Publications by authors named "Capucine Picard"

342 Publications

Alternative pathways for the development of lymphoid structures in humans.

Proc Natl Acad Sci U S A 2021 Jul;118(29)

INSERM UMR 1163, Institut Imagine, 75015 Paris, France;

Lymphoid tissue inducer (LTi) cells are critical for inducing the differentiation of most secondary lymphoid organs (SLOs) in mice. In humans, JAK3 and γc deficiencies result in severe combined immunodeficiency (SCIDs) characterized by an absence of T cells, natural killer cells, innate lymphoid cells (ILCs), and presumably LTi cells. Some of these patients have undergone allogeneic stem cell transplantation (HSCT) in the absence of myeloablation, which leads to donor T cell engraftment, while other leukocyte subsets are of host origin. By using MRI to look for SLOs in nine of these patients 16 to 44 y after HSCT, we discovered that SLOs were exclusively found in the three areas of the abdomen that drain the intestinal tract. A postmortem examination of a child with γc-SCID who had died 3.5 mo after HSCT showed corticomedullary differentiation in the thymus, T cell zones in the spleen, and the appendix, but in neither lymph nodes nor Peyer patches. Tertiary lymphoid organs were observed in the lung. No RAR-related orphan receptor-positive LTi cells could be detected in the existing lymphoid structures. These results suggest that while LTi cells are required for the genesis of most SLOs in humans, SLO in the appendix and in gut-draining areas, as well as tertiary lymphoid organs, can be generated likely by LTi cell-independent mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2108082118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307690PMC
July 2021

Two Monogenetic Disorders, Activated PI3-Kinase-δ Syndrome 2 and Smith-Magenis Syndrome, in One Patient: Case Report and a Literature Review of Neurodevelopmental Impact in Primary Immunodeficiencies Associated With Disturbed PI3K Signaling.

Front Pediatr 2021 24;9:688022. Epub 2021 Jun 24.

Université de Paris, Imagine Institute, Paris, France.

Activated PI3-kinase-δ syndrome 2 (APDS2) is caused by autosomal dominant mutations in the gene encoding the p85α, p55α, and p50α regulatory subunits. Most diagnosed APDS2 patients carry mutations affecting either the splice donor or splice acceptor sites of exon 11 of the gene responsible for an alternative splice product and a shortened protein. The clinical presentation of APDS2 patients is highly variable, ranging from mild to profound combined immunodeficiency features as massive lymphoproliferation, increased susceptibility to bacterial and viral infections, bronchiectasis, autoimmune manifestations, and occurrence of cancer. Non-immunological features such as growth retardation and neurodevelopmental delay have been reported for APDS2 patients. Here, we describe a patient suffering from an APDS2 associated with a Smith-Magenis syndrome (SMS), a complex genetic disorder affecting, among others, neurological manifestations and review the literature describing neurodevelopmental impacts in APDS2 and other PIDs/monogenetic disorders associated with dysregulated PI3K signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2021.688022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266209PMC
June 2021

Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency.

Front Immunol 2021 15;12:669943. Epub 2021 Jun 15.

San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.

Major Histocompatibility Complex (MHC) class II (MHCII) deficiency (MHCII-D), also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. Abnormal cross-talk with developing T cells due to the absence of MHCII expression likely leads to defects in thymic epithelial cells (TEC). However, the contribution of TEC alterations to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC in this disease. We observed an overall perturbation of thymic structure and function in both MHCII mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, we demonstrated that impairment of lymphostromal cross-talk in the thymus of MHCII mice affects mTEC maturation and promiscuous gene expression and causes defects of central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential benefits of hematopoietic stem cell transplantation in MHCII deficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.669943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239840PMC
June 2021

Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance.

J Exp Med 2021 Aug 17;218(8). Epub 2021 Jun 17.

Garvan Institute of Medical Research, Darlinghurst, Australia.

Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20202592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217968PMC
August 2021

Current Spectrum of Infections in Patients with X-Linked Agammaglobulinemia.

