ORCID Profile
0000-0001-8238-4391
Current Organisations
University of Trento
,
Université Pierre et Marie Curie
,
CNRS Délégation Paris B
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Publisher: American Society for Clinical Investigation
Date: 02-2021
DOI: 10.1172/JCI142434
Publisher: American Society of Hematology
Date: 27-02-2020
Abstract: Epstein-Barr virus (EBV) is an enigma on one hand, it infects and persists in latent form in the vast majority of the global population, causing relatively benign disease in otherwise healthy in iduals. On the other hand, EBV represents the first identified oncogenic virus, capable of causing ≥7 different types of malignancies, usually in immunocompromised in iduals. Furthermore, some in iduals with defined inborn errors of immunity exhibit extreme susceptibility to EBV-induced disease, developing severe and often fatal infectious mononucleosis, hemophagocytic lymphohistiocytosis, lymphoproliferative disease, and/or EBV+ B-cell lymphoma. Thus, host and pathogen have coevolved to enable viral persistence and survival with minimal collateral damage to the healthy host. However, acquired or genetic disruptions to host defense that tip the balance in favor of EBV can have catastrophic effects. The study of primary immunodeficiencies has provided opportunities to define nonredundant requirements for host defense against EBV infection. This has not only revealed mechanisms underlying EBV-induced disease in these primary immunodeficiencies but also identified molecules and pathways that could be targeted to enhance the efficacy of an EBV-specific vaccine or treat severe EBV infection and pathological consequences in immunodeficient hosts.
Publisher: American Society of Hematology
Date: 03-12-2020
Abstract: Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33 CD70, n = 16), including 24 previously unreported in iduals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 10-07-2020
Abstract: The WAVE regulatory complex (WRC) is a multiunit complex that regulates actin cytoskeleton formation. Although other actin-regulatory proteins modulate human immune responses, the precise role for the WRC has not yet been established. Cook et al. studied five patients from four unrelated families who harbor missense variants of the gene encoding the WRC component HEM1. These patients presented with recurrent infections and poor antibody responses, along with enhanced allergic and autoimmune disorders. HEM1 was found to be required for the regulation of cortical actin and granule release in T cells and also interacted with a key metabolic signaling complex contributing to the disease phenotype. By linking these interactions to immune function, this work suggests potential targets for future immunotherapies. Science , this issue p. 202
Publisher: Rockefeller University Press
Date: 20-04-2022
DOI: 10.1084/JEM.20220028
Abstract: Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-β). Remarkably, this IFNAR1 variant has a minor allele frequency & % in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in in iduals of Polynesian ancestry with severe viral illnesses.
Publisher: American Society for Clinical Investigation
Date: 12-03-2020
Publisher: MDPI AG
Date: 11-03-2013
DOI: 10.3390/IJGI2010201
Publisher: Rockefeller University Press
Date: 03-11-2022
DOI: 10.1084/JEM.20220484
Abstract: Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αβ T lymphocytopenia with a concomitant expansion of CD4−CD8− double-negative (DN) αβ and Vδ2− γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES− phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αβ T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients’ T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients’ total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ–producing T cell subsets, thereby underlying TB.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Springer Science and Business Media LLC
Date: 08-01-2012
DOI: 10.1007/S10875-011-9638-Z
