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1.
J Allergy Clin Immunol ; 151(2): 572-578.e1, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36243222

RESUMEN

BACKGROUND: The type II transmembrane protein fibrinogen-like protein 2 (FGL2) plays critical roles in hemostasis and immune regulation. The C-terminal immunoregulatory domain of FGL2 can be secreted and is a mediator of regulatory T (Treg) cell suppression. Fgl2-/- mice develop autoantibodies and glomerulonephritis and have impaired Treg cell function. OBJECTIVE: Our aim was to identify the genetic underpinning and immune function in a patient with childhood onset of leukocytoclastic vasculitis, systemic inflammation, and autoantibodies. METHODS: Whole-exome sequencing was performed on patient genomic DNA. FGL2 protein expression was examined in HEK293 transfected cells by immunoblotting and in PBMCs by flow cytometry. T follicular helper cells and Treg cells were examined by flow cytometry. Treg cell suppression of T-cell proliferation was assessed in vitro. RESULTS: The patient had a homozygous mutation in FGL2 (c.614_617del:p.V205fs), which led to the expression of a truncated FGL2 protein that preserves the N-terminal domain but lacks the C-terminal immunoregulatory domain. The patient had an increased percentage of circulating T follicular helper and Treg cells. The patient's Treg cells had impaired in vitro suppressive ability that was rescued by the addition of full-length FGL2. Unlike full-length FGL2, the truncated FGL2V205fs mutant failed to suppress T-cell proliferation. CONCLUSIONS: We identified a homozygous mutation in FGL2 in a patient with immune dysregulation and impaired Treg cell function. Soluble FGL2 rescued the Treg cell defect, suggesting that it may provide a useful therapy for the patient.


Asunto(s)
Autoanticuerpos , Linfocitos T Reguladores , Ratones , Humanos , Animales , Células HEK293 , Activación de Linfocitos , Mutación , Fibrinógeno/genética , Fibrinógeno/metabolismo
2.
J Allergy Clin Immunol ; 152(3): 771-782, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37150360

RESUMEN

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) results in heterogeneous manifestations including systemic vasculitis and red cell aplasia. The basis of different disease phenotypes remains incompletely defined. OBJECTIVE: We sought to further delineate disease phenotypes in DADA2 and define the mechanistic basis of ADA2 variants. METHODS: We analyzed the clinical features and ADA2 variants in 33 patients with DADA2. We compared the transcriptomic profile of 14 patients by bulk RNA sequencing. ADA2 variants were expressed experimentally to determine impact on protein production, trafficking, release, and enzymatic function. RESULTS: Transcriptomic analysis of PBMCs from DADA2 patients with the vasculitis phenotype or pure red cell aplasia phenotype exhibited similar upregulation of TNF, type I interferon, and type II interferon signaling pathways compared with healthy controls. These pathways were also activated in 3 asymptomatic individuals with DADA2. Analysis of ADA2 variants, including 7 novel variants, showed different mechanisms of functional disruption including (1) unstable transcript leading to RNA degradation; (2) impairment of ADA2 secretion because of retention in the endoplasmic reticulum; (3) normal expression and secretion of ADA2 that lacks enzymatic function; and (4) disruption of the N-terminal signal peptide leading to cytoplasmic localization of unglycosylated protein. CONCLUSIONS: Transcriptomic signatures of inflammation are observed in patients with different disease phenotypes, including some asymptomatic individuals. Disease-associated ADA2 variants affect protein function by multiple mechanisms, which may contribute to the clinical heterogeneity of DADA2.


