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1.
Clin Immunol ; 203: 125-133, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31028919

RESUMO

Intestinal epithelial cells (IECs) form a fundamental mucosal barrier and actively participate in tolerance and immunity against intestinal contents. Major histocompatibility complex class II (MHC II) and invariant chain (Ii) molecules are essential for adaptive immune response. MHC II deficiency often presents with gastrointestinal disorders. Intestinal biopsy samples revealed an absence of HLA-DR, Ii, and local immunoglobulins in both hematopoietic immune cells and IECs accompanied by a lack of faecal sIgA. After successful hematopoietic stem cell transplantation (HSCT) absent HLA-DR and Ii expression persisted in IECs and faecal stool analysis indicated inflammation and high microbial activity. We describe multifaceted disturbance of adaptive mucosal immunity in MHC II deficient patients suffering from enteropathy. HLA-DR and Ii expression on enterocytes is not restored by HSCT. This may account for increased susceptibility to enteric infections and intestinal inflammation leading to prolonged enteropathy reported in MHC II deficient patients.

2.
Clin Immunol ; 201: 30-34, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30776520

RESUMO

Severe combined immunodeficiencies (SCID) comprise a group of genetic diseases characterized by abrogated development of T lymphocytes. In some case reports of atypical SCID patients elevated proportions of γδ T lymphocytes have been reported. However, it is unknown whether these γδ T cells modulate or reflect the patient's clinical phenotype. We investigated the frequency of elevated γδ T cell proportions and associations with clinical disease manifestations in a cohort of 76 atypical SCID patients. Increased proportions of γδ T lymphocytes were present in approximately 60% of these patients. Furthermore, we identified positive correlations between elevated proportions of γδ T cells and the occurrence of CMV infections and autoimmune cytopenias. We discuss that CMV infections might trigger an expansion of γδ T lymphocytes, which could drive the development of autoimmune cytopenias. We advocate that atypical SCID patients should be screened for elevated proportions of γδ T lymphocytes, CMV infection and autoimmune cytopenias.

4.
Proc Natl Acad Sci U S A ; 116(3): 970-975, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30591564

RESUMO

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.


Assuntos
Diferenciação Celular , Imunidade nas Mucosas/genética , Doenças Inflamatórias Intestinais , Mucosa Intestinal , Proteína Serina-Treonina Quinases de Interação com Receptores , Imunodeficiência Combinada Severa , Linfócitos B/imunologia , Linfócitos B/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Células HCT116 , Células HEK293 , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Mutação , NF-kappa B/genética , NF-kappa B/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
5.
Pediatr Allergy Immunol ; 27(2): 177-84, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26592211

RESUMO

BACKGROUND: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by elevated serum IgE, eczema, and recurrent infections. Despite the availability of confirmatory molecular diagnosis of several distinct HIES entities, the differentiation of HIES particularly from severe forms of atopic dermatitis remains a challenge. The two most common forms of HIES are caused by mutations in the genes STAT3 and DOCK8. METHODS: Here, we assess the clinical and immunologic phenotype of DOCK8- and STAT3-HIES patients including the cell activation, proliferation, and cytokine release after stimulation. RESULTS: Existing HIES scoring systems are helpful to identify HIES patients. However, those scores may fail in infants and young children due to the age-related lack of clinical symptoms. Furthermore, our long-term observations showed a striking variation of laboratory results over time in the individual patient. Reduced memory B-cell counts in concert with low specific antibody production are the most consistent findings likely contributing to the high susceptibility to bacterial and fungal infection. In DOCK8-HIES, T-cell lymphopenia and low IFN-gamma secretion after stimulation were common, likely promoting viral infections. In contrast to STAT3-HIES, DOCK8-HIES patients showed more severe inflammation with regard to allergic manifestations, elevated activation markers (HLA-DR, CD69, CD86, and CD154), and significantly increased inflammatory cytokines (IL1-beta, IL4, IL6, and IFN-gamma). CONCLUSION: Differentiating HIES from other diseases such as atopic dermatitis early in life is essential for patients because treatment modalities differ. To expedite the diagnosis process, we propose here a diagnostic workflow.


