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BACKGROUND: Inborn errors of immunity are a growing group of disorders with a wide spectrum of genotypic and phenotypic profiles. CARMIL2 (previously named RLTPR) deficiency is a recently described cause of immune dysregulation, mainly presenting with allergy, mucocutaneous infections, and inflammatory bowel disease. CARMIL2 deficiency is categorized under diseases of immune dysregulation with susceptibility to lymphoproliferative conditions. CASE PRESENTATION: Here we describe a 29-years-old male from a consanguineous family, with food and sting allergy, allergic rhinitis, facial molluscum contagiosum (viral infection of the skin in the form of umbilicated papules), eosinophilia and highly elevated serum IgE level. Whole exome sequencing revealed numerous homozygous variants, including a CARMIL2 nonsense mutation, a gene regulating actin polymerization, and promoting cell protrusion formation. CONCLUSION: The selective role of CARMIL2 in T cell activation and maturation through cyto-skeletal organization is proposed to be the cause of immune dysregulation in individuals with CARMIL2 deficiency. CARMIL2 has an important role in immune pathways regulation, through cell maturation and differentiation, giving rise to a balance between Th1, Th2, and Th17 immune response. This case can improve the understanding of the different impacts of CARMIL2 mutations on immune pathways and further guide the diagnosis of patients with similar phenotypes.
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BACKGROUND: X-linked severe combined immunodeficiency is caused by IL2RG gene mutation. Several variations have been identified in the IL2RG gene, which potentially can prevent the production of nonfunctional proteins. Herein, a novel X-linked variant in the IL2RG gene is reported in twin brothers, associated with inflammatory bowel symptoms. CASE PRESENTATION: The patients were 26-month-old monozygotic twin middle-eastern males with failure to thrive and several inpatient admissions due to severe chronic nonbloody diarrhea that started at the age of 12 months. Pancolitis was revealed after performing upper and lower gastrointestinal endoscopies on the twin with more severe gastrointestinal symptoms. Flow cytometric evaluation of the peripheral blood cells showed low levels of CD4+ cells in both patients. Next generation sequencing-based gene panel test results of the two patients proved a novel heterozygous missense X-linked IL2RG mutation (70330011 A > G, p.Trp197Arg) in one of the patients, which was predicted to be deleterious (CADD score of 28), which soon after was confirmed by Sanger segregation in his twin brother. Both parents were wild types and had never experienced similar symptoms. The patients received an human leukocyte antigen (HLA)-matched cord blood transplant. The twin with more severe gastrointestinal symptoms died 1 month after transplantation. In his brother, watery diarrhea eventually subsided after transplantation. CONCLUSION: Intestinal involvement in X-linked severe combined immunodeficiency is a rare presentation that might be neglected. The increasing availability of genetic screening tests worldwide could be helpful for early detection of such lethal primary immunodeficiency diseases and in implementing effective interventions to handle the severe outcomes.
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Enfermedades Inflamatorias del Intestino , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X , Masculino , Humanos , Lactante , Preescolar , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética , Hermanos , Mutación , Enfermedades Inflamatorias del Intestino/genética , Diarrea/genética , Subunidad gamma Común de Receptores de Interleucina/genéticaRESUMEN
BACKGROUND: Severe Congenital Neutropenia type 4 (SCN4), is a rare autosomal recessive condition, due to mutations in the G6PC3 gene. The phenotype comprises neutropenia of variable severity and accompanying anomalies. CASE PRESENTATION: We report a male patient with confirmed G6PC3 deficiency presented with recurrent bacterial infections and multi-systemic complications. Our case was the first with a novel homozygous frameshift mutation in G6PC3. The patient demonstrated large platelets on his peripheral blood smear which is a rare presentation of this disease. CONCLUSION: As SCN4 patients could be easily missed, it is recommended to consider G6PC3 mutation for any case of congenital, unexplained neutropenia.
