Asunto(s)
Adenosina Desaminasa , Inmunodeficiencia Combinada Grave , Humanos , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Inmunodeficiencia Combinada Grave/terapia , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/diagnóstico , Agammaglobulinemia/terapia , Agammaglobulinemia/genética , Agammaglobulinemia/tratamiento farmacológico , Masculino , Lactante , Femenino , Terapia de Reemplazo EnzimáticoRESUMEN
BACKGROUND: Severe combined immunodeficiency secondary to adenosine deaminase deficiency is rare. The deficiency of this enzyme results in the accumulation of substrates in the tissues, including the brain. Clinical signs of neurological involvement may include seizures, neurodevelopmental disorders, hypotonia, and sensorineural hearing loss. Hematopoietic stem cell transplantation corrects the failure of the immune system but not the neurological involvement. OBJECTIVES: To describe the spectrum of neurological complications identified in a series of children with severe combined immunodeficiency due to adenosine deaminase deficiency. Additionally, we propose a neurological approach including electrophysiological, radiological, and neurocognitive studies to address this group of children in an efficient and timely manner. METHODS: A descriptive, observational, retro-, and prospective analysis of patients with a confirmed immunological diagnosis seen between 1996 and 2021 and referred to the Department of Neurology for neurological evaluation was conducted. RESULTS: Ten patients met the inclusion criteria. The median age at diagnosis was 4 months (range, 1-36 months). All patients had neurodevelopmental delay with hypotonia in six, language delay in three, sensorineural hearing loss in four, and spastic paraparesis in one patient. Two children developed an epileptic syndrome, consisting of generalized epilepsy in one and focal epilepsy in the other. Neuroimaging showed brain calcifications in the basal ganglia and/or centrum semiovale in four patients and enlarged subarachnoid spaces in two other patients. CONCLUSION: In this pediatric series, the rate of neurological involvement associated with abnormalities on neuroimaging was high. Although this involvement could be related to accumulation of adenosine metabolites in the central nervous system, the possibility of associated chronic infections should be ruled out. Given the neurological manifestations, it is important to involve the pediatric neurologist in the multidisciplinary follow-up team.
Asunto(s)
Adenosina Desaminasa , Agammaglobulinemia , Inmunodeficiencia Combinada Grave , Humanos , Adenosina Desaminasa/deficiencia , Preescolar , Lactante , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/terapia , Femenino , Masculino , Agammaglobulinemia/complicaciones , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA editing. However, the functional role of ADAR2 in NAFLD is unclear. ADAR2+/+/GluR-BR/R mice (wild type, WT) and ADAR2-/-/GluR-BR/R mice (ADAR2 KO) mice are fed with standard chow or high-fat diet (HFD) for 12 weeks. ADAR2 KO mice exhibit protection against HFD-induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, ADAR2 KO mice display reduced liver lipid droplets in concert with decreased hepatic TG content, improved hepatic insulin signaling, better pyruvate tolerance, and increased glycogen synthesis. Mechanistically, ADAR2 KO effectively mitigates excessive lipid production via AMPK/Sirt1 pathway. ADAR2 KO inhibits hepatic gluconeogenesis via the AMPK/CREB pathway and promotes glycogen synthesis by activating the AMPK/GSK3ß pathway. These results provide evidence that ADAR2 KO protects against NAFLD progression through the activation of AMPK signaling pathways.
Asunto(s)
Adenosina Desaminasa , Dieta Alta en Grasa , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico , Proteínas de Unión al ARN , Transducción de Señal , Animales , Adenosina Desaminasa/metabolismo , Adenosina Desaminasa/genética , Adenosina Desaminasa/deficiencia , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/etiología , Dieta Alta en Grasa/efectos adversos , Masculino , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Resistencia a la Insulina , Ratones Obesos , Obesidad/metabolismo , Obesidad/genética , Ratones Endogámicos C57BL , Hígado/metabolismoRESUMEN
A girl in the early adolescent age group presented with multisystem manifestations in the form of periodic fever, recurrent abdominal pain, hypertension, seizure, skin lesions over the chest and gangrene over the left ring and middle fingertips. Her condition had remained undiagnosed for 11 years. On evaluation, she had features of polyarteritis nodosa (PAN) (multiple aneurysms, symmetric sensorimotor peripheral neuropathy, superficial ulcers, digital necrosis, myalgia, hypertension and proteinuria). As childhood PAN is a phenocopy of adenosine deaminase 2 with a different management strategy, whole-exome sequencing was performed, which revealed a pathogenic variant in ADA2 gene. The child was treated with TNF alpha inhibitors and showed improvement in the Paediatric Vasculitis Activity Score. The paper highlights the gratifying consequences of correct diagnosis with disease-specific therapy that ended the diagnostic odyssey, providing relief to the patient from debilitating symptoms and to the family from the financial burden of continued out-of-pocket health expenditure.