Assuntos
Dermatite Atópica/diagnóstico , Fatores de Troca do Nucleotídeo Guanina/genética , Síndrome de Job/diagnóstico , Mutação/genética , Fator de Transcrição STAT3/genética , Linfócitos B/imunologia , Células Cultivadas , Pré-Escolar , Citocinas/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Imunoglobulina E/sangue , Memória Imunológica , Lactente , Síndrome de Job/genética , Ativação Linfocitária/genética , Masculino , Linfócitos T/imunologia
6.
J Immunol ; 194(8): 3768-77, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25780036

RESUMO

IL-21 can induce both plasma cells and regulatory B cells. In this article, we demonstrate that untreated HIV patients display CD4(+) T cells with enhanced IL-21 expression and high in vivo frequencies of regulatory B cells overexpressing the serine protease granzyme B. Granzyme B-expressing regulatory B cells (GraB cells) cells from HIV patients exhibit increased expression of CD5, CD43, CD86, and CD147 but do not produce IL-10. The main functional characteristic of their regulatory activity is direct granzyme B-dependent degradation of the TCR-ζ-chain, resulting in significantly decreased proliferative T cell responses. Although Th cells from HIV patients secrete IL-21 in a Nef-dependent manner, they barely express CD40L. When culturing such IL-21(+)CD40L(-) Th cells with B cells, the former directly induce B cell differentiation into GraB cells. In contrast, the addition of soluble CD40L multimers to T cell/B cell cultures redirects B cell differentiation toward plasma cells, indicating that CD40L determines the direction of IL-21-dependent B cell differentiation. As proof of principle, we confirmed this mechanism in a patient lacking intact CD40 signaling due to a NEMO mutation. The majority of peripheral B cells from this patient were GraB cells and strongly suppressed T cell proliferation. In conclusion, GraB cells represent potent regulatory B cells in humans that are phenotypically and functionally distinct from B10 cells and occur in early HIV infection. GraB cells may contribute significantly to immune dysfunction in HIV patients, and may also explain ineffective Ab responses after vaccination. The use of soluble CD40L multimers may help to improve vaccination responses in HIV patients.


Assuntos
Linfócitos B Reguladores/imunologia , Antígenos CD40/imunologia , Diferenciação Celular/imunologia , Regulação Enzimológica da Expressão Gênica/imunologia , Granzimas/imunologia , Infecções por HIV/imunologia , Interleucinas/imunologia , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas contra a AIDS/uso terapêutico , Linfócitos B Reguladores/patologia , Antígenos CD40/genética , Ligante de CD40/genética , Ligante de CD40/imunologia , Diferenciação Celular/genética , Proliferação de Células/genética , Feminino , Granzimas/genética , Infecções por HIV/genética , Infecções por HIV/patologia , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/imunologia , Interleucinas/genética , Masculino , Mutação , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/genética , Linfócitos T Auxiliares-Indutores/patologia , Vacinação
7.
J Clin Immunol ; 35(2): 189-98, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25627830

RESUMO

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.


Assuntos
Estudos de Associação Genética , Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Incidência , Lactente , Infecção/diagnóstico , Infecção/epidemiologia , Infecção/etiologia , Síndrome de Job/complicações , Síndrome de Job/diagnóstico , Síndrome de Job/genética , Síndrome de Job/imunologia , Síndrome de Job/mortalidade , Síndrome de Job/terapia , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/epidemiologia , Neoplasias/etiologia , Fenótipo , Adulto Jovem
8.
J Allergy Clin Immunol ; 134(4): 935-943.e15, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25109802