J Clin Immunol 2021 Aug 21;41(6):1266-1271. Epub 2021 Apr 21.

Necker-Pasteur Center for Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Université de Paris, 149 Rue de Sèvres, 75015, Paris, France.

Outcome of patients with X-linked agammaglobulinemia (XLA) has improved with the widespread use of immunoglobulin replacement therapy (IgRT). There are few data on the spectrum of infections experienced by patients undergoing IgRT. We carried out a retrospective cross-sectional analysis of the records of XLA patients seen at Necker-Enfants Malades Hospital, Paris. For each infection, we evaluated infection site, microbial etiology, antibiotic prophylaxis, immunosuppressive treatment, IgRT route, and last known IgG trough level. Sixty patients were included, who cumulated a follow-up of 1470 patient-years. We recorded 188 infections, including 97 after initiation of IgRT. The rate of infection was highest before IgRT (0.66 vs. 0.06 per person-year (ppy), p < 0.001) and was higher after the age of 16 compared to before (0.14 vs. 0.05 ppy, p = 0.048). It was similar for patients receiving intravenous or subcutaneous Ig (0.09 vs 0.05 ppy, p = 0.54). The lungs and gastrointestinal tract accounted for 71% of infection sites. Forty-six (47%) infections occurred in patients receiving antibiotic prophylaxis. Sixteen (16.5%) infections occurred in patients receiving immunosuppressive therapy, which more frequently occurred after age 16 (35% vs. 2.4%, p < 0.001). The median IgG trough level prior to all infections was 8.4 g/L. Almost half (44.3%) of infections occurred with prior IgG trough levels > 8 g/L, and 16/97 (16.7%) in patients with trough levels > 10 g/L. Infection remains a significant issue in patients with XLA undergoing IgRT despite adequate IgG trough levels. Chronic inflammatory manifestations of X-linked agammaglobulinemia and immunosuppressive therapies may be significant drivers of infection during adulthood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-021-01043-1DOI Listing
August 2021

A New Missense Mutation in CD79B Leads to Autosomal Recessive Agammaglobulinemia in Two Siblings.

J Clin Immunol 2021 Aug 17;41(6):1356-1360. Epub 2021 Mar 17.

Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children - Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-021-01022-6DOI Listing
August 2021

Hemophagocytic Lymphohistiocytosis Gene Mutations in Adult Patients Presenting With CLIPPERS-Like Syndrome.

Neurol Neuroimmunol Neuroinflamm 2021 05 3;8(3). Epub 2021 Mar 3.

From the Department of Neurology (G.T., P.L.), CHU Montpellier, Hospital Gui de Chauliac; Pôle de Neurosciences Cliniques (E.K.), CHU Timone, Assistance Publique Hôpitaux de Marseille; Clinical Research and Epidemiology Unit (C.D.), CHU Montpellier, University Montpellier; Unité de recherche clinique côte d'azur UR2CA (URRIS) (C.L.-F.), CRCSEP Nice; Department of Pathology (V.R.), CHU Montpellier, Hospital Gui de Chauliac; Department of Neurology (E.T.), CHU Carémeau, Nîmes; Department of Neurology (E.D.-G.), CH Valenciennes; Department of Neurology (R.L.), Rouen University Hospital; APHP (K.H.-X.), Sorbonne Université, IHU, ICM, Department of Neurology Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris; Department of Neurology (S.C.), CH Gonesse; Department of Neurology (J.C.O.), CHU de Bordeaux; Department of Neuroradiology (N.M.C.), CHU Montpellier, Hospital Gui de Chauliac; Department of Neurology (C.T.), CHU Strasbourg; Université de Paris (C.P., M.F., F.E.S., G.S.B.), Imagine Institute, INSERM U 1163; Centre d'Etude des Déficits Immunitaires (C.P., M.F., G.S.B.), AP-HP, Hôpital Necker-Enfants Malades, Paris; and Centre national de la recherche scientifique (CNRS) (F.E.S.), Paris, France.

