. 2023 Jun;151(6):1634-1645.

doi: 10.1016/j.jaci.2022.12.822. Epub 2023 Jan 10.

Late-onset enteric virus infection associated with hepatitis (EVAH) in transplanted SCID patients

Quentin Riller¹, Jacques Fourgeaud², Julie Bruneau³, Suk See De Ravin⁴, Grace Smith⁵, Mathieu Fusaro⁶, Samy Meriem⁷, Aude Magerus¹, Marine Luka⁸, Ghaith Abdessalem⁸, Ludovic Lhermitte⁹, Anne Jamet¹⁰, Emmanuelle Six¹¹, Alessandra Magnani¹², Martin Castelle¹³, Romain Lévy¹⁴, Mathilde M Lecuit¹³, Benjamin Fournier¹⁵, Sarah Winter¹⁵, Michaela Semeraro¹⁶, Graziella Pinto¹⁷, Hanène Abid¹⁸, Nizar Mahlaoui¹³, Nathalie Cheikh¹⁹, Benoit Florkin²⁰, Pierre Frange²¹, Eric Jeziorski²², Felipe Suarez²³, Françoise Sarrot-Reynauld²⁴, Dalila Nouar²⁵, Dominique Debray²⁶, Florence Lacaille²⁷, Capucine Picard²⁸, Philippe Pérot²⁹, Béatrice Regnault²⁹, Nicolas Da Rocha²⁹, Camille de Cevins³⁰, Laure Delage¹, Brieuc P Pérot³¹, Angélique Vinit³², Francesco Carbone³³, Camille Brunaud¹, Manon Marchais¹, Marie-Claude Stolzenberg¹, Vahid Asnafi⁹, Thierry Molina³⁴, Frédéric Rieux-Laucat¹, Luigi D Notarangelo⁴, Stefania Pittaluga³⁵, Jean Philippe Jais³⁶, Despina Moshous³⁷, Stephane Blanche¹⁵, Harry Malech⁴, Marc Eloit³⁸, Marina Cavazzana³⁹, Alain Fischer⁴⁰, Mickaël M Ménager³³, Bénédicte Neven⁴¹

Affiliations

¹ University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France.
² University of Paris Cité, Paris, France; Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France; Prise en Charge des Anomalies Congénitales et leur Traitement, Unit 7328, Imagine Institute, University of Paris Cité, Paris, France.
³ University of Paris Cité, Paris, France; Pathology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Imagine Institute, INSERM UMR 1163, Laboratory of Molecular Mechanisms of Hematologic Disorders and Therapeutic Implications, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
⁴ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
⁵ Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md.
⁶ Study Center for Primary Immunodeficiencies, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
⁷ Laboratory of Biostatistics, University of Paris Cité, Paris, France.
⁸ Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, France.
⁹ University of Paris Cité, Paris, France; Laboratory of Onco-Haematology, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; the Institut Necker-Enfants Malades (INEM), INSERM UMR 1151, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁰ University of Paris Cité, Paris, France; Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; the Institut Necker-Enfants Malades (INEM), INSERM UMR 1151, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹¹ University of Paris Cité, Paris, France; Laboratory of Human Lympho-Hematopoiesis, Imagine Institute, INSERM UMR 1163, Paris, France.
¹² Department of Biotherapy, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹³ Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁴ University of Paris Cité, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁵ University of Paris Cité, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁶ University of Paris Cité, Paris, France; Clinical Investigation Center, Clinical Research Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁷ Pediatric Endocrinology, Gynecology, Diabetology, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁸ University of Paris Cité, Paris, France; Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁹ Pediatric Hematology Oncology Unit, University Hospital of Besançon, Besançon, France.
²⁰ Immuno-Hémato-Rhumatologie Pédiatrique, Service de Pédiatrie, CHR Citadelle, Liege, Belgium.
²¹ University of Paris Cité, Paris, France; Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²² Department of Pediatrics, Infectious Diseases, and Immunology, University of Montpellier, CHU Montpellier, Montpellier, France.
²³ University of Paris Cité, Paris, France; Imagine Institute, INSERM UMR 1163, Laboratory of Molecular Mechanisms of Hematologic Disorders and Therapeutic Implications, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Hematology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²⁴ Service de Médecine Interne, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France.
²⁵ Service d'Immunologie Clinique et d'Allergologie, Centre Hospitalier Régional Universitaire, Tours, France.
²⁶ Pediatric Liver Unit, National Reference Center for Rare Diseases, Biliary Atresia and Genetic Cholestasis, Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare Liver, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²⁷ Gastroenterology-Hepatology-Nutrition Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²⁸ Study Center for Primary Immunodeficiencies, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Imagine Institute, INSERM UMR 1163, Paris, France.
²⁹ Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France; OIE Collaborating Center for the Detection and Identification in Humans of Emerging Animal Pathogens, Institut Pasteur, Paris, France.
³⁰ University of Paris Cité, Paris, France; Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, INSERM UMR 1163, Paris, France; Artificial Intelligence & Deep Analytics (AIDA) Group, Data & Data Science (DDS), Sanofi R&D, Chilly-Mazarin, France.
³¹ University of Paris Cité, Paris, France; Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, INSERM UMR 1163, Paris, France.
³² Sorbonne Université, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, Paris, France.
³³ University of Paris Cité, Paris, France; Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, France; Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, INSERM UMR 1163, Paris, France.
³⁴ University of Paris Cité, Paris, France; Pathology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
³⁵ National Cancer Institute, National Institutes of Health, Bethesda, Md.
³⁶ University of Paris Cité, Paris, France; Laboratory of Biostatistics, University of Paris Cité, Paris, France.
³⁷ University of Paris Cité, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le Cancer, Imagine Institute, INSERM UMR 1163, Paris, France.
³⁸ Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France; OIE Collaborating Center for the Detection and Identification in Humans of Emerging Animal Pathogens, Institut Pasteur, Paris, France; Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France.
³⁹ University of Paris Cité, Paris, France; Laboratory of Onco-Haematology, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Human Lympho-Hematopoiesis, Imagine Institute, INSERM UMR 1163, Paris, France.
⁴⁰ Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Collège de France, Paris, France.
⁴¹ University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address: benedicte.neven@aphp.fr.

