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1.
J Allergy Clin Immunol Pract ; 8(1): 273-282, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31377437

RESUMO

BACKGROUND: Rituximab (RTX; anti-CD20 mAb) is a treatment option in children with refractory immune thrombocytopenia, autoimmune hemolytic anemia (AHA), and Evans syndrome (ES). Prevalence and clinical course of RTX-induced hypogammaglobulinemia in these patients are poorly known. OBJECTIVE: To evaluate the prevalence and risk factors for persistent hypogammaglobulinemia (PH) after RTX use. METHODS: Clinical and immunologic data from children treated with RTX for immune thrombocytopenia, AHA, and ES were collected from 16 Italian centers and 1 UK center at pre-RTX time point (0), +6 months, and yearly, up to 4 years post-RTX. Patients with previously diagnosed malignancy or primary immune deficiency (PID) were excluded. RESULTS: We analyzed 53 children treated with RTX for immune thrombocytopenia (n = 36), AHA (n = 13), and ES (n = 4). Median follow-up was 30 months (range, 12-48). Thirty-two percent of patients (17 of 53) experienced PH, defined as IgG levels less than 2 SD for age at last follow-up (>12 months after RTX). Significantly delayed B-cell recovery was observed in children experiencing PH (hazard ratio, 0.55; P < .05), and 6 of 17 (35%) patients had unresolved B-cell lymphopenia at last follow-up. PH was associated with IgA and IgM deficiency, younger age at RTX use (51 vs 116 months; P < .01), a diagnosis of AHA/ES, and better response to RTX. Nine patients with PH (9 of 17 [53%]) were eventually diagnosed with a PID. CONCLUSIONS: Post-RTX PH is a frequent condition in children with autoimmune cytopenia; a sizable proportion of patients with post-RTX PH were eventually diagnosed with a PID. In-depth investigation for PID is therefore recommended in these patients.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31874182

RESUMO

BACKGROUND: Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear. OBJECTIVE: We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations. METHODS: Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR. RESULTS: Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor-related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients' Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor-related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells. CONCLUSIONS: Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.

3.
Front Immunol ; 10: 1908, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456805

RESUMO

Severe combined immunodeficiencies (SCIDs) are a group of inborn errors of the immune system, usually associated with severe or life-threatening infections. Due to the variability of clinical phenotypes, the diagnostic complexity and the heterogeneity of the genetic basis, they are often difficult to recognize, leading to a significant diagnostic delay (DD). Aim of this study is to define presenting signs and natural history of SCID in a large cohort of patients, prior to hematopoietic stem cell or gene therapies. To this purpose, we conducted a 30-year retro-prospective multicenter study within the Italian Primary Immunodeficiency Network. One hundred eleven patients, diagnosed as typical or atypical SCID according to the European Society for Immune Deficiencies criteria, were included. Patients were subsequently classified based on the genetic alteration, pathogenic mechanism and immunological classification. A positive relationship between the age at onset and the DD was found. SCID patients with later onset were identified only in the last decade of observation. Syndromic SCIDs represented 28% of the cohort. Eight percent of the subjects were diagnosed in Intensive Care Units. Fifty-three percent had an atypical phenotype and most of them exhibited a discordant genotype-immunophenotype. Pre-treatment mortality was higher in atypical and syndromic patients. Our study broadens the knowledge of clinical and laboratory manifestations and genotype/phenotype correlation in patients with SCID and may facilitate the diagnosis of both typical and atypical forms of the disease in countries where newborn screening programs have not yet been implemented.

4.
Bone Marrow Transplant ; 54(12): 1995-2003, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31150018

RESUMO

Collection of an adequate amount of autologous haematopoietic stem progenitor cells (HSPC) is required for ex vivo manipulation and successful engraftment for certain inherited disorders. Fifty-seven paediatric patients (age 0.5-11.4 years) underwent a bone marrow harvest for the purpose of HSPC gene therapy (GT), including adenosine deaminase-severe combined immunodeficiency (ADA-SCID), Wiskott-Aldrich syndrome (WAS) and metachromatic leukodystrophy (MLD) patients. Total nucleated cells and the percentage and absolute counts of CD34+ cells were calculated at defined steps of the procedure (harvest, CD34+ cell purification, transduction with the gene transfer vector and infusion of the medicinal product). A minimum CD34+ cell dose for infusion was 2 × 106/kg, with an optimal target at 5-10 × 106/kg. Median volume of bone marrow harvested was 34.2 ml/kg (range 14.2-56.6). The number of CD34+ cells collected correlated inversely with weight and age in all patients and particularly in the MLD children group. All patients reached the minimum target dose for infusion: median dose of CD34+ cells/kg infused was 10.3 × 106/kg (3.7-25.9), with no difference among the three groups. Bone marrow harvest of volumes > 30 ml/kg in infants and children with ADA-SCID, WAS and MLD is well tolerated and allows obtaining an adequate dose of a medicinal product for HSPC-GT.

