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1.
Am J Transplant ; 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31663273

RESUMO

Combined immune deficiency due to athymia in patients with complete DiGeorge Syndrome can be corrected by allogeneic thymus transplantation. Hypoparathyroidism is a frequent concomitant clinical problem in these patients, which persists after thymus transplantation. Co-transplantation of allogeneic thymus and parental parathyroid tissue has been attempted, but does not achieve durable correction of the patients' hypoparathyroidism due to parathyroid graft rejection. Surprisingly, we observed correction of hypoparathyroidism in one patient after thymus transplantation. Immunohistochemical analysis and Fluorescence in Situ Hybridisation confirmed presence of allogeneic parathyroid tissue in the patient's thymus transplant biopsy. Despite a lack of HLA-matching between thymus donor and recipient, the reconstituted immune system displays tolerance towards the thymus donor. Therefore we expect this patient's hypoparathyroidism to be permanently cured. It is recognised that ectopic parathyroid tissue is not infrequently found in the thymus. If such thymuses could be identified, we propose that their use would offer a compelling approach to achieving lasting correction of both immunodeficiency and hypoparathyroidism.

2.
Blood ; 133(24): 2586-2596, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31015189

RESUMO

DiGeorge syndrome (DGS) is a primary immunodeficiency characterized by various degrees of T-cell deficiency. In partial DGS (pDGS), other risk factors could predispose to recurrent infections, autoimmunity, and allergy. The aim of this study was to assess the effect of different factors in the development of infections, autoimmunity, and/or allergy in patients with pDGS. We studied 467 pDGS patients in follow-up at Great Ormond Street Hospital. Using a multivariate approach, we observed that palatal anomalies represent a risk factor for the development of recurrent otitis media with effusion. Gastroesophageal reflux/dysphagia and asthma/rhinitis represent a risk factor for the development of recurrent upper respiratory tract infections. Allergy and autoimmunity were associated with persistently low immunoglobulin M levels and lymphopenia, respectively. Patients with autoimmunity showed lower levels of CD3+, CD3+CD4+, and naïve CD4+CD45RA+CD27+ T lymphocytes compared with pDGS patients without autoimmunity. We also observed that the physiological age-related decline of the T-cell number was slower in pDGS patients compared with age-matched controls. The age-related recovery of the T-cell number depended on a homeostatic peripheral proliferation of T cells, as suggested by an accelerated decline of the naïve T lymphocytes in pDGS as well as a more skewed T-cell repertoire in older pDGS patients. These evidences suggest that premature CD4+ T-cell aging and lymphopenia induced spontaneous peripheral T-cell proliferation might contribute to the pathogenesis of autoimmunity in patients with pDGS. Infections in these patients represent, in most of the cases, a complication of anatomical or gastroenterological anomalies rather than a feature of the underlying immunodeficiency.

3.
J Pediatr ; 209: 97-106.e2, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30850087

RESUMO

OBJECTIVES: To investigate effects and outcome of hematopoietic stem cell transplantation (HSCT) on sclerosing cholangitis, in pediatric patients with different primary immunodeficiencies (PIDs). STUDY DESIGN: From databases in 2 tertiary centers for immunodeficiencies and liver disease, we have identified children with PIDs and sclerosing cholangitis, who have paired clinical, radiologic, and histologic information before and after HSCT and studied their clinical progress and outcome. RESULTS: Seven of 13 children (53.8%) died at a median interval of 4 months (range, 3 months-5 years) after HSCT. However, 6 surviving children (46.2%) with different PIDs and less severe cholangiopathies showed an improvement in markers of liver injury within months of successful unrelated reduced intensity conditioning HSCT. The repeated native liver biopsy, performed in 4 patients at a median of 96 (range, 4-144) months post-HSCT, showed a considerable improvement. Biochemical markers of liver function in the survivors completely normalized after a median of 13 months (range, 2-48). All patients continue to have a mildly dilated extrahepatic biliary system on ultrasonography with no intrahepatic ductal changes on magnetic resonance cholangiography after a follow-up of median 18 years (range, 2-20). CONCLUSIONS: Effective HSCT has the potential to improve biochemical and histologic features of cholangiopathy in children with PIDs, presumably by clearance of chronic infection following establishment of immune competence. However, careful patient selection is critical as advanced liver injury is often associated with serious complications and mortality.