RESUMO

BACKGROUND: Patients with severe combined immunodeficiency disease who have matched sibling donors (MSDs) can proceed to hematopoietic cell transplantation (HCT) without conditioning chemotherapy. OBJECTIVE: We sought to determine whether the results of HCT without chemotherapy-based conditioning from matched unrelated donors (URDs), either from volunteer adults or umbilical cord blood, are comparable with those from MSDs. METHODS: We performed a multicenter survey of severe combined immunodeficiency transplantation centers in North America, Europe, and Australia to compile retrospective data on patients who have undergone unconditioned HCT from either URDs (n = 37) or MSDs (n = 66). RESULTS: Most patients undergoing URD HCT (92%) achieved donor T-cell engraftment compared with 97% for those with MSDs; however, estimated 5-year overall and event-free survival were worse for URD recipients (71% and 60%, respectively) compared with MSD recipients (92% and 89%, respectively; P < .01 for both). URD recipients who received pre-HCT serotherapy had similar 5-year overall survival (100%) to MSD recipients. The incidences of grade II to IV acute and chronic graft-versus-host disease were higher in URD (50% and 39%, respectively) compared with MSD (22% and 5%, respectively) recipients (P < .01 for both). In the surviving patients there was no difference in T-cell reconstitution at the last follow-up between the URD and MSD recipients; however, MSD recipients were more likely to achieve B-cell reconstitution (72% vs 17%, P < .001). CONCLUSION: Unconditioned URD HCT achieves excellent rates of donor T-cell engraftment similar to that seen in MSD recipients, and reconstitution rates are adequate. However, only a minority will have myeloid and B-cell reconstitution, and attention must be paid to graft-versus-host disease prophylaxis. This approach might be safer in children ineligible for intense regimens to spare the potential complications of chemotherapy.


Assuntos
Linfócitos B/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa/terapia , Irmãos , Linfócitos T/imunologia , Doadores não Relacionados , Adulto , Austrália , Criança , Quimerismo , Europa (Continente) , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Histocompatibilidade , Teste de Histocompatibilidade , Humanos , Lactente , Recém-Nascido , Masculino , América do Norte , Estudos Retrospectivos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/mortalidade , Análise de Sobrevida , Condicionamento Pré-Transplante , Resultado do Tratamento , Voluntários
10.
Blood ; 120(17): 3615-24; quiz 3626, 2012 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-22791287

RESUMO

Deficiency of the purine salvage enzyme adenosine deaminase leads to SCID (ADA-SCID). Hematopoietic cell transplantation (HCT) can lead to a permanent cure of SCID; however, little data are available on outcome of HCT for ADA-SCID in particular. In this multicenter retrospective study, we analyzed outcome of HCT in 106 patients with ADA-SCID who received a total of 119 transplants. HCT from matched sibling and family donors (MSDs, MFDs) had significantly better overall survival (86% and 81%) in comparison with HCT from matched unrelated (66%; P < .05) and haploidentical donors (43%; P < .001). Superior overall survival was also seen in patients who received unconditioned transplants in comparison with myeloablative procedures (81% vs 54%; P < .003), although in unconditioned haploidentical donor HCT, nonengraftment was a major problem. Long-term immune recovery showed that regardless of transplant type, overall T-cell numbers were similar, although a faster rate of T-cell recovery was observed after MSD/MFD HCT. Humoral immunity and donor B-cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HCT. These data detail for the first time the outcomes of HCT for ADA-SCID and show that, if patients survive HCT, long-term cellular and humoral immune recovery is achieved.