PMID: 36638922
PMCID: PMC10336473
DOI: 10.1016/j.jaci.2022.12.822

Late-onset enteric virus infection associated with hepatitis (EVAH) in transplanted SCID patients

Quentin Riller et al. J Allergy Clin Immunol. 2023 Jun.

. 2023 Jun;151(6):1634-1645.

doi: 10.1016/j.jaci.2022.12.822. Epub 2023 Jan 10.

Authors

Affiliations

¹ University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France.
² University of Paris Cité, Paris, France; Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France; Prise en Charge des Anomalies Congénitales et leur Traitement, Unit 7328, Imagine Institute, University of Paris Cité, Paris, France.
³ University of Paris Cité, Paris, France; Pathology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Imagine Institute, INSERM UMR 1163, Laboratory of Molecular Mechanisms of Hematologic Disorders and Therapeutic Implications, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
⁴ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
⁵ Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md.
⁶ Study Center for Primary Immunodeficiencies, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
⁷ Laboratory of Biostatistics, University of Paris Cité, Paris, France.
⁸ Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, France.
⁹ University of Paris Cité, Paris, France; Laboratory of Onco-Haematology, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; the Institut Necker-Enfants Malades (INEM), INSERM UMR 1151, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁰ University of Paris Cité, Paris, France; Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; the Institut Necker-Enfants Malades (INEM), INSERM UMR 1151, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹¹ University of Paris Cité, Paris, France; Laboratory of Human Lympho-Hematopoiesis, Imagine Institute, INSERM UMR 1163, Paris, France.
¹² Department of Biotherapy, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹³ Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁴ University of Paris Cité, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁵ University of Paris Cité, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁶ University of Paris Cité, Paris, France; Clinical Investigation Center, Clinical Research Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁷ Pediatric Endocrinology, Gynecology, Diabetology, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁸ University of Paris Cité, Paris, France; Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁹ Pediatric Hematology Oncology Unit, University Hospital of Besançon, Besançon, France.
²⁰ Immuno-Hémato-Rhumatologie Pédiatrique, Service de Pédiatrie, CHR Citadelle, Liege, Belgium.
²¹ University of Paris Cité, Paris, France; Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²² Department of Pediatrics, Infectious Diseases, and Immunology, University of Montpellier, CHU Montpellier, Montpellier, France.
²³ University of Paris Cité, Paris, France; Imagine Institute, INSERM UMR 1163, Laboratory of Molecular Mechanisms of Hematologic Disorders and Therapeutic Implications, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Hematology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²⁴ Service de Médecine Interne, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France.
²⁵ Service d'Immunologie Clinique et d'Allergologie, Centre Hospitalier Régional Universitaire, Tours, France.
²⁶ Pediatric Liver Unit, National Reference Center for Rare Diseases, Biliary Atresia and Genetic Cholestasis, Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare Liver, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²⁷ Gastroenterology-Hepatology-Nutrition Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
²⁸ Study Center for Primary Immunodeficiencies, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Imagine Institute, INSERM UMR 1163, Paris, France.
²⁹ Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France; OIE Collaborating Center for the Detection and Identification in Humans of Emerging Animal Pathogens, Institut Pasteur, Paris, France.
³⁰ University of Paris Cité, Paris, France; Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, INSERM UMR 1163, Paris, France; Artificial Intelligence & Deep Analytics (AIDA) Group, Data & Data Science (DDS), Sanofi R&D, Chilly-Mazarin, France.
³¹ University of Paris Cité, Paris, France; Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, INSERM UMR 1163, Paris, France.
³² Sorbonne Université, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, Paris, France.
³³ University of Paris Cité, Paris, France; Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, France; Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, INSERM UMR 1163, Paris, France.
³⁴ University of Paris Cité, Paris, France; Pathology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
³⁵ National Cancer Institute, National Institutes of Health, Bethesda, Md.
³⁶ University of Paris Cité, Paris, France; Laboratory of Biostatistics, University of Paris Cité, Paris, France.
³⁷ University of Paris Cité, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le Cancer, Imagine Institute, INSERM UMR 1163, Paris, France.
³⁸ Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France; OIE Collaborating Center for the Detection and Identification in Humans of Emerging Animal Pathogens, Institut Pasteur, Paris, France; Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France.
³⁹ University of Paris Cité, Paris, France; Laboratory of Onco-Haematology, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Human Lympho-Hematopoiesis, Imagine Institute, INSERM UMR 1163, Paris, France.
⁴⁰ Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Collège de France, Paris, France.
⁴¹ University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address: benedicte.neven@aphp.fr.