Asunto(s)
Adenosina Desaminasa , Poliarteritis Nudosa , Humanos , Poliarteritis Nudosa/diagnóstico , Poliarteritis Nudosa/tratamiento farmacológico , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Femenino , Diagnóstico Diferencial , Adolescente , Secuenciación del Exoma , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Autoinflamatorias Hereditarias/tratamiento farmacológico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Niño , Péptidos y Proteínas de Señalización IntercelularRESUMEN
Deficiency of Adenosine Deaminase 2 (DADA2) patients presenting with primary immunodeficiency are at risk of uncontrolled EBV infection and secondary malignancies including EBV-related lymphoproliferative disorders (LPD). This paper describes the first case of EBV related diffuse large B-cell lymphoma in a patient with DADA2 and uncontrolled EBV infection. Consideration should be given to monitoring for EBV viraemia and to preventative EBV specific therapy in DADA2 and patients with at risk primary immunodeficiencies. A type I interferon (IFN) gene signature is associated with DADA2 though its association with immune dysregulation is unclear.
Asunto(s)
Adenosina Desaminasa , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/etiología , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/diagnóstico , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Femenino , Enfermedades Autoinflamatorias HereditariasRESUMEN
Deficiency of adenosine deaminase 2 (DADA2) is an inborn error of immunity caused by loss-of-function mutations in the adenosine deaminase 2 (ADA2) gene. Clinical manifestations of DADA2 include vasculopathy and immuno-hematological abnormalities, culminating in bone marrow failure. A major gap exists in our knowledge of the regulatory functions of ADA2 during inflammation and hematopoiesis, mainly due to the absence of an ADA2 orthologue in rodents. Exploring these mechanisms is essential for understanding disease pathology and developing new treatments. Zebrafish possess two ADA2 orthologues, cecr1a and cecr1b, with the latter showing functional conservation with human ADA2. We establish a cecr1b-loss-of-function zebrafish model that recapitulates the immuno-hematological and vascular manifestations observed in humans. Loss of Cecr1b disrupts hematopoietic stem cell specification, resulting in defective hematopoiesis. This defect is caused by induced inflammation in the vascular endothelium. Blocking inflammation, pharmacological modulation of the A2r pathway, or the administration of the recombinant human ADA2 corrects these defects, providing insights into the mechanistic link between ADA2 deficiency, inflammation and immuno-hematological abnormalities. Our findings open up potential therapeutic avenues for DADA2 patients.
Asunto(s)
Adenosina Desaminasa , Hematopoyesis , Células Madre Hematopoyéticas , Inflamación , Pez Cebra , Animales , Pez Cebra/genética , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismo , Adenosina Desaminasa/deficiencia , Células Madre Hematopoyéticas/metabolismo , Inflamación/genética , Inflamación/metabolismo , Hematopoyesis/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Humanos , Transducción de Señal , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismoRESUMEN
PURPOSE: Patients with adenosine deaminase 1 deficient severe combined immunodeficiency (ADA-SCID) are initially treated with enzyme replacement therapy (ERT) with polyethylene glycol-modified (PEGylated) ADA while awaiting definitive treatment with hematopoietic stem cell transplant (HSCT) or gene therapy. Beginning in 1990, ERT was performed with PEGylated bovine intestinal ADA (ADAGEN®). In 2019, a PEGylated recombinant bovine ADA (Revcovi®) replaced ADAGEN following studies in older patients previously treated with ADAGEN for many years. There are limited longitudinal data on ERT-naïve newborns treated with Revcovi. METHODS: We report our clinical experience with Revcovi as initial bridge therapy in three newly diagnosed infants with ADA-SCID, along with comprehensive biochemical and immunologic data. RESULTS: Revcovi was initiated at twice weekly dosing (0.2 mg/kg intramuscularly), and monitored by following plasma ADA activity and the concentration of total deoxyadenosine nucleotides (dAXP) in erythrocytes. All patients rapidly achieved a biochemically effective level of plasma ADA activity, and red cell dAXP were eliminated within 2-3 months. Two patients reconstituted B-cells and NK-cells within the first month of ERT, followed by naive T-cells one month later. The third patient reconstituted all lymphocyte subsets within the first month of ERT. One patient experienced declining lymphocyte counts with improvement following Revcovi dose escalation. Two patients developed early, self-resolving thrombocytosis, but no thromboembolic events occurred. CONCLUSION: Revcovi was safe and effective as initial therapy to restore immune function in these newly diagnosed infants with ADA-SCID, however, time course and degree of reconstitution varied. Revcovi dose may need to be optimized based on immune reconstitution, clinical status, and biochemical data.