Objective: To determine whether adult cases of Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) may be related to familial hemophagocytic lymphohistiocytosis (HLH) causes, we have screened patients with adult-onset CLIPPERS for mutations in primary HLH-associated genes.

Methods: In our cohort of 36 patients fulfilling the criteria for probable or definite CLIPPERS according to the CLIPPERS-2017 criteria, we conducted a first study on 12 patients who consented to genetic testing. In these 12 patients, systemic HLH criteria were searched, and genetic analysis of 8 genes involved in primary HLH was performed.

Results: Four definite and 8 probable CLIPPERS were enrolled (n = 12). Mutations involved in HLH were identified in 2 definite and 2 probable CLIPPERS (4/12). Three of them had biallelic mutations with reduced perforin expression in natural killer cells. The remaining patient had biallelic mutations with cytotoxic lymphocyte impaired degranulation. None of the mutated patients reached the criteria for systemic HLH. During follow-up, 3 of them displayed atypical findings for CLIPPERS, including emergence of systemic non-Hodgkin lymphoma (1/3) and confluent gadolinium-enhancing lesions on brain MRI (3/3).

Conclusions: In our patients presenting with adult-onset CLIPPERS, one-third have HLH gene mutations. This genetic treatable condition should be searched in patients with CLIPPERS, especially in those presenting with atypical findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963436PMC
May 2021

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee.

J Clin Immunol 2021 Apr 18;41(3):666-679. Epub 2021 Feb 18.

Department of Immunology and Microbiology, Laboratory for Inborn Errors of Immunity, Department of Pediatrics, University Hospitals Leuven and KU Leuven, 3000, Leuven, Belgium.

The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-021-00980-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889474PMC
April 2021

Two Novel Homozygous Mutations in Phosphoglucomutase 3 Leading to Severe Combined Immunodeficiency, Skeletal Dysplasia, and Malformations.

J Clin Immunol 2021 Jul 3;41(5):958-966. Epub 2021 Feb 3.

INSERM UMR1163, Imagine Institute, Université de Paris, Paris, France.

Phosphoglucomutase 3 (PGM3) deficiency is a rare congenital disorder of glycosylation. Most of patients with autosomal recessive hypomorphic mutations in PGM3 encoding for phosphoglucomutase 3 present with eczema, skin and lung infections, elevated serum IgE, as well as neurological and skeletal features. A few PGM3-deficient patients suffer from a more severe disease with nearly absent T cells and severe skeletal dysplasia. We performed targeted next-generation sequencing on two kindred to identify the underlying genetic etiology of a severe combined immunodeficiency with developmental defect. We report here two novel homozygous missense variants (p.Gly359Asp and p.Met423Thr) in PGM3 identified in three patients from two unrelated kindreds with severe combined immunodeficiency, neurological impairment, and skeletal dysplasia. Both variants segregated with the disease in the two families. They were predicted to be deleterious by in silico analysis. PGM3 enzymatic activity was found to be severely impaired in primary fibroblasts and Epstein-Barr virus immortalized B cells from the kindred carrying the p.Met423Thr variant. Our findings support the pathogenicity of these two novel variants in severe PGM3 deficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-021-00985-wDOI Listing
July 2021

SARS-CoV-2 induces human plasmacytoid predendritic cell diversification via UNC93B and IRAK4.

J Exp Med 2021 04;218(4)

Université de Paris, Institut de Recherche Saint-Louis, Institut National de la Santé et de la Recherche Médicale U976, Hôpital Saint-Louis, Paris, France.

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20201387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849819PMC
April 2021

SARS-CoV-2 induces human plasmacytoid pre-dendritic cell diversification via UNC93B and IRAK4.

bioRxiv 2021 Jan 8. Epub 2021 Jan 8.

Université de Paris, Institut de Recherche Saint-Louis, INSERM U976, Hôpital Saint-Louis, 75010 Paris, France.

