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1.
Nat Immunol ; 13(12): 1178-86, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23104095

RESUMEN

We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic autoinflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1), a component of the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin 1ß (IL-1ß) was compromised in the patients' fibroblasts. By contrast, the patients' mononuclear leukocytes, particularly monocytes, were hyper-responsive to IL-1ß. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1ß responses thus differed between cell types, consistent with the unique association of autoinflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB-dependent IL-1ß responses differently in different cell types.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo IV/genética , Enfermedades Autoinflamatorias Hereditarias/genética , Síndromes de Inmunodeficiencia/genética , FN-kappa B/metabolismo , Ubiquitina-Proteína Ligasas/genética , Infecciones Bacterianas/genética , Infecciones Bacterianas/inmunología , Proteínas de Ciclo Celular/genética , Línea Celular , Fibroblastos/inmunología , Fibroblastos/metabolismo , Humanos , Síndromes de Inmunodeficiencia/metabolismo , Interleucina-1beta/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Represoras/genética , Factores de Transcripción , Ubiquitina-Proteína Ligasas/deficiencia , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación
2.
Blood ; 118(6): 1675-84, 2011 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-21659547

RESUMEN

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.


Asunto(s)
Linaje de la Célula , Trasplante de Células Madre Hematopoyéticas/métodos , Quimera por Trasplante/sangre , Síndrome de Wiskott-Aldrich/cirugía , Autoinmunidad/inmunología , Donantes de Sangre , Niño , Preescolar , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Mutación , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/inmunología , Estudios Retrospectivos , Análisis de Supervivencia , Trombocitopenia/sangre , Trombocitopenia/etiología , Factores de Tiempo , Síndrome de Wiskott-Aldrich/sangre , Síndrome de Wiskott-Aldrich/genética
3.
Blood ; 116(1): 27-35, 2010 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-20375313

RESUMEN

Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disease caused by mutations in the RMRP gene. Beside dwarfism, CHH has a wide spectrum of clinical manifestations including variable grades of combined immunodeficiency, autoimmune complications, and malignancies. Previous reports in single CHH patients with significant immunodeficiencies have demonstrated that allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for the severe immunodeficiency, while growth failure remains unaffected. Because long-term experience in larger cohorts of CHH patients after HSCT is currently unreported, we performed a European collaborative survey reporting on 16 patients with CHH and immunodeficiency who underwent HSCT. Immune dysregulation, lymphoid malignancy, and autoimmunity were important features in this cohort. Thirteen patients were transplanted in early childhood ( approximately 2.5 years). The other 3 patients were transplanted at adolescent age. Of 16 patients, 10 (62.5%) were long-term survivors, with a median follow-up of 7 years. T-lymphocyte numbers and function have normalized, and autoimmunity has resolved in all survivors. HSCT should be considered in CHH patients with severe immunodeficiency/autoimmunity, before the development of severe infections, major organ damage, or malignancy might jeopardize the outcome of HSCT and the quality of life in these patients.


Asunto(s)
Enfermedades del Desarrollo Óseo/cirugía , Cartílago/anomalías , Trasplante de Células Madre Hematopoyéticas/métodos , Hipotricosis/cirugía , Linfocitos/inmunología , Adolescente , Estatura , Peso Corporal , Enfermedades del Desarrollo Óseo/genética , Enfermedades del Desarrollo Óseo/inmunología , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Hipotricosis/genética , Hipotricosis/inmunología , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Recuento de Linfocitos , Subgrupos Linfocitarios/citología , Subgrupos Linfocitarios/inmunología , Linfocitos/citología , Masculino , Mutación , Evaluación de Resultado en la Atención de Salud , ARN Largo no Codificante , ARN no Traducido/genética
4.
Am J Hum Genet ; 83(1): 64-76, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18606301

RESUMEN

Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.


Asunto(s)
Agammaglobulinemia/sangre , Osteoclastos/patología , Osteopetrosis/genética , Receptor Activador del Factor Nuclear kappa-B/genética , Fosfatasa Ácida/metabolismo , Actinas/metabolismo , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Argentina , Arginina/metabolismo , Biopsia , Estudios de Casos y Controles , Línea Celular Transformada , Proliferación Celular , Transformación Celular Viral , Células Cultivadas , Estudios de Cohortes , Consanguinidad , Cisteína/metabolismo , Análisis Mutacional de ADN , Dendritas/fisiología , Femenino , Genes Recesivos , Herpesvirus Humano 4/fisiología , Heterocigoto , Homocigoto , Humanos , Ilion/cirugía , Isoenzimas/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/patología , Lipopolisacáridos/farmacología , Factor Estimulante de Colonias de Macrófagos/farmacología , Masculino , Modelos Inmunológicos , Datos de Secuencia Molecular , Mutación Missense , Osteoclastos/metabolismo , Osteoclastos/ultraestructura , Osteopetrosis/diagnóstico , Osteopetrosis/diagnóstico por imagen , Osteopetrosis/patología , Osteopetrosis/fisiopatología , Osteoprotegerina/metabolismo , Pakistán , Linaje , Polimorfismo Genético , Estructura Terciaria de Proteína , Ligando RANK/metabolismo , Radiografía Torácica/métodos , Receptor Activador del Factor Nuclear kappa-B/química , Receptor Activador del Factor Nuclear kappa-B/inmunología , Receptores de Vitronectina/metabolismo
5.
J Allergy Clin Immunol ; 126(3): 602-10.e1-11, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20673987

RESUMEN

BACKGROUND: Hematopoietic stem cell transplantation remains the only treatment for most patients with severe combined immunodeficiencies (SCIDs) or other primary immunodeficiencies (non-SCID PIDs). OBJECTIVE: To analyze the long-term outcome of patients with SCID and non-SCID PID from European centers treated between 1968 and 2005. METHODS: The product-limit method estimated cumulative survival; the log-rank test compared survival between groups. A Cox proportional-hazard model evaluated the impact of independent predictors on patient survival. RESULTS: In patients with SCID, survival with genoidentical donors (n = 25) from 2000 to 2005 was 90%. Survival using a mismatched relative (n = 96) has improved (66%), similar to that using an unrelated donor (n = 46; 69%; P = .005). Transplantation after year 1995, a younger age, B(+) phenotype, genoidentical and phenoidentical donors, absence of respiratory impairment, or viral infection before transplantation were associated with better prognosis on multivariate analysis. For non-SCID PID, in contrast with patients with SCID, we confirm that, in the 2000 to 2005 period, using an unrelated donor (n = 124) gave a 3-year survival rate similar to a genoidentical donor (n = 73), 79% for both. Survival was 76% in phenoidentical transplants (n = 23) and worse in mismatched related donor transplants (n = 47; 46%; P = .016). CONCLUSION: This is the largest cohort study of such patients with the longest follow-up. Specific issues arise for different patient groups. Patients with B-SCID have worse survival than other patients with SCID, despite improvements in each group. For non-SCID PID, survival is worse than SCID, although more conditions are now treated. Individual disease categories now need to be analyzed so that disease-specific prognosis may be better understood and the best treatments planned.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/normas , Inmunodeficiencia Combinada Grave/terapia , Niño , Preescolar , Europa (Continente) , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas/tendencias , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Análisis Multivariante , Pronóstico , Tasa de Supervivencia , Factores de Tiempo , Resultado del Tratamiento
6.
Immunol Res ; 44(1-3): 4-17, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-18592143

RESUMEN

We review clinical outcome and immune reconstitution in a consecutive series of 74 infants with severe T cell immunodeficiency who received hematopoietic cell transplantation (HCT) from January 1991 to May 2003. Fifty-three patients (71.6%) are alive. Results were significantly better for recipients of HCT from HLA-matched related donors (100% survival) and unrelated donors (86.4%) than from mismatched related donors (51.6%). A detailed analysis of immune reconstitution and clinical status was performed in 49 surviving patients, most of which have attained robust T and B cell reconstitution and are in very good clinical conditions. No cases of late deaths or of chronic graft-versus-host disease (GvHD) have been observed. However, infections and autoimmunity at >1 year after HCT have been observed in a significant number of patients. Persistence of a low number of circulating naive T cells and long-term requirement for intravenous immunoglobulin were associated with a higher incidence of clinical events.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave/mortalidad , Linfocitos T/inmunología , Autoinmunidad/inmunología , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/terapia , Células Madre Hematopoyéticas/inmunología , Histocompatibilidad/inmunología , Humanos , Lactante , Masculino , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/terapia , Complicaciones Posoperatorias/inmunología , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/terapia , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/cirugía , Linfocitos T/patología , Acondicionamiento Pretrasplante
7.
Am J Hematol ; 84(8): 473-9, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19507210