Asunto(s)
Adenosina Desaminasa , Agammaglobulinemia , Terapia de Reemplazo Enzimático , Inmunodeficiencia Combinada Grave , Animales , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Agammaglobulinemia/terapia , Reconstitución Inmune , Proteínas Recombinantes/uso terapéutico , Inmunodeficiencia Combinada Grave/terapia , Resultado del TratamientoRESUMEN
Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. The patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low Adenosine Deaminase (ADA) activity resulting from methylation of viral promoter. The insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. Blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. Before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. The limited incidence of vector-related adverse events in ADA-deficiency compared to other γ-RV GT trials could be explained by differences in transgenes, background disease and patient's specific factors.
Asunto(s)
Adenosina Desaminasa , Agammaglobulinemia , Terapia Genética , Vectores Genéticos , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Proto-Oncogenes Mas , Inmunodeficiencia Combinada Grave , Humanos , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Terapia Genética/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Inmunodeficiencia Combinada Grave/terapia , Inmunodeficiencia Combinada Grave/genética , Vectores Genéticos/genética , Agammaglobulinemia/terapia , Agammaglobulinemia/genética , Masculino , Retroviridae/genéticaRESUMEN
Deficiency of adenosine deaminase 2 (DADA2) is a monogenic disease caused by biallelic mutations in adenosine deaminase 2 (ADA2). The varying phenotypes of the disease often lead to delayed diagnosis or misdiagnosis. We report an 11-year-old boy with DADA2 and provide a preliminary analysis of genotype-phenotype correlation. The age of onset of the disease was 8 years old. The disease successively involved the brainstem, muscles, joints, and cerebrum. After three relapse-remission episodes over 3 years, the patient was finally diagnosed with DADA2 by whole-exome sequencing. Compound heterozygous variants in the ADA2 gene (NM_001282225.2: c.1072G>A, p.Gly358Arg; c.419dupC, p.Arg141Lysfs*37) were found in the patient. He did not receive anti-TNF therapy and had no relapse after a 8-month follow-up. We identified a novel variant of the ADA2 gene, and the associated disease course may follow a relapse-remission pattern. Homozygous mutations of p.Gly358Arg can cause pure red cell aplasia, whereas compound heterozygous variations may lead to different phenotypes. Variants in the catalytic domain and frameshift mutations may also cause relatively benign phenotypes besides causing hematological disorders. Further studies are needed to clarify the genotypic-phenotypic relationship of this disease.
Asunto(s)
Adenosina Desaminasa , Estudios de Asociación Genética , Enfermedades Autoinflamatorias Hereditarias , Péptidos y Proteínas de Señalización Intercelular , Mutación , Humanos , Adenosina Desaminasa/genética , Adenosina Desaminasa/deficiencia , Masculino , Niño , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Mutación/genética , Fenotipo , Secuenciación del Exoma , Recurrencia , GenotipoRESUMEN
ABSTRACT: Deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive monogenic autoinflammatory syndrome that is classically characterised by polyarteritis nodosa, systemic vasculitis and stroke. The spectrum of disease manifestations has broadened to encompass a range of cutaneous, vascular and haematological manifestations. We report a novel association in two sisters with heterozygous p.R169G/p.M309l mutations in ADA2 with low serum ADA2 activity who both presented similarly with clinical and histological features consistent with histiocytoid Sweet syndrome.