Assuntos
Agamaglobulinemia/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa/tratamento farmacológico , Condicionamento Pré-Transplante , Adenosina Desaminase/deficiência , Adenosina Desaminase/imunologia , Agamaglobulinemia/imunologia , Agamaglobulinemia/mortalidade , Agamaglobulinemia/patologia , Criança , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Teste de Histocompatibilidade , Humanos , Imunidade Celular , Imunidade Humoral , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Masculino , Agonistas Mieloablativos/uso terapêutico , Estudos Retrospectivos , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/patologia , Irmãos , Linfócitos T/imunologia , Resultado do Tratamento , Doadores não Relacionados
11.
Blood ; 118(6): 1675-84, 2011 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-21659547

RESUMO

In this retrospective collaborative study, we have analyzed long-term outcome and donor cell engraftment in 194 patients with Wiskott-Aldrich syndrome (WAS) who have been treated by hematopoietic cell transplantation (HCT) in the period 1980- 2009. Overall survival was 84.0% and was even higher (89.1% 5-year survival) for those who received HCT since the year 2000, reflecting recent improvement of outcome after transplantation from mismatched family donors and for patients who received HCT from an unrelated donor at older than 5 years. Patients who went to transplantation in better clinical conditions had a lower rate of post-HCT complications. Retrospective analysis of lineage-specific donor cell engraftment showed that stable full donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte count and post-HCT autoimmunity, and myeloid donor cell chimerism < 50% was associated with persistent thrombocytopenia. These observations indicate continuous improvement of outcome after HCT for WAS and may have important implications for the development of novel protocols aiming to obtain full correction of the disease and reduce post-HCT complications.


Assuntos
Linhagem da Célula , Transplante de Células-Tronco Hematopoéticas/métodos , Quimeras de Transplante/sangue , Síndrome de Wiskott-Aldrich/cirurgia , Autoimunidade/imunologia , Doadores de Sangue , Criança , Pré-Escolar , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Mutação , Avaliação de Resultados (Cuidados de Saúde)/estatística & dados numéricos , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/imunologia , Estudos Retrospectivos , Análise de Sobrevida , Trombocitopenia/sangue , Trombocitopenia/etiologia , Fatores de Tempo , Síndrome de Wiskott-Aldrich/sangue , Síndrome de Wiskott-Aldrich/genética
12.
Hematol Oncol Clin North Am ; 25(1): 31-44, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21236388

RESUMO

Curative treatment of Severe Combined Immunodeficiency (SCID) by Hematopoietic Cell Transplantation (HCT) remains a challenge, in particular in infants presenting with serious, poorly controllable complications. In the absence of a matched family donor, HLA-haploidentical transplantation from parental donors represents a uniformly and readily available treatment option, offering a high chance to be successful. Concerning outcomes of HCT in SCID, other important parameters beside survival need to be taken into consideration, in particular the stability and robustness of the graft and its function, as well as potential late complications, related either to the disease or to the treatment.

13.
Immunity ; 33(5): 736-51, 2010 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-21093318

RESUMO

Whether the recently identified innate lymphocyte population coexpressing natural killer cell receptors (NKRs) and the nuclear receptor RORγt is part of the NK or lymphoid tissue inducer (LTi) cell lineage remains unclear. By using adoptive transfer of genetically tagged LTi-like cells, we demonstrate that NKR⁻RORγt(+) innate lymphocytes but not NK cells were direct progenitors to NKR(+)RORγt(+) cells in vivo. Genetic lineage tracing revealed that the differentiation of LTi-like cells was characterized by the stable upregulation of NKRs and a progressive loss of RORγt expression. Whereas interleukin-7 (IL-7) and intestinal microbiota stabilized RORγt expression within such NKR-LTi cells, IL-12 and IL-15 accelerated RORγt loss. RORγt(+) NKR-LTi cells produced IL-22, whereas RORγt⁻ NKR-LTi cells released IFN-γ and were potent inducers of colitis. Thus, the RORγt gradient in NKR-LTi cells serves as a tunable rheostat for their functional program. Our data also define a previously unappreciated role of RORγt⁻ NKR-LTi cells for the onset or maintenance of inflammatory bowel diseases.