6.
Front Immunol ; 10: 316, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031743

RESUMO

Background: Primary Immunodeficiencies (PIDs) are a heterogeneous group of genetic immune disorders. While some PIDs can manifest with more than one phenotype, signs, and symptoms of various PIDs overlap considerably. Recently, novel defects in immune-related genes and additional variants in previously reported genes responsible for PIDs have been successfully identified by Next Generation Sequencing (NGS), allowing the recognition of a broad spectrum of disorders. Objective: To evaluate the strength and weakness of targeted NGS sequencing using custom-made Ion Torrent and Haloplex (Agilent) panels for diagnostics and research purposes. Methods: Five different panels including known and candidate genes were used to screen 105 patients with distinct PID features divided in three main PID categories: T cell defects, Humoral defects and Other PIDs. The Ion Torrent sequencing platform was used in 73 patients. Among these, 18 selected patients without a molecular diagnosis and 32 additional patients were analyzed by Haloplex enrichment technology. Results: The complementary use of the two custom-made targeted sequencing approaches allowed the identification of causative variants in 28.6% (n = 30) of patients. Twenty-two out of 73 (34.6%) patients were diagnosed by Ion Torrent. In this group 20 were included in the SCID/CID category. Eight out of 50 (16%) patients were diagnosed by Haloplex workflow. Ion Torrent method was highly successful for those cases with well-defined phenotypes for immunological and clinical presentation. The Haloplex approach was able to diagnose 4 SCID/CID patients and 4 additional patients with complex and extended phenotypes, embracing all three PID categories in which this approach was more efficient. Both technologies showed good gene coverage. Conclusions: NGS technology represents a powerful approach in the complex field of rare disorders but its different application should be weighted. A relatively small NGS target panel can be successfully applied for a robust diagnostic suspicion, while when the spectrum of clinical phenotypes overlaps more than one PID an in-depth NGS analysis is required, including also whole exome/genome sequencing to identify the causative gene.

8.
Lancet Haematol ; 6(5): e239-e253, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30981783

RESUMO

BACKGROUND: Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC) gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy. METHODS: We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP) expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462) and EudraCT (number 2009-017346-32). FINDINGS: Between April 20, 2010, and Feb 26, 2015, nine patients (all male) were enrolled of whom one was excluded after screening; the age range of the eight treated children was 1·1-12·4 years. At the time of the interim analysis (data cutoff April 29, 2016), median follow-up was 3·6 years (range 0·5-5·6). Overall survival was 100%. Engraftment of genetically corrected HSPCs was successful and sustained in all patients. The fraction of WASP-positive lymphocytes increased from a median of 3·9% (range 1·8-35·6) before gene therapy to 66·7% (55·7-98·6) at 12 months after gene therapy, whereas WASP-positive platelets increased from 19·1% (range 4·1-31·0) to 76·6% (53·1-98·4). Improvement of immune function was shown by normalisation of in-vitro T-cell function and successful discontinuation of immunoglobulin supplementation in seven patients with follow-up longer than 1 year, followed by positive antigen-specific response to vaccination. Severe infections fell from 2·38 (95% CI 1·44-3·72) per patient-year of observation (PYO) in the year before gene therapy to 0·31 (0·04-1·11) per PYO in the second year after gene therapy and 0·17 (0·00-0·93) per PYO in the third year after gene therapy. Before gene therapy, platelet counts were lower than 20 × 109 per L in seven of eight patients. At the last follow-up visit, the platelet count had increased to 20-50 × 109 per L in one patient, 50-100 × 109 per L in five patients, and more than 100 × 109 per L in two patients, which resulted in independence from platelet transfusions and absence of severe bleeding events. 27 serious adverse events in six patients occurred after gene therapy, 23 (85%) of which were infectious (pyrexia [five events in three patients], device-related infections, including one case of sepsis [four events in three patients], and gastroenteritis, including one case due to rotavirus [three events in two patients]); these occurred mainly in the first 6 months of follow-up. No adverse reactions to the investigational drug product and no abnormal clonal proliferation or leukaemia were reported after gene therapy. INTERPRETATION: Data from this study show that gene therapy provides a valuable treatment option for patients with severe Wiskott-Aldrich syndrome, particularly for those who do not have a suitable HSPC donor available. FUNDING: Italian Telethon Foundation, GlaxoSmithKline, and Orchard Therapeutics.


Assuntos
Terapia Genética , Vetores Genéticos/genética , Células-Tronco Hematopoéticas/metabolismo , Lentivirus/genética , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/terapia , Criança , Pré-Escolar , Feminino , Terapia Genética/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Itália , Masculino , Mutação , Linfócitos T/imunologia , Linfócitos T/metabolismo , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Síndrome de Wiskott-Aldrich/sangue , Síndrome de Wiskott-Aldrich/diagnóstico , Proteína da Síndrome de Wiskott-Aldrich/genética
10.
Blood ; 132(22): 2362-2374, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30254128

RESUMO

ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper-immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-α-directed migration. Gene transfer of ARPC1B in patients' T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD8+ T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID.


Assuntos
Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Mutação em Linhagem Germinativa , Síndromes de Imunodeficiência/genética , Linfócitos T/patologia , Complexo 2-3 de Proteínas Relacionadas à Actina/química , Feminino , Homozigoto , Humanos , Síndromes de Imunodeficiência/patologia , Masculino , Modelos Moleculares , Linhagem , Conformação Proteica , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/patologia , Linfócitos T/metabolismo
12.
Front Immunol ; 9: 544, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29651287

RESUMO

Anti-cytokine autoantibodies (ACAAs) have been described in a growing number of primary immunodeficiencies with autoimmune features, including autoimmune polyendocrine syndrome type I (APS-1), a prototypical disease of defective T cell-mediated central tolerance. Whether defects in peripheral tolerance lead to similar ACAAs is unknown. Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) is caused by mutations in FOXP3, a master regulator of T regulatory cells (Treg), and consequently results in defective T cell-mediated peripheral tolerance. Unique autoantibodies have previously been described in IPEX. To test the hypothesis that ACAAs are present in IPEX, we designed and fabricated antigen microarrays. We discovered elevated levels of IgG ACAAs against interferon-α (IFN-α) in a cohort of IPEX patients. Serum from IPEX patients blocked IFN-α signaling in vitro and blocking activity was tightly correlated with ACAA titer. To show that blocking activity was mediated by IgG and not other serum factors, we purified IgG and showed that blocking activity was contained entirely in the immunoglobulin fraction. We also screened for ACAAs against IFN-α in a second geographically distinct cohort. In these samples, ACAAs against IFN-α were elevated in a post hoc analysis. In summary, we report the discovery of ACAAs against IFN-α in IPEX, an experiment of nature demonstrating the important role of peripheral T cell tolerance.


Assuntos
Anticorpos Neutralizantes/imunologia , Autoanticorpos/imunologia , Imunoglobulina G/imunologia , Interferon-alfa/imunologia , Poliendocrinopatias Autoimunes/imunologia , Criança , Humanos , Lactente
13.
Front Immunol ; 9: 543, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29599784

RESUMO

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.


Assuntos
Síndromes de Imunodeficiência/tratamento farmacológico , Imunossupressores/uso terapêutico , Sistema de Registros , Sirolimo/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases , Europa (Continente) , Humanos , Pessoa de Meia-Idade , Sociedades Médicas , Adulto Jovem
14.
Front Immunol ; 9: 113, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29456531

RESUMO

Adenosine deaminase-deficient severe combined immunodeficiency disease (ADA-SCID) is a primary immune deficiency characterized by mutations in the ADA gene resulting in accumulation of toxic compounds affecting multiple districts. Hematopoietic stem cell transplantation (HSCT) from a matched donor and hematopoietic stem cell gene therapy are the preferred options for definitive treatment. Enzyme replacement therapy (ERT) is used to manage the disease in the short term, while a decreased efficacy is reported in the medium-long term. To date, eight cases of lymphomas have been described in ADA-SCID patients. Here we report the first case of plasmablastic lymphoma occurring in a young adult with ADA-SCID on long-term ERT, which turned out to be Epstein-Barr virus associated. The patient previously received infusions of genetically modified T cells. A cumulative analysis of the eight published cases of lymphoma from 1992 to date, and the case here described, reveals a high mortality (89%). The most common form is diffuse large B-cell lymphoma, which predominantly occurs in extra nodal sites. Seven cases occurred in patients on ERT and two after haploidentical HSCT. The significant incidence of immunodeficiency-associated lymphoproliferative disorders and poor survival of patients developing this complication highlight the priority in finding a prompt curative treatment for ADA-SCID.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/complicações , Infecções por Vírus Epstein-Barr/complicações , Linfoma Plasmablástico/etiologia , Imunodeficiência Combinada Severa/complicações , Adenosina Desaminase/uso terapêutico , Adolescente , Agamaglobulinemia/tratamento farmacológico , Agamaglobulinemia/etiologia , Terapia de Reposição de Enzimas , Evolução Fatal , Feminino , Humanos , Linfoma Plasmablástico/diagnóstico , Imunodeficiência Combinada Severa/tratamento farmacológico , Imunodeficiência Combinada Severa/etiologia
16.
J Allergy Clin Immunol ; 141(3): 1036-1049.e5, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29241729

RESUMO

BACKGROUND: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. OBJECTIVE: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. METHODS: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. RESULTS: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. CONCLUSIONS: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia , Fatores de Transcrição Forkhead , Doenças Genéticas Ligadas ao Cromossomo X , Transplante de Células-Tronco Hematopoéticas , Doenças do Sistema Imunitário/congênito , Imunossupressão , Mutação , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/mortalidade , Diabetes Mellitus Tipo 1/terapia , Diarreia/genética , Diarreia/imunologia , Diarreia/mortalidade , Diarreia/terapia , Intervalo Livre de Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/mortalidade , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/mortalidade , Doenças do Sistema Imunitário/terapia , Lactente , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
17.
Ann N Y Acad Sci ; 1417(1): 5-22, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-26918796

RESUMO

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder that increasingly has gained attention as a model of genetic autoimmunity. Numerous papers documenting the key clinical and molecular characteristics of IPEX have provided a detailed understanding of this devastating disease. IPEX is a primary immunodeficiency caused by mutations in the gene FOXP3, which encodes an essential transcription factor required for maintenance of thymus-derived regulatory T (tTreg ) cells. tTreg  cell dysfunction is the main pathogenic event leading to multiorgan autoimmunity in IPEX. In addition to the traditional clinical presentation (i.e., severe enteropathy, type 1 diabetes, and eczema), IPEX may encompass other variable and distinct clinical manifestations. As IPEX awareness and characterization have increased, so has identification of FOXP3 mutations, with at least 70 to date. Thus, while FOXP3 is the unifying gene, IPEX is a complex and diverse clinical continuum of disorders. Despite understanding IPEX pathogenesis, new treatment options have remained elusive, although early diagnosis led to hematopoietic stem cell transplantation (HSCT) and immunosuppression treatment and improved patient outcomes. Here, we review current knowledge about IPEX syndrome and highlight findings that could lead to novel targeted treatments.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia/genética , Diarreia/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças do Sistema Imunitário/congênito , Linfócitos B/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Diarreia/terapia , Feminino , Fatores de Transcrição Forkhead/química , Regulação da Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Imunossupressão , Recém-Nascido , Masculino , Modelos Genéticos , Modelos Imunológicos , Mutação , Fenótipo , Gravidez , Regiões Promotoras Genéticas , Domínios Proteicos , Sequências Reguladoras de Ácido Nucleico , Subpopulações de Linfócitos T/imunologia
18.
Front Immunol ; 9: 2767, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30692987