Asunto(s)
Adenosina Desaminasa , Péptidos y Proteínas de Señalización Intercelular , Síndrome de Sweet , Humanos , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Péptidos y Proteínas de Señalización Intercelular/genética , Mutación , Poliarteritis Nudosa/genética , Síndrome de Sweet/diagnóstico , Síndrome de Sweet/genéticaRESUMEN
The RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) limits the accumulation of endogenous immunostimulatory double-stranded RNA (dsRNA)1. In humans, reduced ADAR1 activity causes the severe inflammatory disease Aicardi-Goutières syndrome (AGS)2. In mice, complete loss of ADAR1 activity is embryonically lethal3-6, and mutations similar to those found in patients with AGS cause autoinflammation7-12. Mechanistically, adenosine-to-inosine (A-to-I) base modification of endogenous dsRNA by ADAR1 prevents chronic overactivation of the dsRNA sensors MDA5 and PKR3,7-10,13,14. Here we show that ADAR1 also inhibits the spontaneous activation of the left-handed Z-nucleic acid sensor ZBP1. Activation of ZBP1 elicits caspase-8-dependent apoptosis and MLKL-mediated necroptosis of ADAR1-deficient cells. ZBP1 contributes to the embryonic lethality of Adar-knockout mice, and it drives early mortality and intestinal cell death in mice deficient in the expression of both ADAR and MAVS. The Z-nucleic-acid-binding Zα domain of ADAR1 is necessary to prevent ZBP1-mediated intestinal cell death and skin inflammation. The Zα domain of ADAR1 promotes A-to-I editing of endogenous Alu elements to prevent dsRNA formation through the pairing of inverted Alu repeats, which can otherwise induce ZBP1 activation. This shows that recognition of Alu duplex RNA by ZBP1 may contribute to the pathological features of AGS that result from the loss of ADAR1 function.
Asunto(s)
Adenosina Desaminasa , Inflamación , Proteínas de Unión al ARN , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Adenosina/metabolismo , Adenosina Desaminasa/química , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/metabolismo , Animales , Apoptosis , Enfermedades Autoinmunes del Sistema Nervioso , Caspasa 8/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/prevención & control , Inosina/metabolismo , Intestinos/patología , Ratones , Necroptosis , Malformaciones del Sistema Nervioso , Edición de ARN , ARN Bicatenario , Proteínas de Unión al ARN/antagonistas & inhibidores , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/metabolismo , Piel/patologíaRESUMEN
Homo sapiens adenosine deaminase 1 (HsADA1; UniProt P00813) is an immunologically relevant enzyme with roles in T-cell activation and modulation of adenosine metabolism and signaling. Patients with genetic deficiency in HsADA1 suffer from severe combined immunodeficiency, and HsADA1 is a therapeutic target in hairy cell leukemias. Historically, insights into the catalytic mechanism and the structural attributes of HsADA1 have been derived from studies of its homologs from Bos taurus (BtADA) and Mus musculus (MmADA). Here, the structure of holo HsADA1 is presented, as well as biochemical characterization that confirms its high activity and shows that it is active across a broad pH range. Structurally, holo HsADA1 adopts a closed conformation distinct from the open conformation of holo BtADA. Comparison of holo HsADA1 and MmADA reveals that MmADA also adopts a closed conformation. These findings challenge previous assumptions gleaned from BtADA regarding the conformation of HsADA1 that may be relevant to its immunological interactions, particularly its ability to bind adenosine receptors. From a broader perspective, the structural analysis of HsADA1 presents a cautionary tale for reliance on homologs to make structural inferences relevant to applications such as protein engineering or drug development.