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BACKGROUND: Increasing evidence links genetic defects affecting actin-regulatory proteins to diseases with severe autoimmunity and autoinflammation, yet the underlying molecular mechanisms are poorly understood. Dedicator of cytokinesis 11 (DOCK11) activates the small Rho guanosine triphosphatase (GTPase) cell division cycle 42 (CDC42), a central regulator of actin cytoskeleton dynamics. The role of DOCK11 in human immune-cell function and disease remains unknown. METHODS: We conducted genetic, immunologic, and molecular assays in four patients from four unrelated families who presented with infections, early-onset severe immune dysregulation, normocytic anemia of variable severity associated with anisopoikilocytosis, and developmental delay. Functional assays were performed in patient-derived cells, as well as in mouse and zebrafish models. RESULTS: We identified rare, X-linked germline mutations in DOCK11 in the patients, leading to a loss of protein expression in two patients and impaired CDC42 activation in all four patients. Patient-derived T cells did not form filopodia and showed abnormal migration. In addition, the patient-derived T cells, as well as the T cells from Dock11-knockout mice, showed overt activation and production of proinflammatory cytokines that were associated with an increased degree of nuclear translocation of nuclear factor of activated T cell 1 (NFATc1). Anemia and aberrant erythrocyte morphologic features were recapitulated in a newly generated dock11-knockout zebrafish model, and anemia was amenable to rescue on ectopic expression of constitutively active CDC42. CONCLUSIONS: Germline hemizygous loss-of-function mutations affecting the actin regulator DOCK11 were shown to cause a previously unknown inborn error of hematopoiesis and immunity characterized by severe immune dysregulation and systemic inflammation, recurrent infections, and anemia. (Funded by the European Research Council and others.).
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Actinas , Anemia , Factores de Intercambio de Guanina Nucleótido , Inflamación , Animales , Humanos , Ratones , Actinas/genética , Actinas/metabolismo , Anemia/etiología , Anemia/genética , Modelos Animales de Enfermedad , Factores de Intercambio de Guanina Nucleótido/deficiencia , Factores de Intercambio de Guanina Nucleótido/genética , Hematopoyesis , Inflamación/etiología , Inflamación/genética , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
The nuclear factor of activated T cells (NFAT) family of transcription factors plays central roles in adaptive immunity in murine models; however, their contribution to human immune homeostasis remains poorly defined. In a multigenerational pedigree, we identified 3 patients who carry germ line biallelic missense variants in NFATC1, presenting with recurrent infections, hypogammaglobulinemia, and decreased antibody responses. The compound heterozygous NFATC1 variants identified in these patients caused decreased stability and reduced the binding of DNA and interacting proteins. We observed defects in early activation and proliferation of T and B cells from these patients, amenable to rescue upon genetic reconstitution. Stimulation induced early T-cell activation and proliferation responses were delayed but not lost, reaching that of healthy controls at day 7, indicative of an adaptive capacity of the cells. Assessment of the metabolic capacity of patient T cells revealed that NFATc1 dysfunction rendered T cells unable to engage in glycolysis after stimulation, although oxidative metabolic processes were intact. We hypothesized that NFATc1-mutant T cells could compensate for the energy deficit due to defective glycolysis by using enhanced lipid metabolism as an adaptation, leading to a delayed, but not lost, activation responses. Indeed, we observed increased 13C-labeled palmitate incorporation into citrate, indicating higher fatty acid oxidation, and we demonstrated that metformin and rosiglitazone improved patient T-cell effector functions. Collectively, enabled by our molecular dissection of the consequences of loss-of-function NFATC1 mutations and extending the role of NFATc1 in human immunity beyond receptor signaling, we provide evidence of metabolic plasticity in the context of impaired glycolysis observed in patient T cells, alleviating delayed effector responses.
