RESUMO
BACKGROUND: The CD3 co-receptor complex is essential for signal transduction after specific binding of the T-cell receptor (TCR). CD3E encodes the CD3ε chain, one of the protein components (γ-, δ-, ε- and ζ-chain) of the CD3 co-receptor. As previously reported in one family CD3ε deficiency causes SCID. PATIENT: We report on a patient with SCID due to CD3ε deficiency treated by HLA-haploidentical stem cell transplantation (SCT) (donor: mother) 15 years ago which resulted in development of normal T- and B-cell immunity. Despite conditioning donor cell engraftment was confined to T cells, while all other blood cell lineages remained of patient origin (split chimerism). In spite of normal functions, T-cell numbers never reached normal levels and naïve CD45+RA+ T-cells remained low. At 6 years after SCT the patient developed signs of humoral immunodeficiency, requiring regular substitution of IgG. RESULTS: In a retrospective genetic work up 11 years after SCT, a homozygous splice site mutation in CD3E was identified resulting in the loss of CD3ε protein. The loss of B-cell function as observed in the patient was reflected by a lack of switched memory B cells. To rule out a primary role of CD3ε in B-cell function we studied expression of CD3E in B-cells which was found not to be expressed. DISCUSSION: The clinical presentation of a secondary loss of specific humoral immunity in this constellation of split chimerism after allogeneic haploidentical SCT is unusual and unexpected in a patient with a primary T-cell defect. A most likely explanation is the gradual loss of T-helper-cell function.
Assuntos
Complexo CD3/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade , Imunoglobulina G/administração & dosagem , Imunodeficiência Combinada Severa/terapia , Linfócitos B/imunologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Triagem de Portadores Genéticos , Genótipo , Haploidia , Homozigoto , Humanos , Imunidade Humoral/genética , Imunidade Humoral/imunologia , Lactente , Recém-Nascido , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
Autosomal dominant hyper-IgE syndrome (AD-HIES), characterised by eczema, increased susceptibility to skin and lung infections, elevated IgE and skeletal abnormalities is associated with heterozygous STAT3 mutations. The autosomal recessive variant (AR-HIES) has similar immunological findings but mainly lacks extraimmune manifestations. Several AR-HIES patients have recently been shown to harbour mutations in the gene for dedicator of cytokinesis 8 (DOCK8). Here, we present the long-term outcome of a girl having received a hematopoietic stem cell graft for an at that time genetically undefined combined immunodeficiency associated with severe eczema, multiple food allergies, excessively elevated serum IgE levels and eosinophilia. She was recently found to carry a homozygous nonsense mutation in the DOCK8 gene. HSCT resulted in complete immunological correction, even though mixed donor chimerism occurred. Clinically, the outcome was characterised by disappearance of skin manifestations and severe infections, improvement of pulmonary function and constant decline of IgE levels. Outcome in untransplanted DOCK8 deficient patients is poor because of frequent life-threatening infections, CNS bleeding and infarction, and increased susceptibility to malignancy. This argues for early curative therapeutic approaches, supported by this report of successful long-term outcome after HSCT.
Assuntos
Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/genética , Transplante de Células-Tronco Hematopoéticas , Síndrome de Job/genética , Síndrome de Job/terapia , Fator de Transcrição STAT3/genética , Criança , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Feminino , Seguimentos , HumanosRESUMO
Patients with human severe combined immunodeficiency (SCID) can be divided into those with B lymphocytes (B+ SCID) and those without (B- SCID). Although several genetic causes are known for B+ SCID, the etiology of B- SCID has not been defined. Six of 14 B- SCID patients tested were found to carry a mutation of the recombinase activating gene 1 (RAG-1), RAG-2, or both. This mutation resulted in a functional inability to form antigen receptors through genetic recombination and links a defect in one of the site-specific recombination systems to a human disease.
Assuntos
Proteínas de Ligação a DNA , Proteínas de Homeodomínio , Proteínas/genética , Imunodeficiência Combinada Severa/genética , Linfócitos B/imunologia , Linhagem Celular , Consanguinidade , Feminino , Genes de Imunoglobulinas , Genes Recessivos , Humanos , Imunofenotipagem , Masculino , Mutação , Proteínas Nucleares , Polimorfismo Conformacional de Fita Simples , Receptores de Antígenos de Linfócitos T/genética , Recombinação Genética , Deleção de Sequência , Imunodeficiência Combinada Severa/imunologia , TransfecçãoRESUMO
Autosomal-recessive hyper-IgE syndrome (AR-HIES) is a combined immunodeficiency recently found to be associated with mutations of DOCK8. Clinically, this disorder is characterized beside recurrent bacterial complications, in particular by an unusual susceptibility to extensive cutaneous viral complications and by a high risk for squamous cell carcinoma. Here, we report on lasting control over the disorder in two patients by hematopoietic cell transplantation (HCT). Both patients were suffering from extensive long-lasting cutaneous viral complications, in particular from disfiguring molluscum contagiosum infections, when treated at the age of 10 and 17 years. Donors were matched unrelated, and conditioning was carried out with a combination of fludarabine, melphalan and BM-targeted radioimmunotherapy. Both patients developed stable, full donor cell chimerism, with the exception of persistent low-IgA serum levels and the exception of normal immune functions. Over the course of several months, cutaneous manifestations of viral disease resolved completely and both patients remain clinically well and free of infectious complications at 4 and 2 years, respectively, after transplantation. This represents the first report indicating HCT to be curative in patients with AR-HIES, which should be considered early before life-threatening complications develop, which include malignancies.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Síndrome de Job/terapia , Adolescente , Criança , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Síndrome de Job/complicações , Molusco Contagioso/etiologia , Molusco Contagioso/terapia , Indução de Remissão , Resultado do TratamentoRESUMO
Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder originally characterized by the clinical triad eczema, thrombocytopenia, and severe immunodeficieny, with recurrent bacterial and viral infections, indicating a profound immune cell defect. Such altered immune cells include monocytes, macrophages, and dendritic cells, which were reported to display disturbed cell polarization or chemotaxis. WAS is caused by mutations in the WAS protein (WASp), which is thought to organize the actin cytoskeleton through the Arp2/3 complex. Here we show that the Arp2/3 complex is an integral part of podosomes, actin-rich adhesion structures of macrophages, and that WAS macrophages fail to organize the Arp2/3 complex into podosomes. We also demonstrate that microinjection of a C-terminal acidic stretch of WASp into normal macrophages displaces Arp2/3 from podosomes and, in combination with chemoattractant stimulation of cells, induces a phenotype resembling the polarization-defective phenotype of stimulated WAS macrophages. These findings point to an important role of the Arp2/3 complex in polarization and migration of immune cells.
Assuntos
Actinas/metabolismo , Polaridade Celular/imunologia , Proteínas do Citoesqueleto , Macrófagos/metabolismo , Síndrome de Wiskott-Aldrich/imunologia , Síndrome de Wiskott-Aldrich/metabolismo , Proteína 2 Relacionada a Actina , Proteína 3 Relacionada a Actina , Actinas/análise , Actinas/fisiologia , Animais , Técnica Direta de Fluorescência para Anticorpo , Humanos , Macrófagos/química , Macrófagos/patologia , Camundongos , Microinjeções , Microscopia de Fluorescência , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/fisiologia , Ligação Proteica/imunologia , Estrutura Terciária de Proteína , Proteínas/imunologia , Proteínas/fisiologia , Pseudópodes/química , Pseudópodes/fisiologia , Coloração e Rotulagem , Síndrome de Wiskott-Aldrich/patologia , Proteína da Síndrome de Wiskott-AldrichRESUMO
Four percent of human severe combined immunodeficiency cases are caused by a deficiency of the enzyme purine nucleoside phosphorylase (PNP). In this study we investigated the molecular basis for this rare autosomal recessive disease. Sequence analyses led to the identification of two new mutations in the PNP gene: an A to G transition in exon 5, which leads to the substitution of tyrosine 192 by a cysteine residue, and a 1-bp deletion in exon 6, which causes premature translation termination of the PNP protein. Both PNP mutations affect predicted major structural motifs of the protein and result in post-translation instability of the enzyme.