Asunto(s)
Adenosina Desaminasa/metabolismo , Adenosina Desaminasa/química , Adenosina Desaminasa/deficiencia , Animales , Catálisis , Bovinos , Cristalografía por Rayos X , Humanos , Concentración de Iones de Hidrógeno , Ratones , Modelos Moleculares , Estructura Molecular , Enfermedades de Inmunodeficiencia Primaria/genética , Conformación Proteica , Receptores Purinérgicos P1/química , Receptores Purinérgicos P1/metabolismoRESUMEN
Deficiency of adenosine deaminase 2 (DADA2) is a monogenic vasculitis syndrome caused by autosomal-recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1). Vasculitis, vasculopathy, and inflammation are dominant clinical features of this disease; the spectrum of manifestations includes immunodeficiency and lymphoproliferation as well as hematologic manifestations. ADA2 is primarily secreted by stimulated monocytes and macrophages. Aberrant monocyte differentiation to macrophages and neutrophils are important in the pathogenesis of DADA2, but little is known about T lymphocytes in this disease. We performed combined single-cell RNA sequencing and single-cell TCR sequencing in order to profile T cell repertoires in 10 patients with DADA2. Although there were no significant alterations of T cell subsets, we observed activation of both CD8+ and CD4+ T cells. There was no clonal expansion of T cells: most TCRs were expressed at basal levels in patients and healthy donors. TCR usage was private to individual patients and not disease specific, indicating as unlikely a common pathogenic background or predisposition to a common pathogen. We recognized activation of IFN pathways as a signature of T cells and STAT1 as a hub gene in the gene network of T cell activation and cytotoxicity. Overall, T cells in DADA2 patients showed distinct cell-cell interactions with monocytes, as compared with healthy donors, and many of these ligand-receptor interactions likely drove up-regulation of STAT1 in both T cells and other immune cells in patients. Our analysis reveals previously undercharacterized cell characteristics in DADA2.
Asunto(s)
Adenosina Desaminasa/deficiencia , Biomarcadores/metabolismo , Regulación de la Expresión Génica , Síndromes de Inmunodeficiencia/patología , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Enfermedades de la Piel/patología , Linfocitos T/patología , Enfermedades Vasculares/patología , Adenosina Desaminasa/genética , Adolescente , Adulto , Estudios de Casos y Controles , Células Cultivadas , Niño , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Péptidos y Proteínas de Señalización Intercelular/genética , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Factor de Transcripción STAT1/genética , Análisis de la Célula Individual , Enfermedades de la Piel/genética , Enfermedades de la Piel/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Enfermedades Vasculares/genética , Enfermedades Vasculares/inmunología , Adulto JovenRESUMEN
BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by deleterious ADA2 variants. The frequency of these variants in the general population, and hence the expected disease prevalence, remain unknown. OBJECTIVE: We aimed to characterize the functional impact and carrier frequency of ADA2 variants. METHODS: We performed functional studies and in silico analysis on 163 ADA2 variants, including DADA2-associated variants and population variants identified in the Genome Aggregation Database. We estimated the carrier rate using the aggregate frequency of deleterious variants. RESULTS: Functional studies of ADA2 variants revealed that 77 (91%) of 85 of DADA2-associated variants reduced ADA2 enzymatic function by >75%. Analysis of 100 ADA2 variants in the database showed a full spectrum of impact on ADA2 function, rather than a dichotomy of benign versus deleterious variants. We found several in silico algorithms that effectively predicted the impact of ADA2 variants with high sensitivity and specificity, and confirmed a correlation between the residual function of ADA2 variants in vitro and the plasma ADA2 activity of individuals carrying these variants (n = 45; r = 0.649; P < .0001). Using <25% residual enzymatic activity as the cutoff to define potential pathogenicity, integration of our results with the database population data revealed an estimated carrier frequency of at least 1 in 236 individuals, corresponding to an expected DADA2 disease prevalence of ~1 in 222,000 individuals. CONCLUSIONS: Functional annotation guides the interpretation of ADA2 variants to create a framework that enables estimation of DADA2 carrier frequency and disease prevalence.