Asunto(s)
Adenosina Desaminasa , Vasculitis , Humanos , Adenosina Desaminasa/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Fenotipo , Mutación
3.
J Autoimmun ; 140: 103119, 2023 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-37797401

RESUMEN

We aimed to characterize the genetic basis of disease in a family with multiple autoimmune manifestations, including systemic lupus erythematosus (SLE), immune thrombocytopenia, and autoimmune thyroiditis. Whole exome sequencing (WES) was conducted to identify candidate variants, which were analyzed by flow cytometry, immunoblotting, immunoprecipitation, and luciferase reporter assay in transfected 293T cells. Gene expression in peripheral blood mononuclear cells (PBMC) was profiled by bulk RNA sequencing and plasma cytokines were measured by proximity extension assay. In two siblings with early-onset SLE and immune thrombocytopenia, WES identified two maternally inherited in cis variants (p. Pro50Leu and p.Ala76Gly) in Suppressor of cytokine signaling 1 (SOCS1), flanking the kinase inhibitory domain that interacts with Janus kinases (JAK). Both variants were predicted to be benign by most in silico algorithms and neither alone affected the ability of SOCS1 to inhibit JAK-STAT1 signaling by functional studies. When both variants were expressed in cis, the mutant SOCS1 protein displayed decreased binding to JAK1 and reduced capacity to inhibit type I interferon (IFN-I) signaling by ∼20-30% compared to the wildtype protein. PBMC from the probands and their mother showed increased expression of interferon-inducible genes compared to healthy controls, supporting defective regulation of IFN-I signaling. Cells from all three subjects displayed heightened sensitivity to IFN-I stimulation, while response to IFN-γ, IL-4, and IL-6 was comparable to healthy controls. Our work illustrates the critical fine-tuning of IFN-I signaling by SOCS1 to prevent autoimmunity. We show that a combination of genetic variants that are individually benign may have deleterious consequences.

4.
J Autoimmun ; 140: 103088, 2023 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-37549449

RESUMEN

Mechanistic studies of autoimmune disorders have identified circulating T follicular helper (cTfh) cells as drivers of autoimmunity. However, the quantification of cTfh cells is not yet used in clinical practice due to the lack of age-stratified normal ranges and the unknown sensitivity and specificity of this test for autoimmunity. We enrolled 238 healthy participants and 130 patients with common and rare disorders of autoimmunity or autoinflammation. Patients with infections, active malignancy, or any history of transplantation were excluded. In 238 healthy controls, median cTfh percentages (range 4.8%-6.2%) were comparable among age groups, sexes, races, and ethnicities, apart from a significantly lower percentages in children less than 1 year of age (median 2.1%, CI: 0.4%-6.8, p < 0.0001). Among 130 patients with over 40 immune regulatory disorders, a cTfh percentage exceeding 12% had 88% sensitivity and 94% specificity for differentiating disorders with adaptive immune cell dysregulation from those with predominantly innate cell defects. This threshold had a sensitivity of 86% and specificity of 100% for active autoimmunity and normalized with effective treatment. cTfh percentages exceeding 12% distinguish autoimmunity from autoinflammation, thereby differentiating two endotypes of immune dysregulation with overlapping symptoms and different therapies.

5.
PLoS Biol ; 18(5): e3000676, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32463837

RESUMEN

We have used magnetic resonance imaging (MRI) to provide important new insights into the function of the human placenta in utero. We have measured slow net flow and high net oxygenation in the placenta in vivo, which are consistent with efficient delivery of oxygen from mother to fetus. Our experimental evidence substantiates previous hypotheses on the effects of spiral artery remodelling in utero and also indicates rapid venous drainage from the placenta, which is important because this outflow has been largely neglected in the past. Furthermore, beyond Braxton Hicks contractions, which involve the entire uterus, we have identified a new physiological phenomenon, the 'utero-placental pump', by which the placenta and underlying uterine wall contract independently of the rest of the uterus, expelling maternal blood from the intervillous space.


Asunto(s)
Placenta/fisiología , Circulación Placentaria , Adulto , Velocidad del Flujo Sanguíneo , Estudios de Casos y Controles , Femenino , Humanos , Angiografía por Resonancia Magnética , Oxígeno/metabolismo , Placenta/diagnóstico por imagen , Preeclampsia/fisiopatología , Embarazo , Útero/fisiología , Adulto Joven
6.
J Allergy Clin Immunol ; 149(2): 736-746, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34111452

RESUMEN

BACKGROUND: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness. OBJECTIVE: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level. METHODS: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated. RESULTS: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed. CONCLUSION: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.