5.
Eur J Immunol ; 49(5): 790-800, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30801692

RESUMO

STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN-α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon-related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

6.
Eur J Immunol ; 48(4): 716-719, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29318612

RESUMO

Nude mouse human thymus transplant model: Fresh or cryopreserved and thawed human thymus slices were transplanted subcutaneously into recipient nude mice. Nude mice subsequently produced mouse CD3+ CD4+ T-cells.

7.
Pediatr Infect Dis J ; 36(5): 504-506, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28403054

RESUMO

A prospective cohort study of children with primary immunodeficiencies undergoing hematopoietic stem cell transplant in the United Kingdom investigated the extent and significance of Cryptosporidium carriage in this high risk group. Three of 42 children recruited were infected with Cryptosporidium, a lower proportion than previously described. One had serious disease. The underlying immunodeficiency likely had a bearing on the clinical presentation and possible outcome of infection.


Assuntos
Criptosporidiose/epidemiologia , Cryptosporidium/isolamento & purificação , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/epidemiologia , Criança , Pré-Escolar , Criptosporidiose/imunologia , Criptosporidiose/parasitologia , Criptosporidiose/terapia , Cryptosporidium/crescimento & desenvolvimento , Europa (Continente)/epidemiologia , Feminino , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/parasitologia , Síndromes de Imunodeficiência/terapia , Lactente , Masculino , Prevalência , Estudos Prospectivos
8.
J Allergy Clin Immunol ; 140(6): 1660-1670.e16, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28400115

RESUMO

BACKGROUND: Thymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). METHODS: Twelve patients with cDGS underwent transplantation with allogeneic cultured thymus. OBJECTIVE: We sought to confirm and extend the results previously obtained in a single center. RESULTS: Two patients died of pre-existing viral infections without having thymopoiesis, and 1 late death occurred from autoimmune thrombocytopenia. One infant had septic shock shortly after transplantation, resulting in graft loss and the need for a second transplant. Evidence of thymopoiesis developed from 5 to 6 months after transplantation in 10 patients. Median circulating naive CD4 counts were 44 × 106/L (range, 11-440 × 106/L) and 200 × 106/L (range, 5-310 × 106/L) at 12 and 24 months after transplantation and T-cell receptor excision circles were 2,238/106 T cells (range, 320-8,807/106 T cells) and 4,184/106 T cells (range, 1,582-24,596/106 T cells). Counts did not usually reach normal levels for age, but patients were able to clear pre-existing infections and those acquired later. At a median of 49 months (range, 22-80 months), 8 have ceased prophylactic antimicrobials, and 5 have ceased immunoglobulin replacement. Histologic confirmation of thymopoiesis was seen in 7 of 11 patients undergoing biopsy of transplanted tissue, including 5 showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator expression was also demonstrated. Autoimmune complications were seen in 7 of 12 patients. In 2 patients early transient autoimmune hemolysis settled after treatment and did not recur. The other 5 experienced ongoing autoimmune problems, including thyroiditis (3), hemolysis (1), thrombocytopenia (4), and neutropenia (1). CONCLUSIONS: This study confirms the previous reports that thymus transplantation can reconstitute T cells in patients with cDGS but with frequent autoimmune complications in survivors.


Assuntos
Doenças Autoimunes/imunologia , Síndrome de DiGeorge/terapia , Transplante de Órgãos , Complicações Pós-Operatórias/imunologia , Linfócitos T/imunologia , Timo/transplante , Doenças Autoimunes/etiologia , Células Cultivadas , Criança , Pré-Escolar , Síndrome de DiGeorge/imunologia , Europa (Continente) , Feminino , Humanos , Reconstituição Imune , Lactente , Masculino , Técnicas de Cultura de Órgãos , Transplante Homólogo , Resultado do Tratamento
9.
Am J Hum Genet ; 100(2): 281-296, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28132690

RESUMO

EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities.