PMID: 36638922
PMCID: PMC10336473
DOI: 10.1016/j.jaci.2022.12.822

Abstract

Background: Allogenic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are potentially curative treatments for severe combined immunodeficiency (SCID). Late-onset posttreatment manifestations (such as persistent hepatitis) are not uncommon.

Objective: We sought to characterize the prevalence and pathophysiology of persistent hepatitis in transplanted SCID patients (SCIDH+) and to evaluate risk factors and treatments.

Methods: We used various techniques (including pathology assessments, metagenomics, single-cell transcriptomics, and cytometry by time of flight) to perform an in-depth study of different tissues from patients in the SCIDH+ group and corresponding asymptomatic similarly transplanted SCID patients without hepatitis (SCIDH-).

Results: Eleven patients developed persistent hepatitis (median of 6 years after HSCT or GT). This condition was associated with the chronic detection of enteric viruses (human Aichi virus, norovirus, and sapovirus) in liver and/or stools, which were not found in stools from the SCIDH- group (n = 12). Multiomics analysis identified an expansion of effector memory CD8⁺ T cells with high type I and II interferon signatures. Hepatitis was associated with absence of myeloablation during conditioning, split chimerism, and defective B-cell function, representing 25% of the 44 patients with SCID having these characteristics. Partially myeloablative retransplantation or GT of patients with this condition (which we have named as "enteric virus infection associated with hepatitis") led to the reconstitution of T- and B-cell immunity and remission of hepatitis in 5 patients, concomitantly with viral clearance.

Conclusions: Enteric virus infection associated with hepatitis is related to chronic enteric viral infection and immune dysregulation and is an important risk for transplanted SCID patients with defective B-cell function.

Keywords: B-cell function; CD8(+) T cells; SCID; enteric virus; gene therapy; interferon; transplantation.

PubMed Disclaimer

Conflict of interest statement

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

Figures

**FIG 1.**
Late-onset hepatitis, failure to thrive, and concomitant immunophenotypic changes. Changes over time in laboratory and clinical variables for P1 (**A-C**), P5 (**G-I**), and P6 (**M-O**). *A, G*, and M, Serum transaminase levels (AST for aspartate aminotransferase in orange and ALT for alanine aminotransferase in blue) over time expressed as a multiple of the normal value. *B, H*, and N, Changes over time in CD4⁺ T-cell counts (*dark green*), CD8⁺ T-cell counts (*purple*), and percentage of naive CD4⁺ T cells among CD4⁺ T cells (*light green*). C and I, Weight (lower curve) and height (upper curve) changes over time. O, CT scan of the abdomen (axial view) of P6, 9 months after the onset of hepatitis. Histological assessments of liver biopsies from P1 (**D-F**), P5 (**J-L**), and P6 (P and Q). *D, J*, and P, Hematoxylin-eosin-saffron staining ×200. *E, K*, and Q, CD3 staining. F and L, CD8 staining.