Asunto(s)
Antígeno CTLA-4/genética , Mutación de Línea Germinal , Síndromes de Inmunodeficiencia/terapia , Adolescente , Adulto , Agammaglobulinemia/etiología , Anciano , Enfermedades Autoinmunes/etiología , Antígeno CTLA-4/deficiencia , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Trasplante de Células Madre Hematopoyéticas , Humanos , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/genética , Lactante , Enfermedades Pulmonares Intersticiales/etiología , Masculino , Persona de Mediana Edad , Trasplante Homólogo , Adulto Joven
7.
Clin Immunol ; 238: 109014, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35447312

RESUMEN

Potential etiologies of T-B+NK+ SCID include both hematopoietic defects and thymic aplasia. The management of patients with this phenotype, identified by newborn screen, may be unclear in the absence of a genetic diagnosis. We report an infant with lymphocyte flow cytometry consistent with T-B+NK+ SCID and reduced proliferative response to phytohemagglutinin. The patient had no genetic diagnosis after targeted panel and exome sequencing. The decision to trend laboratory values rather than move immediately to hematopoietic cell transplant was made given the absence of a genetic defect and the finding of a normal thymus on ultrasound. During the course of evaluation for transplant, the patient unexpectedly had normalization of T cell number and function. This case demonstrates a role for mediastinal ultrasound and the utility of trending laboratory values in patients with severe T cell lymphopenia but no genetic diagnosis, given the small but important possibility of spontaneous resolution.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfopenia , Inmunodeficiencia Combinada Grave , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Recién Nacido , Linfopenia/complicaciones , Tamizaje Neonatal , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genética , Linfocitos T
8.
Clin Immunol ; 235: 108930, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35063669

RESUMEN

We report a female patient presenting with generalized pustular psoriasis and hypogammaglobulinemia due to digenic mutations in IL-36RA and SEC61A1. The patient presented with recurrent fevers, elevated inflammatory markers, hepatosplenomegaly, and recurrent sinopulmonary infections in the context of hypogammaglobulinemia which improved on immunoglobulin replacement. This report demonstrates how digenic inheritance leads to complex phenotypes, and illustrates the importance of following an unbiased approach to identifying variants, especially in patients with atypical clinical presentations.


Asunto(s)
Agammaglobulinemia/genética , Predisposición Genética a la Enfermedad , Interleucinas/genética , Psoriasis/genética , Canales de Translocación SEC/genética , Agammaglobulinemia/patología , Preescolar , Consanguinidad , Femenino , Humanos , Mutación , Linaje , Psoriasis/patología
9.
J Allergy Clin Immunol ; 147(2): 723-726, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32888943

RESUMEN

BACKGROUND: Next-generation sequencing has become a first-line tool for the diagnosis of primary immunodeficiency. However, patient access remains limited because of restricted insurance coverage and a lack of guidelines addressing the use of targeted panels versus whole-exome sequencing (WES). OBJECTIVES: We sought to compare targeted next-generation sequencing with WES in a global population of patients with primary immunodeficiency. METHODS: This was a longitudinal study of 878 patients with likely primary immunodeficiency sequenced between 2010 and 2020. Most patients (n = 780) were first sequenced using a 264 gene panel. This was followed by WES in selected cases if a candidate gene was not found. A subset of patients (n = 98) were selected for a WES-only pipeline if the history was atypical for genes within the targeted panel. RESULTS: Disease-causing variants were identified in 498 of the 878 probands (56%), encompassing 152 distinct monogenic disorders. Sixteen patients had disorders that were novel at the time of sequencing (1.8%). Diagnostic yield in patients sequenced by targeted panel was 56% (433 of 780 patients), with subsequent WES leading to an additional 18 diagnoses (overall diagnostic yield 58%, 451 of 780 patients). The WES-only approach had a diagnostic yield of 45% (45 of 98 patients), reflecting that these cases had less common clinical and laboratory phenotypes. Cost analysis, based on current commercial WES and targeted panel prices, demonstrated savings ranging from $300 to $950 with a WES-only approach, depending on diagnostic yield. CONCLUSIONS: Advantages of WES over targeted next-generation sequencing include simplified workflow, reduced overall cost, and the potential for identification of novel diseases.