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here, we have isolated primary SARS-CoV-2 viral strains, and studied their interaction with human plasmacytoid pre-dendritic cells (pDC), a key player in antiviral immunity. We show that pDC are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.07.10.197343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805442PMC
January 2021

Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden.

Haematologica 2021 Jan 14. Epub 2021 Jan 14.

Pediatric Oncology Immunology Hematology Unit, Armand-Trousseau University Hospital, AP-HP, Paris.

Pediatric-onset Evans syndrome (pES) is defined by both immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) before the age of 18 years. There have been no comprehensive long-term studies of this rare disease, which can be associated to various immunopathological manifestations (IMs). We report outcomes of the 151 patients with pES and more than 5 years of follow-up from the nationwide French prospective OBS'CEREVANCE cohort. Median age at final follow-up was 18.5 (6.8-50.0) years and the median follow-up period was 11.3 (5.1-38.0) years. At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively. The frequency and number of clinical and biological IMs increased with age: at 20 years old, 74% had at least one clinical cIM. A wide range of cIMs occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IMs. The number of cIMs was associated with a subsequent increase in the number of second-line treatments received (other than steroids and immunoglobulins; hazard ratio, 1.4; 95% confidence interval, 1.15-1.60; p = 0.0002, Cox proportional hazards method). Survival at 15 years after diagnosis was 84%. Death occurred at a median age of 18 (1.7-31.5) years, and the most frequent cause was infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In conclusion, longterm outcomes of pES showed remission of cytopenias but frequent IMs linked to high secondline treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2020.271106DOI Listing
January 2021

Life-Saving, Dose-Adjusted, Targeted Therapy in a Patient with a STAT3 Gain-of-Function Mutation.

J Clin Immunol 2021 May 11;41(4):807-810. Epub 2021 Jan 11.

Pediatric Immunohematology and Rheumatology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), 149 rue de Sèvres, F-75015, Paris, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-020-00914-3DOI Listing
May 2021

Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency.

J Clin Invest 2021 Feb;131(3)

Garvan Institute of Medical Research, Sydney, New South Wales, Australia.

Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI142434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843233PMC
February 2021

Early-onset autoimmunity associated with SOCS1 haploinsufficiency.

Nat Commun 2020 10 21;11(1):5341. Epub 2020 Oct 21.

Service de Génétique, Hospices Civils de Lyon - GHE, and Institut Neuromyogène, CNRS UMR 5310 - INSERM U1217, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18925-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578789PMC
October 2020

IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation.

J Clin Immunol 2021 Jan 20;41(1):125-135. Epub 2020 Oct 20.

Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Science, 1-2-3 Kasumi, Minami-Ku, Hiroshima-Shi, Hiroshima, 734-8551, Japan.

IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition that is characterized by psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation. It typically occurs in adult females associated with tumors. Only a few infantile cases with anti-NMDAR encephalitis have been so far reported. We identified a 10-month-old boy with IRAK4 deficiency presenting with anti-NMDAR encephalitis and human herpes virus 6 (HHV6) reactivation. The diagnosis of IRAK4 deficiency was confirmed by the identification of compound heterozygous mutations c.29_30delAT (p.Y10Cfs*9) and c.35G>C (p.R12P) in the IRAK4 gene, low levels of IRAK4 protein expression in peripheral blood, and defective fibroblastic cell responses to TLR and IL-1 (TIR) agonist. We established a novel NF-κB reporter assay using IRAK4-null HEK293T, which enabled the precise evaluation of IRAK4 mutations. Using this system, we confirmed that both novel mutations identified in the patient are deleterious. Our study provides a new simple and reliable method to analyze IRAK4 mutant alleles. It also suggests the possible link between inborn errors of immunity and early onset anti-NMDAR encephalitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-020-00885-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846526PMC
January 2021

Rapid identification and characterization of infected cells in blood during chronic active Epstein-Barr virus infection.

J Exp Med 2020 11;217(11)

Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, Imagine Institute, Paris, France.

Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20192262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596820PMC
November 2020

Letter to the Editor: Coexistence of Autoimmune Lymphoproliferative Syndrome and Familial Mediterranean Fever.