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Factores de Transcripción NFATC , Linfocitos T , Humanos , Ratones , Animales , Linfocitos T/metabolismo , Factores de Transcripción NFATC/metabolismo , Linfocitos T CD8-positivos , Glucólisis/genética , MutaciónRESUMEN
BACKGROUND: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder. ICF1 is caused by bi-allelic mutations in the gene encoding deoxyribonucleic acid methyltransferase-3B (DNMT3B). Herein, we report a novel homozygous DNMT3B mutation in a patient with ICF1. CASE PRESENTATION: An eight-month-old Iranian Caucasian infant of consanguineous 1st-degree cousins presented to our clinic for evaluation of neutropenia. Physical examination was unremarkable except for low-set ears and a systolic cardiac murmur. He had a history of recurrent respiratory infections and oral thrush. Moreover, a collateral artery between the bronchial and pulmonary arteries was observed on the angiogram, mimicking a patent ductus arteriosus on the echocardiogram. Growth percentiles were normal; however, he had a neurodevelopmental delay. Family history was significant for a sibling who deceased at nine months of age after recurrent respiratory infections. Laboratory evaluation revealed a normal white blood cell count with neutropenia and normal bone marrow studies. He had hypogammaglobinemia with normal flow cytometric studies and was treated with prophylactic trimethoprim-sulfamethoxazole and itraconazole. After that, he was re-admitted three times due to recurrent episodes of pneumonia and an episode of pseudomonas aeruginosa meningitis. Currently, he is five years old and doing well on monthly intravenous immunoglobulin. Due to recurrent infections, hypogammaglobulinemia, and neutropenia, as well as a family history of consanguinity and a sibling who deceased during infancy, a primary immune deficiency was suspected. Genetic studies utilizing whole-exome sequencing demonstrated a homozygous missense mutation in DNMT3B (LRG_56t1:c.2008C>T; p.Arg670Trp) in the patient studied. The mutation has not been previously reported. CONCLUSION: We describe a novel homozygous DNMT3B mutation in an Iranian boy with ICF1. It is associated with recurrent infections, hypogammaglobinemia, neutropenia, mild facial anomalies, and a bronchopulmonary collateral artery.
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Síndromes de Inmunodeficiencia , Neutropenia , Enfermedades de Inmunodeficiencia Primaria , Infecciones del Sistema Respiratorio , Masculino , Lactante , Humanos , Preescolar , Metiltransferasas/genética , Irán , Reinfección , ADN (Citosina-5-)-Metiltransferasas/genética , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Mutación , ArteriasRESUMEN
BACKGROUND: Lymphoproliferative disorders include a heterogeneous list of conditions that commonly involve dysregulation of lymphocyte proliferation resulting in lymphadenopathy and bone marrow infiltration. These disorders have various presentations, most notably autoimmune manifestations, organomegaly, lymphadenopathy, dysgammaglobulinemia, and increased risk of chronic infections. CASE PRESENTATION: A young boy presented with symptoms overlapping different lymphoproliferative disorders, including episodes of chronic respiratory tract infections, dysgammaglobulinemia, lymphadenopathy-associated with splenomegaly as well as skin rashes. Genetic studies revealed multiple heterozygous variants, including a novel mutation in the NFκB1 gene. CONCLUSION: This novel mutation can reveal new aspects in the pathogenesis of lymphoproliferative disorders and propose new treatments for them.
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Disgammaglobulinemia , Linfadenopatía , Trastornos Linfoproliferativos , Disgammaglobulinemia/complicaciones , Humanos , Linfadenopatía/complicaciones , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/patología , Masculino , Mutación , Esplenomegalia/genéticaRESUMEN
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.
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Mutación de Línea Germinal , Proteómica , Células Germinativas , Humanos , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
BACKGROUND: Dedicator of Cytokinesis 8 (DOCK8) deficiency, the most frequent cause of autosomal recessive hyper immunoglobulin (Ig)E syndrome, is a rare combined immunodeficiency. OBJECTIVE: In this study, we report seven patients, with consanguineous parents, with five novel variants within the DOCK8 gene. METHODS: For genetic analysis, we performed Whole Exome Sequencing (WES) or targeted sequencing by means of Next-generation sequencing (NGS) for some of the patients. For others, Sanger sequencing, Fluorescence-activated cell sorting (FACS), or polymerase chain reaction (PCR) were used. RESULTS: We report five novel variants within the DOCK8 gene: three deletions (deletion of exons 4-12, 24-30, and 22-27), one frameshift (LRG_196:g.189315dup;p.(Leu1052Profs*7)), and a splice region variant (LRG_196t1:c.741+5G>T). Patients presented with skin lesions, food allergy, candidiasis, otitis, recurrent respiratory infections, short stature, aortic aneurism, gynecomastia, and coarse facial features. Patients had leukocytosis, eosinophilia, lymphopenia, and monocytosis, elevated IgE, IgG, IgA, reduced IgM and IgA levels. Patients had a low percentage of CD3+ and CD4+ cells and a high percentage of CD19+, CD27+CD19+, and recent thymic emigrants T cells. The percentage of natural killer cells was increased in one of the patients while it was decreased in another patient. One patient died due to disseminated intravascular coagulation after hematopoietic stem cell transplantation. CONCLUSION: We reported novel variants within the DOCK8 gene and highlighted the risk of aneurysms in these patients, which have been rarely reported in these patients.