Asunto(s)
Secuenciación del Exoma/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADN , Adulto Joven
10.
J Allergy Clin Immunol ; 148(3): 732-738.e1, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34224783

RESUMEN

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a pediatric complication of severe acute respiratory syndrome coronavirus 2 infection that is characterized by multiorgan inflammation and frequently by cardiovascular dysfunction. It occurs predominantly in otherwise healthy children. We previously reported haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of type I and II interferons, as a genetic risk factor for MIS-C. OBJECTIVES: We aimed to identify additional genetic mechanisms underlying susceptibility to severe acute respiratory syndrome coronavirus 2-associated MIS-C. METHODS: In a single-center, prospective cohort study, whole exome sequencing was performed on patients with MIS-C. The impact of candidate variants was tested by using patients' PBMCs obtained at least 7 months after recovery. RESULTS: We enrolled 18 patients with MIS-C (median age = 8 years; interquartile range = 5-12.25 years), of whom 89% had no conditions other than obesity. In 2 boys with no significant infection history, we identified and validated hemizygous deleterious defects in XIAP, encoding X-linked inhibitor of apoptosis, and CYBB, encoding cytochrome b-245, beta subunit. Including the previously reported SOCS1 haploinsufficiency, a genetic diagnosis was identified in 3 of 18 patients (17%). In contrast to patients with mild COVID-19, patients with defects in SOCS1, XIAP, or CYBB exhibit an inflammatory immune cell transcriptome with enrichment of differentially expressed genes in pathways downstream of IL-18, oncostatin M, and nuclear factor κB, even after recovery. CONCLUSIONS: Although inflammatory disorders are rare in the general population, our cohort of patients with MIS-C was enriched for monogenic susceptibility to inflammation. Our results support the use of next-generation sequencing in previously healthy children who develop MIS-C.


Asunto(s)
COVID-19/etiología , COVID-19/metabolismo , Susceptibilidad a Enfermedades , Predisposición Genética a la Enfermedad , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , Biomarcadores , COVID-19/complicaciones , COVID-19/diagnóstico , COVID-19/virología , Niño , Preescolar , Citocinas/metabolismo , Femenino , Interacciones Huésped-Patógeno/inmunología , Humanos , Masculino , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico
11.
J Allergy Clin Immunol ; 148(2): 381-393, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33872655

RESUMEN

BACKGROUND: Recognition of viral nucleic acids is one of the primary triggers for a type I interferon-mediated antiviral immune response. Inborn errors of type I interferon immunity can be associated with increased inflammation and/or increased susceptibility to viral infections as a result of dysbalanced interferon production. NFX1-type zinc finger-containing 1 (ZNFX1) is an interferon-stimulated double-stranded RNA sensor that restricts the replication of RNA viruses in mice. The role of ZNFX1 in the human immune response is not known. OBJECTIVE: We studied 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic lymphohistiocytosis-like disease, early-onset seizures, and renal and lung disease. METHODS: Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, posttranscriptional regulation of interferon-stimulated genes (ISGs) and predisposition to viral infections in primary cells from patients and controls stimulated with synthetic double-stranded nucleic acids. RESULTS: Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients. Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of the mRNA of ISGs and also associated with poorer clearance of viral infections by monocytes. CONCLUSION: ZNFX1 is an important regulator of the response to double-stranded nucleic acids stimuli following viral infections. ZNFX1 deficiency predisposes to severe viral infections and a multisystem inflammatory disease.