**FIG 2.**
CyTOF analysis of PBMCs from the patients in the SCIDH+ and SCIDH− groups revealed a skewed phenotype for CD8⁺ T cells. A, A UMAP plot of cells after quality control, split by group, and colored according to the immune subsets identified after *FlowSOM and ConsensusClusterPlus* clustering (see this article’s Materials section in the Online Repository at www.jacionline.org). B, Scaled expression of CD38 on PBMCs split by group and visualized as a UMAP plot and a histogram of median CD38 expression. C, Scaled expression of HLA-DR on PBMCs split by group visualized as a UMAP plot and a histogram of median HLA-DR expression. The Mann-Whitney-Wilcoxon test was used to compare the median expression of CD38 and HLA-DR in the SCIDH+ and SCIDH− groups. *cDC*, Classical dendritic cells; CM, central memory; GD, gamma-delta; *MAITs*, mucosal-associated invariant T-cells, *pDC*, plasmacytoid dendritic cells; *UMAP*, uniform manifold approximation and projection for dimensionality reduction. *P < .05.

**FIG 3.**
scRNAseq analysis of PBMCs from patients in the SCIDH+ and SCIDH− groups and controls revealed an inflammatory CD8⁺ T-cell phenotype and strong IFN signatures. A, A principal-component analysis of pseudo-bulk transcriptomic expression of CD8⁺ T cells (green: controls; *blue*: SCIDH–; *brown:* SCIDH+). B, A volcano plot showing differentially expressed genes in CD8⁺ T cells (pseudo-bulk expression). The *red dots* correspond to genes above both the fold change threshold and the P value threshold. C, A histogram of the results of a gene ontology analysis (GO Biological Process 2021) for upregulated genes in CD8⁺ T cells from patients in the SCIDH+ group vs the SCIDH− group. D and E, A heatmap showing the mean of the module score for a published IFN-α response gene set (Fig 3, D) (MSigDB, Hallmark Interferon Alpha Response) and a published IFN-γ response gene set (Fig 3, E) (MSigDB, Hallmark Interferon Gamma Response) in each cluster, by group. F, A histogram showing the median expression of CD57 on CD8⁺ T cells, as assessed by CyTOF (*left panel*), and a dot plot showing the mean expression and the proportions of CD8⁺ T cells expressing the mentioned genes (scRNAseq, *right panel*) in samples from patients in the SCIDH+ and SCIDH− groups and controls. *cDC*, Classical dendritic cells; CM, central memory; *CTLA-4*, cytotoxic T lymphocyte–associated antigen 4; *CXCL13*, Chemokine (C-X-C motif) ligand 13; GD, gamma-delta; *MAITs*, mucosal-associated invariant T-cells; *pDC*, plasmacytoid dendritic cells; TIGIT, T-cell immunoreceptor with Ig and *ITIM* domain; *UMAP*, uniform manifold approximation and projection.

**FIG 4.**
Subclustering of CD8⁺ T cells enabled the identification of an ISG^high CD8⁺ T-cell cluster in the SCIDH+ group. A, A UMAP plot of CD8⁺ T cells subclustered from PBMCs. B, A boxplot showing the proportion of CD8⁺ T cells in cluster 6. C, A volcano plot showing upregulated and downregulated genes from cluster 6 (marker genes) vs all CD8⁺ T cells, as assessed by the Seurat *FindMarkers* function. D, A histogram showing the results of a gene ontology analysis (using GO Biological Process 2021 database and *EnrichR*) for marker genes in cluster 6. The top 10 enriched pathways are shown and ranked according to their combined score. E and F, A heatmap showing the mean of the module score for a published IFN-α response gene set (Fig 4, E) and for a published IFN-γ response gene set (Fig 4, F) in each cluster of CD8⁺ T cells separated by group. *UMAP*, Uniform manifold approximation and projection.

**FIG 5.**
Frequency and risk factors of hepatitis. A, A classification and regression tree analysis of the variables that best predicted the development of hepatitis. B, The cumulative probability of survival without developing hepatitis for the cohort. The vertical line indicates 2 years. *MAC*, Myeloablative conditioning; *RIC*, reduced-intensity conditioning (oral busulfan 8 mg/kg and cyclophosphamide 200 mg/kg only).

See this image and copyright information in PMC

References

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Late-onset enteric virus infection associated with hepatitis (EVAH) in transplanted SCID patients

Affiliations

Late-onset enteric virus infection associated with hepatitis (EVAH) in transplanted SCID patients

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical