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1.
J Allergy Clin Immunol ; 146(1): 192-202, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31862378

RESUMO

BACKGROUND: The gene AK2 encodes the phosphotransferase adenylate kinase 2 (AK2). Human variants in AK2 cause reticular dysgenesis, a severe combined immunodeficiency with agranulocytosis, lymphopenia, and sensorineural deafness that requires hematopoietic stem cell transplantation for survival. OBJECTIVE: We investigated the mechanisms underlying recurrent sinopulmonary infections and hypogammaglobulinemia in 15 patients, ranging from 3 to 34 years of age, from 9 kindreds. Only 2 patients, both of whom had mildly impaired T-cell proliferation, each had a single clinically significant opportunistic infection. METHODS: Patient cells were studied with next-generation DNA sequencing, tandem mass spectrometry, and assays of lymphocyte and mitochondrial function. RESULTS: We identified 2 different homozygous variants in AK2. AK2G100S and AK2A182D permit residual protein expression, enzymatic activity, and normal numbers of neutrophils and lymphocytes. All but 1 patient had intact hearing. The patients' B cells had severely impaired proliferation and in vitro immunoglobulin secretion. With activation, the patients' B cells exhibited defective mitochondrial respiration and impaired regulation of mitochondrial membrane potential and quality. Although activated T cells from the patients with opportunistic infections demonstrated impaired mitochondrial function, the mitochondrial quality in T cells was preserved. Consistent with the capacity of activated T cells to utilize nonmitochondrial metabolism, these findings revealed a less strict cellular dependence of T-cell function on AK2 activity. Chemical inhibition of ATP synthesis in control T and B cells similarly demonstrated the greater dependency of B cells on mitochondrial function. CONCLUSIONS: Our patients demonstrate the in vivo sequelae of the cell-specific requirements for the functions of AK2 and mitochondria, particularly in B-cell activation and antibody production.


Assuntos
Adenilato Quinase/genética , Linfócitos B/imunologia , Homozigoto , Ativação Linfocitária/genética , Mutação de Sentido Incorreto , Imunodeficiência Combinada Severa/genética , Adenilato Quinase/imunologia , Adulto , Substituição de Aminoácidos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia
2.
Clin Immunol ; 178: 39-44, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27890707

RESUMO

BACKGROUND: Hyper-IgE syndrome (HIES) due to DOCK8 deficiency is an autosomal recessive (AR) primary combined immunodeficiency which results in significant morbidity and mortality at a young age. Different mutations in the DOCK8 gene can lead to variable severity of the disease. OBJECTIVE: We evaluated the genetic mutations in three related patients with severe clinical manifestations suggestive of AR HIES. We also explored whether treatment with stem cell transplantation could lead to complete disease resolution. METHOD: We examined the clinical manifestations and immunological workup of these patients. Their DNA was also screened for causative mutation. Post transplantation, clinical and immunological data for the transplanted patient was also collected. RESULTS: All patients had a severe course of the disease with rarely reported severe complications in HIES. One patient died with lymphoma while another died with progressive multifocal leukoencephalopathy (PML) due to a slow virus. All our patients had two novel mutations in the DOCK8 gene. One of these mutations was a novel pathogenic mutation and explains the severity of the disease (homozygous splice site mutation at position 5 after the end of exon 45), while the other mutation was mostly non-pathogenic. Hematopoietic stem cell transplantation (HSCT) was performed in the youngest patient with excellent engraftment and full reversibility of the clinical manifestations. CONCLUSION: We report 3 patients from a consanguineous family diagnosed with AR-HIES due to a novel pathogenic mutation in DOCK8 gene leading to fatal outcome in 2 patients and complete resolution of the clinical and immunological features in the third patient by HSCT.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Síndrome de Job/genética , Adolescente , Neoplasias das Glândulas Suprarrenais/etiologia , Neoplasias das Glândulas Suprarrenais/virologia , Criança , Pré-Escolar , Colangite Esclerosante/etiologia , Consanguinidade , Eczema/etiologia , Eosinofilia/etiologia , Infecções por Vírus Epstein-Barr/etiologia , Esofagite/etiologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Herpes Simples/etiologia , Humanos , Síndrome de Job/complicações , Síndrome de Job/imunologia , Síndrome de Job/terapia , Leiomioma/etiologia , Leiomioma/virologia , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Leucoencefalopatia Multifocal Progressiva/etiologia , Leucoencefalopatia Multifocal Progressiva/patologia , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/virologia , Imageamento por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Neoplasias Nasofaríngeas/etiologia , Neoplasias Nasofaríngeas/virologia , Linhagem , Recidiva , Infecções Estafilocócicas/etiologia , Adulto Jovem
3.
Biol Blood Marrow Transplant ; 16(6): 818-23, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20079864

RESUMO

Major histocompatibility complex class II (MHC II) deficiency is a rare combined immunodeficiency disease. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Between June 1994 and February 2007, 30 children with MHC II deficiency underwent a total of 33 HSCT procedures. Median age at HSCT was 27 months. The stem cell source was unmanipulated bone marrow from HLA-identical related donors in 26 patients, one HLA antigen-mismatched bone marrow in 3 patients, and unrelated umbilical cord blood in 1 patient. Conditioning was with one of 3 myeloablative regimens--regimen A (18 patients): busulfan (Bu), cyclophosphamide (Cy), and etoposide; regimen B (2 patients): Bu, Cy, and antithymocyte globulin (ATG); or regimen C (1 patient): CY and total body irradiation (TBI)--or with a reduced-intensity regimen (12 patients): fludarabine, melphalan, and ATG. The median CD34 cell dose was 8.3 x 10(6)/kg. Twenty patients experienced immune reconstitution and had sustained engraftment ranging from 9% to 100% for lymphoid lines and from 5% to 100% for myeloid lines that were significant to cure the disease. The overall disease-free survival rate was 66% and 76% after HLA-identical HSCT, with a median follow-up of 6.3 years, which is higher than previously reported. In HLA-identical transplant recipients, reliable donor stem cell engraftment and immune reconstitution were achieved through myeloablative or reduced-intensity conditioning. Further studies and long-term follow-up are needed to determine the appropriate conditioning regimen.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Antígenos de Histocompatibilidade Classe II , Síndromes de Imunodeficiência/cirurgia , Agonistas Mieloablativos/uso terapêutico , Condicionamento Pré-Transplante/métodos , Contagem de Células Sanguíneas , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/métodos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto/imunologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histocompatibilidade/imunologia , Humanos , Imunoglobulina G/sangue , Síndromes de Imunodeficiência/imunologia , Lactente , Recém-Nascido , Contagem de Linfócitos , Linfócitos/citologia , Linfócitos/imunologia , Masculino , Estudos Retrospectivos , Quimeras de Transplante/imunologia , Transplante Homólogo , Resultado do Tratamento
4.
Sci Immunol ; 5(44)2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111619

RESUMO

We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T cell reconstitution after allogeneic hematopoietic stem cell transplantation, despite successful engraftment in three of them. We identified rare biallelic PAX1 rare variants in all patients. We demonstrated that these mutant PAX1 proteins have an altered conformation and flexibility of the paired box domain and reduced transcriptional activity. We generated patient-derived induced pluripotent stem cells and differentiated them into thymic epithelial progenitor cells and found that they have an altered transcriptional profile, including for genes involved in the development of the thymus and other tissues derived from pharyngeal pouches. These results identify biallelic, loss-of-function PAX1 mutations as the cause of a syndromic form of SCID due to altered thymus development.


Assuntos
Fatores de Transcrição Box Pareados/imunologia , Timo/imunologia , Síndrome Brânquio-Otorrenal/genética , Síndrome Brânquio-Otorrenal/imunologia , Síndrome Brânquio-Otorrenal/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Humanos , Lactente , Masculino , Fatores de Transcrição Box Pareados/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Timo/patologia
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