Asunto(s)
Antígenos de Neoplasias/genética , Secuenciación del Exoma , Predisposición Genética a la Enfermedad , Enfermedades de Inmunodeficiencia Primaria/inmunología , Virosis/genética , Antígenos de Neoplasias/inmunología , Niño , Preescolar , Femenino , Humanos , Lactante , Inflamación/diagnóstico por imagen , Inflamación/genética , Inflamación/inmunología , Masculino , Enfermedades de Inmunodeficiencia Primaria/diagnóstico por imagen , Enfermedades de Inmunodeficiencia Primaria/genética , Virosis/diagnóstico por imagen , Virosis/inmunología
12.
J Allergy Clin Immunol ; 146(5): 1194-1200.e1, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32853638

RESUMEN

BACKGROUND: We studied 2 unrelated patients with immune thrombocytopenia and autoimmune hemolytic anemia in the setting of acute infections. One patient developed multisystem inflammatory syndrome in children in the setting of a severe acute respiratory syndrome coronavirus 2 infection. OBJECTIVES: We sought to identify the mechanisms underlying the development of infection-driven autoimmune cytopenias. METHODS: Whole-exome sequencing was performed on both patients, and the impact of the identified variants was validated by functional assays using the patients' PBMCs. RESULTS: Each patient was found to have a unique heterozygous truncation variant in suppressor of cytokine signaling 1 (SOCS1). SOCS1 is an essential negative regulator of type I and type II IFN signaling. The patients' PBMCs showed increased levels of signal transducer and activator of transcription 1 phosphorylation and a transcriptional signature characterized by increased expression of type I and type II IFN-stimulated genes and proapoptotic genes. The enhanced IFN signature exhibited by the patients' unstimulated PBMCs parallels the hyperinflammatory state associated with multisystem inflammatory syndrome in children, suggesting the contributions of SOCS1 in regulating the inflammatory response characteristic of multisystem inflammatory syndrome in children. CONCLUSIONS: Heterozygous loss-of-function SOCS1 mutations are associated with enhanced IFN signaling and increased immune cell activation, thereby predisposing to infection-associated autoimmune cytopenias.


Asunto(s)
Anemia Hemolítica Autoinmune/inmunología , Anemia Hemolítica Autoinmune/virología , Infecciones por Coronavirus/complicaciones , Neumonía Viral/complicaciones , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/virología , Trombocitopenia/inmunología , Trombocitopenia/virología , Adolescente , Anemia Hemolítica Autoinmune/genética , Betacoronavirus , COVID-19 , Preescolar , Infecciones por Coronavirus/inmunología , Haploinsuficiencia , Humanos , Masculino , Mutación , Pandemias , Neumonía Viral/inmunología , SARS-CoV-2 , Proteína 1 Supresora de la Señalización de Citocinas/genética , Trombocitopenia/genética
13.
J Allergy Clin Immunol ; 145(1): 46-69, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31568798

RESUMEN

Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have a profound effect on clinical management decisions. Therefore clinical providers must demonstrate proficiency in interpreting genetic data. Because of the need for increased knowledge regarding this practice, the American Academy of Allergy, Asthma & Immunology Primary Immunodeficiency Diseases Committee established a work group that reviewed and summarized information concerning appropriate methods, tools, and resources for evaluating variants identified by genetic testing. Strengths and limitations of tests frequently ordered by clinicians were examined. Summary statements and tables were then developed to guide the interpretation process. Finally, the need for research and collaboration was emphasized. Greater understanding of these important concepts will improve the diagnosis and management of patients with suspected primary immunodeficiency diseases.


Asunto(s)
Pruebas Genéticas , Enfermedades de Inmunodeficiencia Primaria , Asma , Humanos , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/terapia , Estados Unidos
14.
J Allergy Clin Immunol ; 145(6): 1664-1672.e10, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31945408

RESUMEN

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable. OBJECTIVE: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. METHODS: Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum. RESULTS: We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function. CONCLUSIONS: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.