Abstract: Deficiency of X-linked inhibitor of apoptosis (XIAP) caused by XIAP/BIRC4 gene mutations is an inherited immune defect recognized as X-linked lymphoproliferative syndrome type 2. This disease is mainly observed in patients with hemophagocytic lymphohistiocytosis (HLH) often associated with Epstein-Barr virus infection. We described nine Japanese patients from six unrelated families with XIAP deficiency and studied XIAP protein expression, XIAP gene analysis, invariant natural killer T (iNKT) cell counts, and the cytotoxic activity of CD8(+) alloantigen-specific cytotoxic T lymphocytes. Of the nine patients, eight patients presented with symptoms in infancy or early childhood. Five patients presented with recurrent HLH, one of whom had severe HLH and died after cord blood transplantation. One patient presented with colitis, as did another patient's maternal uncle, who died of colitis at 4 years of age prior to diagnosis with XIAP deficiency. Interestingly, a 17-year-old patient was asymptomatic, while his younger brother suffered from recurrent HLH and EBV infection. Seven out of eight patients showed decreased XIAP protein expression. iNKT cells from patients with XIAP deficiency were significantly decreased as compared with age-matched healthy controls. These results in our Japanese cohort are compatible with previous studies, confirming the clinical characteristics of XIAP deficiency.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2014
DOI: 10.1038/NATURE13386
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-07-0004
DOI: 10.1126/SCIIMMUNOL.ABQ3277
Abstract: High-level expression of the transcription factor T-bet characterizes a phenotypically distinct murine B cell population known as “age-associated B cells” (ABCs). T-bet–deficient mice have reduced ABCs and impaired humoral immunity. We describe a patient with inherited T-bet deficiency and largely normal humoral immunity including intact somatic hypermutation, affinity maturation and memory B cell formation in vivo, and B cell differentiation into Ig-producing plasmablasts in vitro. Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4, and IgE, along with reduced IgG2, both in vivo and in vitro. Moreover, T-bet was required for the in vivo and in vitro development of a distinct subset of human B cells characterized by reduced expression of CD21 and the concomitantly high expression of CD19, CD20, CD11c, FCRL5, and T-bet, a phenotype that shares many features with murine ABCs. Mechanistically, human T-bet governed CD21 lo CD11c hi B cell differentiation by controlling the chromatin accessibility of lineage-defining genes in these cells: FAS , IL21R , SEC61B , DUSP4 , DAPP1 , SOX5 , CD79B , and CXCR4 . Thus, human T-bet is largely redundant for long-lived protective humoral immunity but is essential for the development of a distinct subset of human CD11c hi CD21 lo B cells.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-08-2015
Abstract: The immune system needs its full array of soldiers—including cells and the molecules they secrete—to optimally protect the host. When this isn't the case, minor infections can become chronic or even deadly. Markle et al. report the discovery of seven in iduals carrying loss-of-function mutations in RORC, which encodes the transcription factors RORγ and RORγT. These in iduals lacked immune cells that produce the cytokine interleukin-17, causing them to suffer from chronic candidiasis. RORC-deficient in iduals also exhibited impaired immunity to mycobacterium, probably due to reduced production of the cytokine interferon-γ, a molecule not known to require RORC for its induction. Science , this issue p. 606
Publisher: Elsevier BV
Date: 03-2014
Publisher: American Society of Hematology
Date: 11-04-2022
DOI: 10.1182/BLOODADVANCES.2021006367
Abstract: Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3 encoding Ikaros and Aiolos have recently been identified in patients with phenotypically similar immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p.R291X)- and 4 distinct missense variants) in six patients with systemic lupus erythematosus, immune thrombocytopenia or EBV-associated hemophagocytic lymphohistiocytosis. Patients exhibited hypogammaglobulinemia, decreased number of T-follicular helper and NK cells. Single-cell RNA sequencing of PBMCs from the patient carrying the R291X variant revealed upregulation of proinflammatory genes associated with T-cell receptor activation and T-cell exhaustion. Functional assays revealed the inability of HeliosR291X to homodimerize and bind target DNA as dimers. Moreover, proteomic analysis by proximity-dependent Biotin Identification revealed aberrant interaction of 3/5 Helios mutants with core components of the NuRD complex conveying HELIOS-mediated epigenetic and transcriptional dysregulation.
Publisher: Italian Society of Sivilculture and Forest Ecology (SISEF)
Date: 10-2013
DOI: 10.3832/IFOR0897-006
Publisher: Elsevier BV
Date: 12-2012
No related grants have been discovered for Sylvain Latour.