Iran J Immunol 2020 06;17(2):172-174

Department of Pediatric Hematology, Dr. Behçet Uz Children's Hospital, Izmir, Turkey.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.22034/iji.2020.85774.1725DOI Listing
June 2020

DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity.

J Allergy Clin Immunol 2021 Feb 17;147(2):740-743.e9. Epub 2020 Jun 17.

Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut National de la Santé et de la Recherche Médicale (Inserm) UMR 1163, F-75015, Paris, France; Université de Paris, Imagine Institute, F-75015, Paris, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2020.05.052DOI Listing
February 2021

Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation.

JCI Insight 2020 03 12;5(5). Epub 2020 Mar 12.

Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, Imagine Institute, Paris, France.

Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. The CTPS1T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T cell leukemia fully abolished cell proliferation. Expression of CTPS1T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT CTPS1. This indicates that CTPS1T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1T566Dfs26X is completely attributable to protein instability. This study supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.133880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141395PMC
March 2020

Correction to: Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee.

J Clin Immunol 2020 Jan;40(1):65

Division of Allergy Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

The original version of this article unfortunately contained mistakes in reference numbers. The in-text citations and the references were mismatched. The original article has been corrected.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-020-00763-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645445PMC
January 2020

Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification.

J Clin Immunol 2020 01 11;40(1):66-81. Epub 2020 Feb 11.

Garvan Institute of Medical Research, Darlinghurst, Australia.

Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-020-00758-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082388PMC
January 2020

Infection in Humans With STAT3-Deficiency Is Associated With Defective Interferon-Gamma and Th17 Responses.

Front Immunol 2020 28;11:38. Epub 2020 Jan 28.

Unité des Aspergillus, Institut Pasteur, Paris, France.

In humans, loss-of-function mutation in the gene is frequently associated with susceptibility to bacterial as well as fungal infections including aspergillosis, although its pathogenesis remains largely unknown. In the present study, we investigated the immune responses obtained after stimulation with in STAT3-deficient patients. conidial killing efficiencies of both monocytes and neutrophils isolated from whole blood samples of STAT3-deficient patients were not different compared to those of healthy controls. After stimulation with conidia, lower concentrations of adaptive cytokines (IFN-γ, IL-17 and IL-22) were secreted by peripheral blood mononuclear cells from STAT3-deficient patients compared to those from healthy controls. Moreover, the frequency of IFN-γ and IL-17 producing CD4+ T cells was lower in STAT3-deficient patients vs. healthy controls. Among the STAT3-deficient patients, those with aspergillosis showed further lower secretion of IFN-γ upon stimulation of their PBMCs with conidia compared to the patients without aspergillosis. Together, our study indicated that STAT3-deficiency leads to a defective adaptive immune response against infection, particularly with a lower IFN-γ and IL-17 responses in those with aspergillosis, suggesting potential therapeutic benefit of recombinant IFN-γ in STAT3-deficient patients with aspergillosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997434PMC
February 2021

Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee.

J Clin Immunol 2020 01 17;40(1):24-64. Epub 2020 Jan 17.

Division of Allergy Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-019-00737-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082301PMC
January 2020

A gain-of-function RAC2 mutation is associated with bone-marrow hypoplasia and an autosomal dominant form of severe combined immunodeficiency.

Haematologica 2021 02 1;106(2):404-411. Epub 2021 Feb 1.

Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest,Assistance Publique.

Severe combined immunodeficiencies (SCIDs) constitute a heterogeneous group of life-threatening genetic disorders that typically present in the first year of life. They are defined by the absence of autologous T cells and the presence of an intrinsic or extrinsic defect in the B-cell compartment. In three newborns presenting with frequent infections and profound leukopenia, we identified a private, heterozygous mutation in the RAC2 gene (p.G12R). This mutation was de novo in the index case, who had been cured by hematopoietic stem cell transplantation but had transmitted the mutation to her sick daughter. Biochemical assays showed that the mutation was associated with a gain of function. The results of in vitro differentiation assays showed that RAC2 is essential for the survival and differentiation of hematopoietic stem/progenitor cells. Therefore, screening for RAC2 gain-of-function mutations should be considered in patients with a SCID phenotype and who lack a molecular diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2019.230250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849581PMC
February 2021

Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency.