Assuntos
Células Matadoras Naturais/imunologia , Tecido Linfoide/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Animais , Linhagem da Célula/imunologia , Regulação para Baixo , Doenças Inflamatórias Intestinais/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-12/imunologia , Interleucina-12/metabolismo , Interleucina-15/imunologia , Interleucina-15/metabolismo , Interleucina-7/genética , Interleucina-7/imunologia , Interleucina-7/metabolismo , Interleucinas/imunologia , Interleucinas/metabolismo , Intestinos/imunologia , Intestinos/microbiologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Regulação para Cima
14.
Blood ; 116(13): 2229-36, 2010 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-20530285

RESUMO

Seventeen patients transplanted with hematopoietic cells to correct severe T lymphocyte immunodeficiency resulting from complete DiGeorge anomaly were identified worldwide, and retrospective data were obtained using a questionnaire-based survey. Patients were treated at a median age of 5 months (range, 2-53 months) between 1995 and 2006. Bone marrow was used in 11 procedures in 9 cases: 6 from matched unrelated donors, 4 from human leukocyte antigen (HLA)-identical siblings, and one haploidentical parent with T-cell depletion. Unmobilized peripheral blood was used in 8 cases: 5 from HLA-identical siblings, one from a matched unrelated donor, one from an HLA-identical parent, and one unrelated matched cord blood. Conditioning was used in 5 patients and graft-versus-host disease prophylaxis in 11 patients. Significant graft-versus-host disease occurred in 9 patients, becoming chronic in 3. Median length of follow-up was 13 months, with transplantation from HLA-matched sibling showing the best results. Median survival among deceased patients (10 patients) was 7 months after transplantation (range, 2-18 months). The overall survival rate was 41%, with a median follow-up of 5.8 years (range, 4-11.5 years). Among survivors, median CD3 and CD4 counts were 806 (range, 644-1224) and 348 (range, 225-782) cells/mm(3), respectively, CD4(+)/CD45RA(+) cells remained very low, whereas mitogen responses were normalized.


Assuntos
Síndrome de DiGeorge/terapia , Transplante de Células-Tronco Hematopoéticas , Transplante de Medula Óssea , Pré-Escolar , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Síndrome de DiGeorge/sangue , Síndrome de DiGeorge/imunologia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Contagem de Linfócitos , Linfopoese , Masculino , Estudos Retrospectivos , Inquéritos e Questionários , Condicionamento Pré-Transplante , Resultado do Tratamento
15.
Immunol Allergy Clin North Am ; 30(1): 31-44, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20113885

RESUMO

Curative treatment of Severe Combined Immunodeficiency (SCID) by Hematopoietic Cell Transplantation (HCT) remains a challenge, in particular in infants presenting with serious, poorly controllable complications. In the absence of a matched family donor, HLA-haploidentical transplantation from parental donors represents a uniformly and readily available treatment option, offering a high chance to be successful. Concerning outcomes of HCT in SCID, other important parameters beside survival need to be taken into consideration, in particular the stability and robustness of the graft and its function, as well as potential late complications, related either to the disease or to the treatment.


Assuntos
Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/imunologia , Imunodeficiência Combinada Severa/terapia , Condicionamento Pré-Transplante/métodos , Seleção do Doador , Antígenos HLA/genética , Haplótipos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células-Tronco Hematopoéticas/citologia , Humanos , Pais , Imunodeficiência Combinada Severa/imunologia , Doadores de Tecidos
16.
Hum Mutat ; 31(2): 197-207, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19953608

RESUMO

The nuclease ARTEMIS is an essential factor of V(D)J recombination during lymphocyte development and in the repair of DNA double-strand breaks (DSB) by the nonhomologous end joining (NHEJ) pathway. Patients with mutations in the DCLRE1C gene, which encodes ARTEMIS, suffer from radiosensitive B(-/low) T(-/low) severe combined immunodeficiency (SCID) or radiosensitive Omenn syndrome. To date, causative DCLRE1C mutations inherited as a recessive trait have been reported in 49 patients. In this study, molecular diagnoses of 29 novel patients presenting with the phenotype of B(-/low) SCID revealed mutations in the DCLRE1C gene. In total, 13 different mutated DCLRE1C alleles were detected, nine of which have not been described before. By far the most frequent mutations (59%) were gross deletions of exons 1-3 or exons 1-4 due to a homologous recombination of the wild-type DCLRE1C gene with a pseudo-DCLRE1C gene located 61.2 kb 5' to the DCLRE1C start codon. Fine mapping of the recombination intervals revealed private mutations in most cases. MEIG1, a gene encoding a protein that is essential for spermatogenesis in mice, is lost by the gross deletions. Functional analyses on patients' fibroblasts demonstrated that the corresponding alleles carry null mutations of the DCLRE1C gene.


Assuntos
Mutação/genética , Proteínas Nucleares/genética , Recombinação Genética/genética , Linfócitos B/patologia , Bioensaio , Células Cultivadas , Endonucleases , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica , Humanos , Proteínas Nucleares/deficiência , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tolerância a Radiação/genética , Deleção de Sequência/genética , Imunodeficiência Combinada Severa/genética , Éxons VDJ/genética
17.
Immunol Res ; 44(1-3): 18-24, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-18846321

RESUMO

In this report, we present an analysis in 39 WAS patients treated by hematopoietic stem cell transplantation (HSCT) in our center since 1983. Fifteen patients received transplants from HLA-identical unrelated donors, 15 from nonidentical parental donors, and 9 from matched siblings. The overall survival rate is 90% in patients with matched donors and 50% in patients after nonidentical transplantation, with a mean follow-up time of 11 years. Treatment failures in the latter group were mainly related to graft rejections and to GvHD and infections following repeat transplants. Long-term survivors in both patient groups remain with few exceptions free of late complications and with stable graft function and complete donor cell chimerism. Based on our findings, we recommend early and prompt treatment of each diagnosed WAS patient if an HLA-matched, related or unrelated, donor can be identified. If this is not the case, HLA-nonidentical donor transplantation represents an alternative to be considered early in patients with severe disease.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndrome de Wiskott-Aldrich/mortalidade , Antivirais/uso terapêutico , Criança , Pré-Escolar , Quimerismo , Cidofovir , Ciclosporina/uso terapêutico , Citosina/análogos & derivados , Citosina/uso terapêutico , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/mortalidade , Rejeição de Enxerto/terapia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/terapia , Antígenos HLA/imunologia , Células-Tronco Hematopoéticas/imunologia , Histocompatibilidade/imunologia , Humanos , Imunossupressores/uso terapêutico , Lactente , Doadores Vivos , Masculino , Organofosfonatos/uso terapêutico , Falha de Tratamento , Síndrome de Wiskott-Aldrich/imunologia , Síndrome de Wiskott-Aldrich/cirurgia
18.
Nat Genet ; 41(1): 101-5, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19043417

RESUMO

Human severe combined immunodeficiencies (SCID) are phenotypically and genotypically heterogeneous diseases. Reticular dysgenesis is the most severe form of inborn SCID. It is characterized by absence of granulocytes and almost complete deficiency of lymphocytes in peripheral blood, hypoplasia of the thymus and secondary lymphoid organs, and lack of innate and adaptive humoral and cellular immune functions, leading to fatal septicemia within days after birth. In bone marrow of individuals with reticular dysgenesis, myeloid differentiation is blocked at the promyelocytic stage, whereas erythro- and megakaryocytic maturation is generally normal. These features exclude a defect in hematopoietic stem cells but point to a unique aberration of the myelo-lymphoid lineages. The dramatic clinical course of reticular dysgenesis and its unique hematological phenotype have spurred interest in the unknown genetic basis of this syndrome. Here we show that the gene encoding the mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2) is mutated in individuals with reticular dysgenesis. Knockdown of zebrafish ak2 also leads to aberrant leukocyte development, stressing the evolutionarily conserved role of AK2. Our results provide in vivo evidence for AK2 selectivity in leukocyte differentiation. These observations suggest that reticular dysgenesis is the first example of a human immunodeficiency syndrome that is causally linked to energy metabolism and that can therefore be classified as a mitochondriopathy.