Assuntos
Anormalidades Musculoesqueléticas/genética , N-Acetilglucosaminiltransferases/genética , Osteocondrodisplasias/genética , Alelos , Linhagem Celular , Linhagem Celular Tumoral , Condroitina/sangue , Condroitina/urina , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Glicosaminoglicanos/metabolismo , Humanos , Anormalidades Musculoesqueléticas/diagnóstico , Mutação de Sentido Incorreto , Osteocondrodisplasias/diagnóstico , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética
10.
J Allergy Clin Immunol Pract ; 4(6): 1160-1166.e10, 2016 Nov - Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27707659

RESUMO

BACKGROUND: Methylenetetrahydrofolate dehydrogenase (MTHFD1) deficiency has recently been reported to cause a folate-responsive syndrome displaying a phenotype that includes megaloblastic anemia and severe combined immunodeficiency. OBJECTIVE: To describe our investigative approach to the molecular diagnosis and evaluation of immune dysfunction in a family with MTHFD1 deficiency. METHODS: The methods used were exome sequencing and analysis of variants in genes involved in the folate metabolic pathway in a family with 2 affected siblings. Routine laboratory and research data were analyzed to gain an in-depth understanding of innate, humoral, and cell-mediated immune function before and after folinic acid supplementation. RESULTS: Interrogation of exome data for concordant variants between the siblings in the genes involved in folate metabolic pathway identified a heterozygous mutation in exon 3 of the MTHFD1 gene that was shared with their mother. In view of highly suggestive phenotype, we extended our bioinformatics interrogation for structural variants in the MTHFD1 gene by manual evaluation of the exome data for sequence depth coverage of all the exons. A deletion involving exon 13 that was shared with their father was identified. Routine laboratory data showed lymphopenia involving all subsets and poor response to vaccines. In vitro analysis of dendritic cell and lymphocyte function was comparable to that in healthy volunteers. Treatment with folinic acid led to immune reconstitution, enabling discontinuation of all prophylactic therapies. CONCLUSIONS: Exome sequencing demonstrated MTHFD1 deficiency as a novel cause of a combined immunodeficiency. Folinic acid was established as precision therapy to reverse the clinical and laboratory phenotype of this primary immunodeficiency.


Assuntos
Anemia Megaloblástica/diagnóstico , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Antígenos de Histocompatibilidade Menor/genética , Imunodeficiência Combinada Severa/diagnóstico , Anemia Megaloblástica/tratamento farmacológico , Anemia Megaloblástica/genética , Anemia Megaloblástica/imunologia , Criança , Pré-Escolar , Exoma , Humanos , Lactente , Recém-Nascido , Leucovorina/uso terapêutico , Masculino , Metilenotetra-Hidrofolato Desidrogenase (NADP)/deficiência , Mutação , Imunodeficiência Combinada Severa/tratamento farmacológico , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia
13.
Nat Genet ; 48(1): 74-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26642240

RESUMO

Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.


Assuntos
Antígenos CD/genética , Antígenos CD/imunologia , Síndromes de Imunodeficiência/genética , Mutação de Sentido Incorreto , Receptores da Transferrina/genética , Receptores da Transferrina/imunologia , Imunidade Adaptativa/genética , Anemia/genética , Animais , Antígenos CD/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Cultivadas , Endocitose , Feminino , Fibroblastos/fisiologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Linhagem , Receptores da Transferrina/metabolismo
14.
J Immunol ; 195(12): 5608-15, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26546606

RESUMO

Nonhomologous end-joining (NHEJ) is one of the major DNA double-strand break repair pathways in mammalian cells and is required for both V(D)J recombination and class switch recombination (CSR), two Ig gene-diversification processes occurring during B cell development. DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) is a component of the classical NHEJ machinery and has a critical function during V(D)J recombination. However, its role in CSR has been controversial. In this study, we examined the pattern of recombination junctions from in vivo-switched B cells from two DNA-PKcs-deficient patients. One of them harbored mutations that did not affect DNA-PKcs kinase activity but caused impaired Artemis activation; the second patient had mutations resulting in diminished DNA-PKcs protein expression and kinase activity. These results were compared with those from DNA-PKcs-deficient mouse B cells. A shift toward the microhomology-based alternative end-joining at the recombination junctions was observed in both human and mouse B cells, suggesting that the classical NHEJ pathway is impaired during CSR when DNA-PKcs is defective. Furthermore, cells from the second patient showed additional or more severe alterations in CSR and/or NHEJ, which may suggest that DNA-PKcs and/or its kinase activity have additional, Artemis-independent functions during these processes.