Front Immunol 2019 7;10:2592. Epub 2019 Nov 7.

Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Paris, France.

Mutations in the tetratricopeptide repeat domain 7A (TTC7A) gene cause very early onset inflammatory bowel diseases (VOIBD) or multiple intestinal atresia associated with immune deficiency of various severities, ranging from combined immune deficiency to mild lymphopenia. In this manuscript, we report the clinical, biological and molecular features of a patient born from consanguineous parents, presenting with recurrent lymphoproliferative syndrome and pan-hypergammaglobulinemia associated with chronic intestinal pseudo obstruction (CIPO). Genetic screening revealed the novel c.974G>A (p.R325Q) mutation in homozygosity in the gene. The patient's phenotype differs significantly from that previously associated with TTC7A deficiency in humans. It becomes closer to the one reported in the ttc7a-deficient mice that invariably develop a proliferative lymphoid and myeloid disorder. Functional studies showed that the extreme variability in the clinical phenotype couldn't be explained by the cellular phenotype. Indeed, the patient's TTC7A mutation, as well as the murine-ttc7 mutant, have the same functional impact on protein expression, DNA instability and chromatin compaction, as the other mutations that lead to classical TTC7A-associated phenotypes. Co-inheritance of genetic variants may also contribute to the unique nature of the patient's phenotype. The present case report shows that the clinical spectrum of TTC7A deficiency is much broader than previously suspected. Our findings should alert the physicians to consider screening of mutations in patients with lymphoproliferative syndrome and hypergammaglobulinemia and/or chronic intestinal pseudo-obstruction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.02592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853864PMC
September 2020

BCG Moreau Vaccine Safety Profile and NK Cells-Double Protection Against Disseminated BCG Infection in Retrospective Study of BCG Vaccination in 52 Polish Children with Severe Combined Immunodeficiency.

J Clin Immunol 2020 01 20;40(1):138-146. Epub 2019 Nov 20.

Department of Paediatrics, Rheumatology, Immunology and Metabolic Bone Diseases, Medical University of Bialystok, Białystok, Poland.

Objectives: The aim of the study was to estimate the rate of adverse reactions to live BCG Moreau vaccine, manufactured by Biomed in Poland, in severe combined immunodeficiency (SCID) patients.

Material: The profiles of 52 SCID patients vaccinated at birth with BCG, hospitalized in Children's Memorial Health Institute, Warsaw (CMHI), in the years 1980-2015 were compared with those of 349 BCG-vaccinated SCID patients from other countries analyzed by Beatriz E. Marciano et al. in a retrospective study (Marciano et al. J Allergy Clin Immunol. 2014;133(4):1134-1141).

Results: Significantly less disseminated BCG infections (10 out of 52 SCID, 19%) occurred in comparison with Marciano study-119 out of 349, 34% (p = 0.0028), with no death in patients treated with SCID anti-TB drug, except one in lethal condition. In our study, disseminated BCG infection was observed only in SCID with T-B+NK- phenotype and significantly lower NK cell counts (p = 0.0161). NK cells do not influence on the frequency of local BCG reaction. A significantly higher number of hematopoietic stem cells transplantations (HSCT) were performed in CMHI study (p = 0.0001). Anti-TB treatment with at least two medicines was provided.

Conclusion: The BCG Moreau vaccine produced in Poland, with well-documented genetic characteristics, seems to be safer than other BCG substrains used in other regions of the world. Importantly, NK cells seem to play a role in protecting SCID patients against disseminated BCG complications, which NK- SCID patients are more prone to. HSCT and TB therapy could be relevant due to the patients' survival and the fact that they protect against BCG infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-019-00709-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082382PMC
January 2020
-->