Assuntos
Adenilato Quinase/genética , Isoenzimas/genética , Mitocôndrias/enzimologia , Mutação/genética , Imunodeficiência Combinada Severa/enzimologia , Imunodeficiência Combinada Severa/genética , Peixe-Zebra/genética , Adenilato Quinase/metabolismo , Animais , Apoptose , Células da Medula Óssea/enzimologia , Células da Medula Óssea/patologia , Linhagem Celular , Embrião não Mamífero/enzimologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação Enzimológica da Expressão Gênica , Humanos , Isoenzimas/metabolismo , Leucócitos Mononucleares/enzimologia , Leucócitos Mononucleares/patologia , Masculino , Potencial da Membrana Mitocondrial , Espécies Reativas de Oxigênio/metabolismo
19.
Immunol Res ; 38(1-3): 165-73, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17917023

RESUMO

Immune reconstitution was studied in 31 long-term surviving patients after bone marrow transplantation for severe combined immunodeficiency. Donors in 7 cases were HLA-identical and in 25 cases HLA-haploidentical family members, and in 13 of these latter cases cytoreductive conditioning had been used prior to transplantation. At a mean follow-up of 15 years after transplantation (range 10 to 22 years), T cell numbers and functions had remained stable and within normal limits in the majority of patients. Marked variability however was observed with regard to reconstitution of B cell immunity. Furthermore numbers of circulating naïve CD4+ T cells were variable and markedly diminished in a substantial proportion of patients at recent evaluations. Normal B cell immunity and persistently normal naïve T cell numbers were strongly correlated with the continued detection of donor type CD34+ precursor cells in the patients marrow, which were absent in non conditioned patients. These findings indicate that stable donor precursor cell engraftment in the marrow may be of relevance for complete and stable long-term immune reconstitution in transplanted SCID patients.


Assuntos
Transplante de Medula Óssea , Imunodeficiência Combinada Severa/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Resultado do Tratamento
20.
Blood ; 109(8): 3595-602, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17185467

RESUMO

Adenosine deaminase (ADA) deficiency is a systemic metabolic disease that causes an autosomal recessive variant of severe combined immunodeficiency (SCID) and less consistently other complications including neurologic abnormalities. Hematopoietic stem cell transplantation (HSCT) is able to correct the immunodeficiency, whereas control of nonimmunologic complications has not been extensively explored. We applied HSCT in 15 ADA-deficient patients consecutively treated at our institutions since 1982 and analyzed long-term outcome. Seven patients received transplants without conditioning from HLA-matched family donors (MFDs); the other 8 patients received conditioning and were given transplants either from HLA-mismatched family donors (MMFDs; n = 6) or from matched unrelated donors (MUDs; n = 2). At a mean follow-up period of 12 years (range, 4-22 years), 12 patients are alive with stable and complete immune reconstitution (7 of 7 after MFD, 4 of 6 after MMFD, and 1 of 2 after MUD transplantation). Six of 12 surviving patients show marked neurologic abnormalities, which include mental retardation, motor dysfunction, and sensorineural hearing deficit. We were unable to identify disease or transplantation-related factors correlating with this divergent neurologic outcome. The high rate of neurologic abnormalities observed in long-term surviving patients with ADA deficiency indicates that HSCT commonly fails to control CNS complications in this metabolic disease.


Assuntos
Adenosina Desaminase/deficiência , Transplante de Células-Tronco Hematopoéticas , Doadores Vivos , Doenças do Sistema Nervoso/etiologia , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/terapia , Pré-Escolar , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Teste de Histocompatibilidade , Humanos , Lactente , Recém-Nascido , Masculino , Doenças do Sistema Nervoso/mortalidade , Estudos Retrospectivos , Imunodeficiência Combinada Severa/mortalidade , Transplante Homólogo
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