Asunto(s)
Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Péptidos y Proteínas de Señalización Intercelular/genética , Trastornos de Fallo de la Médula Ósea/genética , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Masculino , Mutación/genética , Fenotipo , Aplasia Pura de Células Rojas/genética , Vasculitis/genética
15.
Clin Immunol ; 218: 108520, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32629161

RESUMEN

Severe Combined Immunodeficiency (SCID) is a genetically heterogeneous group of disorders characterized by severe T cell lymphopenia and defective T and B cell function. Without prompt diagnosis and early intervention, patients with SCID typically die from infection within the first year of life. Advances in molecular genetics have led to rapid and efficient diagnosis of SCID cases, particularly when paired with newborn screening. However, some cases remain unsolved, and this is of particular relevance to families that plan to have more children. Here we report a patient who died from complications of SCID in whom whole exome sequencing failed to reveal a candidate variant. We describe how Sanger sequencing of parents was used to study the genomic regions that were poorly covered by WES, and how immune phenotyping results were used in the setting of genetic counseling.


Asunto(s)
Inmunodeficiencia Combinada Grave/genética , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/inmunología , Resultado Fatal , Femenino , Humanos , Inmunofenotipificación , Lactante , Recuento de Leucocitos , Neumonía Viral/etiología , Neumonía Viral/genética , Neumonía Viral/inmunología , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/inmunología , Secuenciación del Exoma
16.
Clin Immunol ; 216: 108459, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32418917

RESUMEN

The COVID-19 pandemic is one of the greatest infectious challenges in recent history. Presently, few treatment options exist and the availability of effective vaccines is at least one year away. There is an urgent need to find currently available, effective therapies in the treatment of patients with COVID-19 infection. In this review, we compare and contrast the use of intravenous immunoglobulin and hyperimmune globulin in the treatment of COVID-19 infection.


Asunto(s)
Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/patología , Inmunoglobulinas Intravenosas/administración & dosificación , Factores Inmunológicos/administración & dosificación , Pandemias , Neumonía Viral/tratamiento farmacológico , Inmunidad Adaptativa/efectos de los fármacos , Enzima Convertidora de Angiotensina 2 , Acrecentamiento Dependiente de Anticuerpo/efectos de los fármacos , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , COVID-19 , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/prevención & control , Expresión Génica , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunización Pasiva/efectos adversos , Inmunización Pasiva/métodos , Inmunoglobulinas Intravenosas/efectos adversos , Factores Inmunológicos/efectos adversos , Terapia Molecular Dirigida , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/inmunología , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Neumonía Viral/virología , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/virología , Sueroterapia para COVID-19
17.
Clin Immunol ; 210: 108311, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31760094

RESUMEN

Activated PI3Kδ syndrome (APDS) Type I results from gain-of-function mutations in PIK3CD, which encodes the p110δ subunit of PI3Kδ. Abnormal actin dynamics have been hypothesized to contribute to the lymphopenia associated with this disease but have not been studied in patients with APDS. We report a patient with APDS who had widespread necrotic skin lesions that were responsive specifically to immunosuppressive therapy. EBV-transformed lymphoblastoid cells (EBV-LCLs) from patients with APDS exhibit increased polymerized actin and increased apoptosis, suggesting a contribution of impaired actin dynamics to this disease.


Asunto(s)
Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Piel/patología , Citoesqueleto de Actina/genética , Apoptosis , Células Cultivadas , Preescolar , Fosfatidilinositol 3-Quinasa Clase I/genética , Femenino , Mutación con Ganancia de Función/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linfopenia , Necrosis , Enfermedades de Inmunodeficiencia Primaria/genética
18.
J Allergy Clin Immunol ; 144(2): 574-583.e5, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30872117

RESUMEN

BACKGROUND: The tumor TNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a costimulatory signal that enhances CD8+ T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB is expressed on antigen-presenting cells and EBV-transformed B cells. OBJECTIVE: We investigated the genetic basis of recurrent sinopulmonary infections, persistent EBV viremia, and EBV-induced lymphoproliferation in 2 unrelated patients. METHODS: Whole-exome sequencing, immunoblotting, immunophenotyping, and in vitro assays of lymphocyte and mitochondrial function were performed. RESULTS: The 2 patients shared a homozygous G109S missense mutation in 4-1BB that abolished protein expression and ligand binding. The patients' CD8+ T cells had reduced proliferation, impaired expression of IFN-γ and perforin, and diminished cytotoxicity against allogeneic and HLA-matched EBV-B cells. Mitochondrial biogenesis, membrane potential, and function were significantly reduced in the patients' activated T cells. An inhibitory antibody against 4-1BB recapitulated the patients' defective CD8+ T-cell activation and cytotoxicity against EBV-infected B cells in vitro. CONCLUSION: This novel immunodeficiency demonstrates the critical role of 4-1BB costimulation in host immunity against EBV infection.