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Factores de Intercambio de Guanina Nucleótido/genética , Síndrome de Job/genética , Adolescente , Niño , Preescolar , Consanguinidad , Análisis Mutacional de ADN , Femenino , Factores de Intercambio de Guanina Nucleótido/deficiencia , Humanos , Irán , Síndrome de Job/inmunología , Síndrome de Job/patología , Masculino , Mutación , Linaje , Secuenciación del ExomaRESUMEN
BACKGROUND: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms. OBJECTIVES: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions. METHODS: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs. RESULTS: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies-defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification. CONCLUSIONS: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities.
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Enfermedades Genéticas Congénitas/clasificación , Enfermedades del Sistema Inmune/clasificación , Enfermedades Raras/clasificación , Ontologías Biológicas , Humanos , FenotipoRESUMEN
Helios, a member of the Ikaros family of transcription factors, is predominantly expressed in developing thymocytes, activated T cells, and regulatory T cells (Tregs). Studies in mice have emphasized its role in maintenance of Treg immunosuppressive functions by stabilizing Foxp3 expression and silencing the Il2 locus. However, its contribution to human immune homeostasis and the precise mechanisms by which Helios regulates other T cell subsets remain unresolved. Here, we investigated a patient with recurrent respiratory infections and hypogammaglobulinemia and identified a germline homozygous missense mutation in IKZF2 encoding Helios (p.Ile325Val). We found that HeliosI325V retains DNA binding and dimerization properties but loses interaction with several partners, including epigenetic remodelers. Whereas patient Tregs showed increased IL-2 production, patient conventional T cells had decreased accessibility of the IL2 locus and consequently reduced IL-2 production. Reduced chromatin accessibility was not exclusive to the IL2 locus but involved a variety of genes associated with T cell activation. Single-cell RNA sequencing of peripheral blood mononuclear cells revealed gene expression signatures indicative of a shift toward a proinflammatory, effector-like status in patient CD8+ T cells. Moreover, patient CD4+ T cells exhibited a pronounced defect in proliferation with delayed expression of surface checkpoint inhibitors, suggesting an impaired onset of the T cell activation program. Collectively, we identified a previously uncharacterized, germline-encoded inborn error of immunity and uncovered a cell-specific defect in Helios-dependent epigenetic regulation. Binding of Helios with specific partners mediates this regulation, which is ultimately necessary for the transcriptional programs that enable T cell homeostasis in health and disease.
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Células Germinativas/inmunología , Factor de Transcripción Ikaros/inmunología , Adolescente , Epigénesis Genética/genética , Epigénesis Genética/inmunología , Humanos , Factor de Transcripción Ikaros/genética , Interleucina-2/biosíntesis , Masculino , Mutación Missense , Linfocitos T Reguladores/inmunologíaRESUMEN
Introduction and objectives: Severe combined immunodeficiency (SCID) is a subset of primary immunodeficiency diseases caused by a hereditary deficiency of the adaptive immune system. Mutation in recombination activating gene (RAG) is known as the underlying genetic cause of SCID. RAG protein plays a pivotal role in V(D)J recombination which is the main process to assemble lymphocyte antigen receptors during T- and B-cell development. The patients are characterized by recurrent infections, failure to thrive, chronic diarrhea, and fever, in early infancy. Herein, we present a case of SCID with rare neurological manifestations affected by a mutation in RAG1. Patients and methods: The patient was a 15-month-old infant born to a consanguineous family. She was presented with neurological abnormalities including facial nerve palsy, seizure, and decreased consciousness. Next-generation sequencing (NGS)-based primary immunodeficiency disease (PID)-gene panel screen and Sanger sequencing were performed to identify the genetic mutation. Results: We found a novel homozygous missense mutation in RAG1, c.1210C>T,p.Arg404Trp, which was predicted to be deleterious (combined annotation dependent depletion, CADD score of 27.4). Both parents were heterozygous carriers for this mutation. According to her laboratory data, both T cell and B cell numbers were decreased and the patient was diagnosed as RAG1- SCID. Conclusions: SCID is a pediatric emergency with a variety of manifestations in infants. Therefore, accurate diagnosis importantly in the case of rare manifestations must be considered in these patients. Our findings point toward the importance of genetic assessment for early diagnosis and timely treatment of this disorder (AU)