Assuntos
Linfócitos B/imunologia , Proteína Quinase Ativada por DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Switching de Imunoglobulina , Síndromes de Imunodeficiência/imunologia , Proteínas Nucleares/metabolismo , Animais , Diferenciação Celular , Proteína Quinase Ativada por DNA/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Mutação/genética , Proteínas Nucleares/genética
15.
J Clin Immunol ; 35(4): 366-72, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25875700

RESUMO

PURPOSE: Adenosine deaminase (ADA) deficiency is a systemic disorder of purine metabolism. Deficiency of the purine salvage enzyme ADA leads to the build-up of the toxic metabolites, deoxyadenosine triphosphate and deoxyadenosine. ADA is ubiquitously expressed in all tissues of the body but most profoundly affects lymphocyte development and function leading to severe combined immunodeficiency (SCID). Unlike most other forms of SCID, ADA deficiency also results in non-immunologic manifestations. Associations between ADA deficiency and sensorineural hearing loss, behavioural abnormalities, non-infectious pulmonary disease and skeletal dysplasia are all recognised, and affect the long term outcome for these patients. Identification of new non-immunological manifestations and clinical presentations of ADA deficiency is essential to allow early optimisation of supportive care. METHODS AND RESULTS: Here we report four patients with ADA deficiency whose presenting feature was haemolytic uremic syndrome (HUS). 3 of 4 patients were diagnosed with ADA deficiency only after developing HUS, and one diagnosis was made post mortem, after a sibling was diagnosed with SCID. Shiga-toxigenic organisms were not isolated from any of the patients. 2 patients made a good recovery from their HUS with supportive treatment and initiation of PEG-ADA. Both remain well on enzyme replacement with mild or no residual renal impairment. CONCLUSIONS: Clinicians should be aware of this previously unreported non-immunologic manifestation of ADA deficiency.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Imunodeficiência Combinada Severa/diagnóstico , Adenosina Desaminase/genética , Agamaglobulinemia/tratamento farmacológico , Criança , Diagnóstico Diferencial , Evolução Fatal , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação , Imunodeficiência Combinada Severa/tratamento farmacológico
16.
J Clin Immunol ; 35(2): 147-57, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25663137

RESUMO

PURPOSE: Mutations in RMRP primarily give rise to Cartilage Hair Hypoplasia (CHH), a highly diverse skeletal disorder which can be associated with severe immunodeficiency. Increased availability of RMRP mutation screening has uncovered a number of infants with significant immunodeficiency but only mild or absent skeletal features. We surveyed the clinical and immunological phenotype of children who have undergone allogeneic haematopoietic stem cell transplantation for this condition in the UK. METHODS: Thirteen patients with confirmed RMRP mutations underwent allogeneic stem cell transplantation (SCT) at two nationally commissioned centres using a variety of donors and conditioning regimens. Records were retrospectively reviewed. RESULTS: Median time from clinical presentation to diagnosis was 12 months (range 1 to 276 months), with three infants diagnosed with severe combined immunodeficiency (SCID) without radiographical manifestations of CHH. A total of 17 allogeneic procedures were performed on 13 patients including two stem-cell top-ups. The median age at transplant was 32.4 months (range 1.5 to 125 months). Of the eleven surviving patients, median follow-up was 50 months (range 21.6 to 168 months). CONCLUSIONS: RMRP mutations can cause short stature and significant immunodeficiency which can be corrected by allogeneic SCT and the diagnosis should be considered even in the absence of skeletal manifestations.