Asunto(s)
Adenosina Desaminasa/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Adenosina Desaminasa/sangre , Adenosina Desaminasa/deficiencia , Algoritmos , Predisposición Genética a la Enfermedad , Variación Genética , Células HEK293 , Humanos , Enfermedades del Sistema Inmune/genética , Péptidos y Proteínas de Señalización Intercelular/sangre , Péptidos y Proteínas de Señalización Intercelular/deficienciaRESUMEN
Objectives: Deficiency of adenosine deaminase 2 (DADA2) is a rare disease with varying phenotypes and disease outcomes. We evaluated the treatment of DADA2 and explored the factors associated with disease outcome.Methods: A systemic literature review of DADA2 was conducted. Cases were included if they had documented detailed genotypes, phenotypes, treatment protocols, and outcomes. Patients were categorized as having uncontrolled and controlled disease. Factors associated with disease outcome were analyzed using logistic regression models.Results: The study population comprised 242 DADA2 patients with data on treatment protocols and responses, of whom 17 required no treatment. Tumor necrosis factor a inhibitors (TNFi) were effective in 78.6% (103/131). Hematological abnormalities and increased acute phase reactants are independently associated with the effectiveness of TNFi (OR, 0.21 [95%CI, 0.07-0.661; P=.007] and 9.62 [95%CI, 2.31-40.00; P=.002, respectively). Among the 225 patients requiring active treatment, 157 (69.8%) had controlled disease and 68 (30.2%) uncontrolled disease. Neither age of disease onset nor genotype was associated with disease outcome. Increased acute phase reactant values, constitutional symptoms, neurological symptoms, and treatment with TNFi were independently associated with disease control, while recurrent infections and severe vascular events were the main causes of mortality (10/21 and 6/21, respectively).Conclusion: In patients requiring treatment, symptoms of systemic inflammation and vasculitis and treatment with TNFi are associated with disease control. Recurrent infections and severe vascular events should be treated intensively, as they are the main causes of death. Hematological abnormalities should be monitored, as they decrease the effectiveness of TNFi (AU)
Objetivos: El déficit de adenosina desaminasa 2 (DADA2) es una enfermedad rara con diferentes fenotipos y una evolución variable de laenfermedad. Nuestro objetivo es resumir los tratamientos de DADA2 y explorar los factores asociados con la evolución de la enfermedad.Métodos: Se realizó una revisión bibliográfica sistémica de DADA2. Los casos que se incluyeron fueron aquellos que habían documentadoel genotipo, fenotipos, protocolo de tratamiento y evolución. Los pacientes se clasificaron en grupos controlados y no controlados. Losfactores asociados con la evolución de la enfermedad se analizaron con modelos de regresión logística.Resultados: Se incluyeron un total de 242 pacientes con DADA2 con los protocolos de su tratamiento y la respuesta al mismo, 17 de los cualesno requirieron tratamiento. La eficacia general de los inhibidores de TNF-a (TNFi) fue del 78,6% (103/131). Las anomalías hematológicasy el aumento de los reactantes de fase aguda se asociaron de forma independiente con la eficacia del TNFi, OR = 0,21 (IC del 95%: 0,07 a0,661, p = 0,007) y 9,62 (IC del 95%: 2,31 a 40,00, p = 0,002), respectivamente. Entre los 225 pacientes que requirieron tratamiento activo,157 (69,8%) pacientes estaban en el grupo controlado y 68 (30,2%) en el grupo no controlado. Ni la edad de inicio de la enfermedad niel genotipo se asociaron con la evolución de la enfermedad. El aumento de los reactantes de fase aguda (APR), el deterioro constitucional,los síntomas neurológicos y el tratamiento con TNFi, se asociaron de forma independiente con el control de la enfermedad, mientras quelas infecciones recurrentes y los eventos vasculares graves fueron las principales causas de mortalidad (10/21 y 6/21, respectivamente).Conclusión: Los síntomas de inflamación sistémica, la vasculitis y el tratamiento con TNFi se asociaron con el control de la enfermedad enaquellos pacientes con DADA2 que requirieron tratamiento.
Asunto(s)
Humanos , Adenosina Desaminasa/deficiencia , Vasculitis , Enfermedades del Sistema Inmune/terapia , Inmunodeficiencia Combinada Grave/terapia , Péptidos y Proteínas de Señalización Intercelular/deficiencia , FenotipoRESUMEN
Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme intrinsic to the purine salvage pathway, leads to severe combined immunodeficiency (SCID) both in humans and mice. Lack of ADA results in the intracellular accumulation of toxic metabolites which have effects on T cell development and function. While untreated ADA-SCID is a fatal disorder, there are different therapeutic options available to restore ADA activity and reconstitute a functioning immune system, including enzyme replacement therapy (ERT). Administration of ERT in the form of pegylated bovine ADA (PEG-ADA) has proved a life-saving though non-curative treatment for ADA-SCID patients. However, in many patients treated with PEG-ADA, there is suboptimal immune recovery with low T and B cell numbers. Here, we show reduced thymus cellularity in ADA-SCID mice despite weekly PEG-ADA treatment. This was associated with lack of effective adenosine (Ado) detoxification in the thymus. We also show that thymocyte development in ADA-deficient thymi is arrested at the DN3-to-DN4 stage transition with thymocytes undergoing dATP-induced apoptosis rather than defective TCRß rearrangement or ß-selection. Our studies demonstrate at a detailed level that exogenous once-a-week enzyme replacement does not fully correct intra-thymic metabolic or immunological abnormalities associated with ADA deficiency.