Asunto(s)
Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/inmunología , Trastornos Linfoproliferativos/inmunología , Mutación Missense , Enfermedades de Inmunodeficiencia Primaria/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Preescolar , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/patología , Femenino , Herpesvirus Humano 4/genética , Humanos , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/virología , Masculino , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/patología , Enfermedades de Inmunodeficiencia Primaria/virología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Secuenciación del Exoma
19.
Clin Immunol ; 207: 40-42, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31301515

RESUMEN

Mutations in MYD88 cause susceptibility to invasive bacterial infections through impaired signaling downstream of toll-like receptors (TLRs) and IL-1 receptors. We studied a patient presenting with neutropenia, delayed umbilical cord separation, BCG adenitis, andP. aeruginosapneumonia. Next-generation DNA sequencing identified a novel homozygous truncation mutation in MYD88 that abolishes MyD88 expression. The patient's dermal fibroblasts had severely impaired IL-6 production after stimulation with ligands for the MyD88-dependent receptors TLR2, TLR4 and IL-1R, while responses to ligands for the MyD88-independent receptors TLR3 and TNF-α were preserved. Notably, secretion of TNF-α, which is essential for BCG control, was also impaired after LPS stimulation. In this first report of BCG infection in MyD88 deficiency, data suggest that MyD88-dependent TNF-α production contributes to control of mycobacterial disease.


Asunto(s)
Vacuna BCG/efectos adversos , Linfadenitis/patología , Factor 88 de Diferenciación Mieloide/genética , Neutropenia/genética , Neumonía Bacteriana/microbiología , Cordón Umbilical/patología , Vacuna BCG/inmunología , Predisposición Genética a la Enfermedad , Humanos , Masculino , Neutropenia/patología , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa
20.
Histopathology ; 74(6): 959-963, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30592780

RESUMEN

AIMS: There is evidence that four or five gastric cancer biopsies are required for accurate HER2 interpretation. However, the number of biopsies that need to be taken to reach this number of viable cancer biopsies is without evidence. This study aimed to address this gap by assessing the number of biopsies required to gain at least four viable biopsies containing cancer. METHODS AND RESULTS: A total of 105 consecutive biopsy cases of gastric and oesophageal adenocarcinoma were retrieved from files. Only definite cancer diagnoses were included; missed cancers or unproven cases were not considered. The cases were reviewed and the number of biopsies taken, and the number containing viable tumour was recorded. In total, 667 biopsies were taken, of which 471 had viable tumour (70.6%). Seventy of 105 cases (67%) had four viable tumour biopsies, but only 47 of 105 (45%) had five viable tumour biopsies. In order to have a >90% chance of having four viable tumour biopsies, seven needed to be taken, while 10 or more were required for a >90% chance of five viable tumour biopsies. Mathematically, using a 0.7 probability for a single biopsy, eight biopsies would be required for a 94% chance of at least four viable tumour biopsies. CONCLUSION: In our large upper GI cancer centre, many biopsy cases do not contain sufficient material for adequate HER2 assessment. In order to meet the four-biopsy requirement for adequate HER2 assessment in >90% of cases, at least eight biopsies need to be taken, while 10 biopsies would be required for the 5-cancer biopsy threshold.


Asunto(s)
Adenocarcinoma/diagnóstico , Biopsia/métodos , Neoplasias Esofágicas/diagnóstico , Patología Quirúrgica/métodos , Neoplasias Gástricas/diagnóstico , Endoscopía Gastrointestinal/métodos , Gastroenterología/métodos , Humanos , Receptor ErbB-2/análisis
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