minjoz, Besançon, France.
²⁵ Department of Gastroenterology, CHRU de Nîmes, Hôpital universitaire Carémeau, Nîmes, France.
²⁶ Department of Gastroenterology, AP-HP, Nord-Université Paris Cité, Hôpital Bichat, Paris, France.
²⁷ Department of Pediatric Immunology and Hematology, AP-HP, Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
²⁸ Department of Haematology, AP-HP. Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
²⁹ Université de Paris Cité, INSERM UMR 1163 and Imagine Institute, Laboratory of Intestinal Immunity and Department of Paediatric Gastroenterology, AP-HP-Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
³⁰ Service de Médecine Interne, Centre de Référence Maladies Autoimmunes Systémiques Rares d'Ile de France, AP-HP-Centre-Université Paris Cité, Hôpital Cochin, Paris, France.

PMID: 35944833
PMCID: PMC10165659
DOI: 10.1016/j.cgh.2022.07.030

Genetic Diagnosis Guides Treatment of Autoimmune Enteropathy

Fabienne Charbit-Henrion et al. Clin Gastroenterol Hepatol. 2023 May.

. 2023 May;21(5):1368-1371.e2.

doi: 10.1016/j.cgh.2022.07.030. Epub 2022 Aug 6.

Authors

Affiliations

¹ Université Paris Cité, INSERM UMR 1163 and Imagine Institute, Laboratory of Intestinal Immunity, Paris, France; Department of Molecular Genetics, AP-HP, Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
² Université Paris Cité, INSERM UMR 1163 and Imagine Institute, Laboratory of Intestinal Immunity, Paris, France; Department of Gastroenterology, AP-HP, Centre-Université Paris Cité, Hôpital Cochin, Paris, France.
³ Department of Gastroenterology, AP-HP, Centre-Université Paris Cité, Hôpital Cochin, Paris, France.
⁴ Department of Gastroenterology, AP-HP, Centre-Université Paris Cité, Hôpital Européen Georges Pompidou, Paris, France.
⁵ Université Paris Cité, INSERM UMR 1163 and Imagine Institute, Laboratory of Intestinal Immunity, Paris, France. Electronic address: nadine.cerf-bensussan@inserm.fr.
⁶ Université Paris Cité, INSERM UMR 1163 and Imagine Institute, Laboratory of Intestinal Immunity, Paris, France; Department of Gastroenterology, AP-HP, Centre-Université Paris Cité, Hôpital Cochin, Paris, France. Electronic address: georgia.malamut@aphp.fr.
⁷ Department of Immunology, AP-HP, Centre-Université Paris Cité, Hôpital Européen Georges Pompidou, Paris, France.
⁸ Université de Paris Cité, INSERM UMR 1163 and Imagine Institute, Laboratory of Intestinal Immunity, Paris, France.
⁹ Department of Pathology, AP-HP, Centre-Université Paris Cité, Hôpital Cochin, Paris, France.
¹⁰ Department of Pathology AP-HP, Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
¹¹ Study Center of Primary Immunodeficiency, AP-HP, Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
¹² Université de Paris, INSERM UMR1163 and Imagine Institute, Immunogenetics of Pediatric Autoimmune Diseases, Paris, France.
¹³ Department of Clinical Investigation and Clinical Epidemiology, AP-HP-Centre-Université Paris Cité, Hôpital Européen Georges Pompidou, Paris, France.
¹⁴ Department of Gastroenterology, AP-HP, Nord-Université Paris Cité, Hôpital Saint Louis, Paris, France.
¹⁵ Department of Clinical Immunology, AP-HP, Nord-Université Paris Cité, Hôpital Saint Louis, Paris, France.
¹⁶ Department of Gastroenterology, CHRU de Tours, Tours, France.
¹⁷ Department of Gastroenterology, CHRU de Nancy, Hôpitaux de Brabois, Nancy, France.
¹⁸ Department of Gastroenterology, CHU de Saint Etienne, Saint Etienne, France.
¹⁹ Department of Gastroenterology, AP-HP. Centre- Université de Paris, Hôpital Cochin, Paris, France.
²⁰ Department of Gastroenterology, AP-HP, Centre- Université de Paris, Hôpital Cochin, Paris, France.
²¹ Department of Gastroenterology, CHRU de Lille, Lille, France.
²² Department of Haematology, AP-HP, Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
²³ Department of Gastroenterology, CHRU de Nantes, Hôpital Hôtel Dieu, Nantes, France.
²⁴ Department of Gastroenterology, CHRU de Besançon, Hôpital Jean Minjoz, Besançon, France.
²⁵ Department of Gastroenterology, CHRU de Nîmes, Hôpital universitaire Carémeau, Nîmes, France.
²⁶ Department of Gastroenterology, AP-HP, Nord-Université Paris Cité, Hôpital Bichat, Paris, France.
²⁷ Department of Pediatric Immunology and Hematology, AP-HP, Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
²⁸ Department of Haematology, AP-HP. Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
²⁹ Université de Paris Cité, INSERM UMR 1163 and Imagine Institute, Laboratory of Intestinal Immunity and Department of Paediatric Gastroenterology, AP-HP-Centre-Université Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
³⁰ Service de Médecine Interne, Centre de Référence Maladies Autoimmunes Systémiques Rares d'Ile de France, AP-HP-Centre-Université Paris Cité, Hôpital Cochin, Paris, France.