RESUMO

Adenosine deaminase 2 (ADA2) deficiency is an auto-inflammatory disease due to mutations in cat eye syndrome chromosome region candidate 1 (CECR1) gene, currently named ADA2. The disease has a wide clinical spectrum encompassing early-onset vasculopathy (targeting skin, gut and central nervous system), recurrent fever, immunodeficiency and bone marrow dysfunction. Different therapeutic options have been proposed in literature, but only steroids and anti-cytokine monoclonal antibodies (such as tumor necrosis factor inhibitor) proved to be effective. If a suitable donor is available, hematopoietic stem cell transplantation (HSCT) could be curative. Here we describe a case of ADA2 deficiency in a 4-year-old Caucasian girl. The patient was initially classified as autoimmune neutropenia and then she evolved toward an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. The diagnosis of ALPS became uncertain due to atypical clinical features and normal FAS-induced apoptosis test. She was treated with G-CSF first and subsequently with immunosuppressive drugs without improvement. Only HSCT from a 9/10 HLA-matched unrelated donor, following myeloablative conditioning, completely solved the clinical signs related to ADA2 deficiency. Early diagnosis in cases presenting with hematological manifestations, rather than classical vasculopathy, allows the patients to promptly undergo HSCT and avoid more severe evolution. Finally, in similar cases highly suspicious for genetic disease, it is desirable to obtain molecular diagnosis before performing HSCT, since it can influence the transplant procedure. However, if HSCT has to be performed without delay for clinical indication, related donors should be excluded to avoid the risk of relapse or partial benefit due to a hereditary genetic defect.


Assuntos
Adenosina Desaminase/deficiência , Síndrome Linfoproliferativa Autoimune/terapia , Transplante de Células-Tronco Hematopoéticas , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Condicionamento Pré-Transplante , Doadores não Relacionados , Adenosina Desaminase/imunologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Síndrome Linfoproliferativa Autoimune/enzimologia , Síndrome Linfoproliferativa Autoimune/imunologia , Síndrome Linfoproliferativa Autoimune/patologia , Pré-Escolar , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Neutropenia/enzimologia , Neutropenia/imunologia , Neutropenia/patologia , Neutropenia/terapia , Transplante Homólogo , Receptor fas/imunologia
19.
Sci Rep ; 7: 40136, 2017 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-28074903

RESUMO

Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzyme replacement therapy with PEG-ADA. These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety-like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency.


Assuntos
Adenosina Desaminase/deficiência , Adenosina/metabolismo , Encéfalo/metabolismo , Doenças do Sistema Nervoso/fisiopatologia , Animais , Comportamento , Comportamento Animal , Humanos , Camundongos , Doenças do Sistema Nervoso/patologia
20.
Blood ; 128(1): 45-54, 2016 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-27129325

RESUMO

Adenosine deaminase (ADA) deficiency is a rare, autosomal-recessive systemic metabolic disease characterized by severe combined immunodeficiency (SCID). The treatment of choice for ADA-deficient SCID (ADA-SCID) is hematopoietic stem cell transplant from an HLA-matched sibling donor, although <25% of patients have such a donor available. Enzyme replacement therapy (ERT) partially and temporarily relieves immunodeficiency. We investigated the medium-term outcome of gene therapy (GT) in 18 patients with ADA-SCID for whom an HLA-identical family donor was not available; most were not responding well to ERT. Patients were treated with an autologous CD34(+)-enriched cell fraction that contained CD34(+) cells transduced with a retroviral vector encoding the human ADA complementary DNA sequence (GSK2696273) as part of single-arm, open-label studies or compassionate use programs. Overall survival was 100% over 2.3 to 13.4 years (median, 6.9 years). Gene-modified cells were stably present in multiple lineages throughout follow up. GT resulted in a sustained reduction in the severe infection rate from 1.17 events per person-year to 0.17 events per person-year (n = 17, patient 1 data not available). Immune reconstitution was demonstrated by normalization of T-cell subsets (CD3(+), CD4(+), and CD8(+)), evidence of thymopoiesis, and sustained T-cell proliferative capacity. B-cell function was evidenced by immunoglobulin production, decreased intravenous immunoglobulin use, and antibody response after vaccination. All 18 patients reported infections as adverse events; infections of respiratory and gastrointestinal tracts were reported most frequently. No events indicative of leukemic transformation were reported. Trial details were registered at www.clinicaltrials.gov as #NCT00598481.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/terapia , Terapia Genética , Recuperação de Função Fisiológica , Retroviridae , Imunodeficiência Combinada Severa/terapia , Adenosina Desaminase/genética , Adenosina Desaminase/imunologia , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Agamaglobulinemia/mortalidade , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/mortalidade , Taxa de Sobrevida
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