Assuntos
Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Mutação , Fenótipo , RNA Longo não Codificante/genética , Alelos , Criança , Pré-Escolar , Feminino , Seguimentos , Genótipo , Doença Enxerto-Hospedeiro/etiologia , Cabelo/anormalidades , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/genética , Humanos , Síndromes de Imunodeficiência/terapia , Imunofenotipagem , Lactente , Recém-Nascido , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Osteocondrodisplasias/congênito , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Índice de Gravidade de Doença , Irmãos , Quimeras de Transplante , Resultado do Tratamento
17.
J Allergy Clin Immunol ; 133(6): 1660-6, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24794685

RESUMO

BACKGROUND: Severe combined immunodeficiency (SCID) can be cured by using allogeneic hematopoietic stem cell transplantation, and the absence of host immunity often obviates the need for preconditioning. Depending on the underlying genetic defect and when blocks in differentiation occur during lymphocyte ontogeny, infants with SCID have absent or greatly reduced numbers of functional T cells. Natural killer (NK) cell populations are usually absent in the SCID-X1 and Janus kinase 3 forms of SCID and greatly reduced in adenosine deaminase deficiency SCID but often present in other forms of the disorder. OBJECTIVE: To determine if SCID phenotypes indicate host permissiveness to donor cell engraftment. METHODS: A retrospective data analysis considered whether host NK cells influenced donor T-cell engraftment, immune reconstitution, and long-term outcomes in children who had undergone nonconditioned allogeneic stem cell transplantation between 1990 and 2011 in the United Kingdom. Detailed analysis of T- and B-cell immune reconstitution and donor chimerism was compared between the NK(+) (n = 24) and NK(-) (n = 53) forms of SCID. RESULTS: Overall, 77 children underwent transplantation, with survival of 90% in matched sibling donor/matched family donor transplants compared with 60% when alternative donors were used. Infants with NK(-)SCID were more likely to survive than NK(+) recipients (87% vs 62%, P < .01) and had high-level donor T-cell chimerism with superior long-term recovery of CD4 T-cell immunity. Notably, 33% of children with NK(+)SCID required additional transplantation procedures compared with only 8% of children with NK(-)SCID (P < .005). CONCLUSIONS: NK(-)SCID disorders are highly permissive for donor T-cell engraftment without preconditioning, whereas the presence of NK cells is a strong indicator that preparative conditioning is required for engraftment of T-cell precursors capable of supporting robust T-cell reconstitution.


Assuntos
Sobrevivência de Enxerto/imunologia , Células Matadoras Naturais/imunologia , Imunodeficiência Combinada Severa/imunologia , Linhagem da Célula/imunologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Recém-Nascido , Masculino , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/terapia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Quimeras de Transplante , Condicionamento Pré-Transplante , Transplante Homólogo
18.
Clin Infect Dis ; 58(3): 309-18, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24421306

RESUMO

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.


Assuntos
Hospedeiro Imunocomprometido , Vacinação/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Humanos , Lactente , Pessoa de Meia-Idade , Adulto Jovem
19.
Clin Infect Dis ; 58(3): e44-100, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24311479

RESUMO

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.


Assuntos
Hospedeiro Imunocomprometido , Vacinação/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Humanos , Lactente , Pessoa de Meia-Idade , Adulto Jovem
20.
J Clin Invest ; 124(1): 328-37, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24292712

RESUMO

Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain­7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development.


Assuntos
Atresia Intestinal/genética , Mucosa Intestinal/patologia , Proteínas/genética , Imunodeficiência Combinada Severa/genética , Sequência de Bases , Polaridade Celular , Células Cultivadas , Criança , Consanguinidade , Análise Mutacional de DNA , Células Epiteliais/fisiologia , Exoma , Feminino , Estudos de Associação Genética , Ligação Genética , Humanos , Lactente , Atresia Intestinal/imunologia , Atresia Intestinal/mortalidade , Atresia Intestinal/patologia , Linfonodos/patologia , Linfopenia/genética , Linfopenia/imunologia , Linfopenia/patologia , Masculino , Linhagem , Proteínas/metabolismo , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/patologia , Timo/anormalidades , Timo/patologia , Quinases Associadas a rho/metabolismo
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