PMID: 35944833
PMCID: PMC10165659
DOI: 10.1016/j.cgh.2022.07.030

No abstract available

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Figures

**Figure 1**
(A) Representative endoscopic aspects in patients with *CTLA4* variants and AIE. (1) Ulcerative gastritis with pseudobstruction in patient P9. (2) Duodenal villous atrophy in P1. (3) Colitis with ulcerations in P9. (B) Representative histologic lesions in patients with AIE. (1) Chronic fundic atrophic gastritis with intestinal metaplasia and focal low-grade dysplasia (×200) in P9 carrying a *CTLA4* variant. (2) Chronic duodenitis in P1 with *CTLA4* mutation with severe villous blunting and increased IEL numbers (×200). (3) Colitis with GVHD-like lesions and cryptic apoptotic bodies (×400) in a patient without identified pathogenic variant (description of numbered patients is provided in Supplementary Table 1). (C) Clinical features of the 48 patients with AIE. (D) Kaplan-Meier enteropathy-free survival curve of patients with (*solid line*) or without molecular diagnosis (*dashed line*). (E) Kaplan-Meier gastrointestinal malignant-free survival curve of patients with (*solid line*) or without molecular diagnosis (*dashed line*). (F) Number of patients for each individual molecular diagnosis. anti-TG2, antitransglutaminase of type 2; AI, autoimmune; AIE-75kDa, autoimmune enteropathy-related 75-kilodalton antibody; BMI, body mass index; C, colitis; IEL, intestinal intraepithelial hyperlymphocytosis; FLH, follicular lymphoid hyperplasia; G, gastritis; GI, gastrointestinal; GVHD, graft-versus-host disease; LPL, lamina propria hyperlymphocytosis; VA, villous atrophy.

**Supplementary Figure 1**
Functional validation of novel mutations. **(A):** RT-PCR of STAT3-target SOCS3 at baseline and in IL-21 activated-EBV cell lines of P3 and P4. Results are shown as relative expression normalized to RPLPO housekeeping gene and represent the mean of 6 independent experiments. ∗P < .05, ∗∗P < .01, ∗∗∗P < ,005 Mann-Whitney test; HC: results pooled from 2 healthy controls (HC1 in green, HC2 in blue), PC: positive control; **(B):** Decreased CTLA-4 mean fluorescence intensity (MFI) on circulating T-cells in P1, P7 and P20 as compared to healthy control (HC) by flow cytometry; **(C):** B-cell immunophenotyping in P8, showing decreased frequency of CD27+ and excess of CD21^lowCD38^low B-cells.

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Genetic Diagnosis Guides Treatment of Autoimmune Enteropathy

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Genetic Diagnosis Guides Treatment of Autoimmune Enteropathy

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