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Humanos , Femenino , Lactante , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genética , Proteínas de Homeodominio/genética , Enfermedades del Sistema Nervioso/genética , Homocigoto , Consanguinidad , LinajeRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes novel coronavirus disease (COVID-19), is the seventh pathogenic coronavirus recently discovered in December 2019 in Wuhan, China. To date, our knowledge about its effect on the human host remains limited. It is well known that host genetic factors account for the individual differences in the susceptibility to infectious diseases. The genetic susceptibility factors to COVID-19 and its severity are associated with several unanswered questions. However, the experience gained from an earlier strain of coronavirus, SARS-CoV-1, which shows 78% genetic similarity to SARS-CoV-2 and uses the same receptor to bind to host cells, could provide some clues. It, therefore, seems possible to assemble new evidence in order to solve a potential genetic predisposition puzzle for COVID-19. In this chapter, the puzzle pieces, including virus entry receptors, immune response, and inflammation-related genes, as well as the probable genetic predisposition models to COVID-19, are discussed.
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COVID-19 , Enfermedades Transmisibles , China/epidemiología , Predisposición Genética a la Enfermedad , Humanos , SARS-CoV-2RESUMEN
Introduction and objectives: X-linked agammaglobulinemia (XLA), the first known primary immunodeficiency, is caused by rare mutations in Brutons tyrosine kinase (BTK) gene. Mutations in the BTK gene lead to a failure in the development and maturation of B-cell linage. A decreased number of B-cells results in agammaglobulinemia and increased susceptibility to a variety of infections. Therefore, patients with XLA usually manifest with repetitive bacterial infections, such as upper respiratory tract infections, septic arthritis, osteomyelitis, and urinary tract infections, since their infancy. Patients We report a 17-year-old Iranian boy with XLA, referred to us with a history of severe and recurrent episodes of bacterial infections for a period of six years. Results Genetic analysis using the whole Exome sequencing revealed a hemizygous missense mutation in the BTK gene (c.428 A > T, p.His143Leu). Conclusion To our knowledge, c.428 A > T has not been reported in the BTK gene (AU)
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Humanos , Masculino , Adolescente , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/genética , Agammaglobulinemia Tirosina Quinasa/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Análisis Mutacional de ADN , Pruebas Genéticas , LinajeRESUMEN
INTRODUCTION AND OBJECTIVES: X-linked agammaglobulinemia (XLA), the first known primary immunodeficiency, is caused by rare mutations in Bruton's tyrosine kinase (BTK) gene. Mutations in the BTK gene lead to a failure in the development and maturation of B-cell linage. A decreased number of B-cells results in agammaglobulinemia and increased susceptibility to a variety of infections. Therefore, patients with XLA usually manifest with repetitive bacterial infections, such as upper respiratory tract infections, septic arthritis, osteomyelitis, and urinary tract infections, since their infancy. PATIENTS: We report a 17-year-old Iranian boy with XLA, referred to us with a history of severe and recurrent episodes of bacterial infections for a period of six years. RESULTS: Genetic analysis using the whole Exome sequencing revealed a hemizygous missense mutation in the BTK gene (c.428 A > T, p.His143Leu). CONCLUSION: To our knowledge, c.428 A > T has not been reported in the BTK gene.
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Agammaglobulinemia Tirosina Quinasa/genética , Agammaglobulinemia/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Adolescente , Agammaglobulinemia/sangre , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/inmunología , Análisis Mutacional de ADN , Enfermedades Genéticas Ligadas al Cromosoma X/sangre , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Pruebas Genéticas , Humanos , Irán , Masculino , Mutación Missense , LinajeRESUMEN
Patients with primary immunodeficiency disease (PID) are not only vulnerable to mycobacterial disease, but are also more likely to develop adverse events following BCG vaccination. These events can range from regional disease (BCGitis) to disseminated disease (BCGosis). Chronic granulomatous disease (CGD), which is characterized by impaired leukocyte phagocytic function, is one of the many inherited PIDs that increase the body's susceptibility to recurrent bacterial and fungal infections. Here, we report a 6-year-old boy with no significant past medical history who presented with progressive lymphadenopathy six years after BCG vaccination. He was later diagnosed with CGD on further evaluation.