Asunto(s)
Adenosina Desaminasa/uso terapéutico , Agammaglobulinemia/tratamiento farmacológico , Inmunodeficiencia Combinada Grave/tratamiento farmacológico , Timocitos/patología , Adenosina Desaminasa/deficiencia , Agammaglobulinemia/patología , Animales , Bovinos , Terapia de Reemplazo Enzimático , Ratones SCID , Inmunodeficiencia Combinada Grave/patología , Timocitos/efectos de los fármacos , Timocitos/metabolismoRESUMEN
Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, such as vasculitis, inflammation, and hematologic manifestations. Some associations of clinical features can mimic autoimmune lymphoproliferative syndrome (ALPS). We report a case of a female patient who fulfilled the 2009 National Institute of Health revised criteria for ALPS and received a delayed diagnosis of DADA2. During her childhood, she suffered from autoimmune hemolytic anemia, immune thrombocytopenia, and chronic lymphoproliferation, which partially responded to multiple lines of treatments and were followed, at 25 years of age, by pulmonary embolism, septic shock, and bone marrow failure with myelodysplastic evolution. The patient died from the progression of pulmonary disease and multiorgan failure. Two previously unreported variants of gene ADA2/CECR1 were found through next-generation sequencing analysis, and a pathogenic role was demonstrated through a functional study. A single somatic STAT3 mutation was also found. Clinical phenotypes encompassing immune dysregulation and marrow failure should be evaluated at the early stage of diagnostic work-up with an extended molecular evaluation. A correct genetic diagnosis may lead to a precision medicine approach consisting of the use of targeted treatments or early hematopoietic stem cell transplantation.
Asunto(s)
Adenosina Desaminasa/deficiencia , Síndrome Linfoproliferativo Autoinmune/genética , Trastornos de Fallo de la Médula Ósea/genética , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Corticoesteroides/uso terapéutico , Anemia Hemolítica Autoinmune/genética , Transfusión de Componentes Sanguíneos , Preescolar , Terapia Combinada , Diagnóstico Tardío , Resultado Fatal , Genes Recesivos , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunosupresores/uso terapéutico , Quelantes del Hierro/uso terapéutico , Insuficiencia Multiorgánica/etiología , Mutación Missense , Linaje , Embolia Pulmonar/etiología , Púrpura Trombocitopénica Idiopática/genética , Factor de Transcripción STAT3/genética , Esplenectomía , Evaluación de SíntomasRESUMEN
PURPOSE: Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients. The aim of this study was to perform in-depth immunophenotyping and functional analysis of the impact of DADA2 on human lymphocytes. METHODS: In-depth immunophenotyping and functional analyses were performed on ten patients with confirmed DADA2 and compared to heterozygous carriers of pathogenic ADA2 mutations and normal healthy controls. RESULTS: The median age of the patients was 10 years (mean 20.7 years, range 1-44 years). Four out of ten patients were on treatment with steroids and/or etanercept or other immunosuppressives. We confirmed a defect in terminal B cell differentiation in DADA2 and reveal a block in B cell development in the bone marrow at the pro-B to pre-B cell stage. We also show impaired differentiation of CD4+ and CD8+ memory T cells, accelerated exhaustion/senescence, and impaired survival and granzyme production by ADA2 deficient CD8+ T cells. Unconventional T cells (i.e. iNKT, MAIT, Vδ2+ γδT) were diminished whereas pro-inflammatory monocytes and CD56bright immature NK cells were increased. Expression of the IFN-induced lectin SIGLEC1 was increased on all monocyte subsets in DADA2 patients compared to healthy donors. Interestingly, the phenotype and function of lymphocytes from healthy heterozygous carriers were often intermediate to that of healthy donors and ADA2-deficient patients. CONCLUSION: Extended immunophenotyping in DADA2 patients shows a complex immunophenotype. Our findings provide insight into the cellular mechanisms underlying some of the complex and heterogenous clinical features of DADA2. More research is needed to design targeted therapy to prevent viral infections in these patients with excessive inflammation as the overarching phenotype.