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We describe a cohort of 25 Iranian patients with infantile inflammatory bowel disease (IBD), 14 (56%) of whom had monogenic defects. After proper screening, patients were referred for whole exome sequencing (WES). Four patients had missense mutations in the IL10 RA, and one had a large deletion in the IL10 RB. Four patients had mutations in genes implicated in host:microbiome homeostasis, including TTC7A deficiency, and two patients with novel mutations in the TTC37 and NOX1. We found a novel homozygous mutation in the SRP54 in a deceased patient and the heterozygous variant in his sibling with a milder phenotype. Three patients had combined immunodeficiency: one with ZAP-70 deficiency (T+B+NK-), and two with atypical SCID due to mutations in RAG1 and LIG4. One patient had a G6PC3 mutation without neutropenia. Eleven of the 14 patients with monogenic defects were results of consanguinity and only 4 of them were alive to this date.
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Enfermedades Inflamatorias del Intestino/genética , Enfermedades de Inmunodeficiencia Primaria/genética , Preescolar , Estudios de Cohortes , Diarrea/genética , Femenino , Humanos , Lactante , Recién Nacido , Irán , Masculino , Mutación , Receptores de Interleucina-10/genética , Sistema de Registros , Secuenciación del ExomaRESUMEN
Coronavirus disease 2019 (COVID-19) pandemic is a global challenge. Several governments of the world have decided to take drastic actions in order to combat the spread of the disease, including the closing of air, maritime and land borders, as an extreme measure of isolation of each country/region. However, such measures had not prevented the disease from spreading globally; as COVID-19 has already spread in almost all countries. This virus's main victims are the healthcare personnel (HCP), who are physically and psychologically affected. The HCP serves as the first line of defense against this pandemic, what if we faced a significant loss in their number? And what if our HCP was going through a deep dark depression? The condition would be terrifying not only for now but also in the future. This raises the need for an intensified International collaboration, that mainly supports the HCP. We are throwing by challenging moments, and it is clear that social distancing, cooperation, hygiene awareness and abide by the recommendation and help of all governments, as well as obtaining the support of international organizations could be an excellent tool for preventing an increase in the number of cases, principally in countries and regions were COVID-19 is in the early stage of the epidemic. However, this is not the final solution for the current pandemic. An intensified global program, which mainly supports the HCP, then considers the other aspects of the COVID19 pandemic might bring this pandemic to a peaceful end.
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Betacoronavirus , Infecciones por Coronavirus/epidemiología , Transmisión de Enfermedad Infecciosa/prevención & control , Personal de Salud/organización & administración , Pandemias/prevención & control , Neumonía Viral/epidemiología , COVID-19 , Humanos , SARS-CoV-2RESUMEN
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 individuals 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 â¼30% 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.
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Ligando CD27/deficiencia , Enfermedades Genéticas Congénitas , Trasplante de Células Madre Hematopoyéticas , Síndromes de Inmunodeficiencia , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/deficiencia , Adolescente , Adulto , Aloinjertos , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/inmunología , Enfermedades Genéticas Congénitas/mortalidad , Enfermedades Genéticas Congénitas/terapia , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/mortalidad , Síndromes de Inmunodeficiencia/terapia , Lactante , Masculino , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The WAVE regulatory complex (WRC) is crucial for assembly of the peripheral branched actin network constituting one of the main drivers of eukaryotic cell migration. Here, we uncover an essential role of the hematopoietic-specific WRC component HEM1 for immune cell development. Germline-encoded HEM1 deficiency underlies an inborn error of immunity with systemic autoimmunity, at cellular level marked by WRC destabilization, reduced filamentous actin, and failure to assemble lamellipodia. Hem1-/- mice display systemic autoimmunity, phenocopying the human disease. In the absence of Hem1, B cells become deprived of extracellular stimuli necessary to maintain the strength of B cell receptor signaling at a level permissive for survival of non-autoreactive B cells. This shifts the balance of B cell fate choices toward autoreactive B cells and thus autoimmunity.