RESUMEN

Infantile malignant osteopetrosis (IMO) includes various genetic disorders that affect osteoclast development and/or function. Genotype-phenotype correlation studies in IMO have been hampered by the rarity and heterogeneity of the disease and by the severity of the clinical course, which often leads to death early in life. We report on the clinical and molecular findings and treatment in 20 consecutive patients (11 males, nine females) with IMO, diagnosed at a single center in the period 1991-2008. Mean age at diagnosis was 3.9 months, and mean follow-up was 66.75 months. Mutations in TCIRG1, OSTM1, ClCN7, and TNFRSF11A genes were detected in nine, three, one, and one patients, respectively. Six patients remain genetically undefined. OSTM1 and ClCN7 mutations were associated with poor neurologic outcome. Among nine patients with TCIRG1 defects, six presented with hypogammaglobulinemia, and one showed primary pulmonary hypertension. Fourteen patients received hematopoietic cell transplantation; of these, nine are alive and eight of them have evidence of osteoclast function. These data may provide a basis for informed decisions regarding the care of patients with IMO.


Asunto(s)
Enfermedades Genéticas Congénitas/terapia , Trasplante de Células Madre Hematopoyéticas , Osteopetrosis/terapia , Agammaglobulinemia/genética , Agammaglobulinemia/mortalidad , Agammaglobulinemia/terapia , Canales de Cloruro/genética , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/mortalidad , Humanos , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/mortalidad , Hipertensión Pulmonar/terapia , Lactante , Recién Nacido , Masculino , Proteínas de la Membrana/genética , Osteopetrosis/genética , Osteopetrosis/mortalidad , Receptor Activador del Factor Nuclear kappa-B/genética , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo , Ubiquitina-Proteína Ligasas/genética , ATPasas de Translocación de Protón Vacuolares/genética
8.
J Allergy Clin Immunol ; 122(6): 1178-84, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18804272

RESUMEN

BACKGROUND: Cartilage hair hypoplasia is an autosomal recessive type of metaphyseal chondrodysplasia, caused by mutations in the ribonuclease mitochondrial RNA processing (RMRP) gene. Typical features of cartilage hair hypoplasia include short stature, a predisposition to malignancy, and a variable degree of impairment of cellular immunity. OBJECTIVE: We sought to describe the heterogeneity of clinical and immunologic phenotype in 12 consecutive patients with RMRP mutations who were referred to 2 different institutions for immunologic evaluation. METHODS: We have retrospectively analyzed the clinical and laboratory features in 12 patients with molecular defects in the RMRP gene. T-cell repertoire was investigated by quantitating Vbeta families' expression and analyzing their diversity. T-cell receptor excision circle analysis was used to study thymic output. RESULTS: All 12 patients had significant immune abnormalities, leading to severe immune deficiency in 9. CD8 lymphocytopenia was identified as a novel phenotype associated with RMRP mutations. Significant, even intrafamilial, phenotypic heterogeneity was observed. In 3 cases, severe immunodeficiency was the only phenotypic manifestation associated with RMRP mutations, a novel finding. Mutations leading to significant immune defects were most often located in the promoter, and the first case of a compound heterozygote for 2 such mutations is reported. CONCLUSION: This report broadens the spectrum of phenotypes associated with RMRP mutations and suggests that mutations in this gene should be considered when evaluating patients with combined immune deficiency, regardless of the presence of other manifestations.


Asunto(s)
Enfermedades de los Cartílagos/genética , Enfermedades de los Cartílagos/inmunología , Endorribonucleasas/genética , Endorribonucleasas/inmunología , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/inmunología , Linfopenia/genética , Linfopenia/inmunología , Mutación/inmunología , Osteocondrodisplasias/genética , Osteocondrodisplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Enfermedades de los Cartílagos/enzimología , Endorribonucleasas/metabolismo , Femenino , Enfermedades Genéticas Congénitas/enzimología , Heterocigoto , Humanos , Linfopenia/metabolismo , Masculino , Osteocondrodisplasias/enzimología , Regiones Promotoras Genéticas/genética , Regiones Promotoras Genéticas/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Estudios Retrospectivos
9.
J Clin Invest ; 115(3): 728-32, 2005 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15696198

RESUMEN

Omenn syndrome is a severe primary immunodeficiency with putative autoimmune manifestations of the skin and gastrointestinal tract. The disease is caused by hypomorphic mutations in recombination-activating genes that impair but do not abolish the process of VDJ recombination, leading to the generation of autoreactive T cells with a highly restricted receptor repertoire. Loss of central tolerance in genetically determined autoimmune diseases, e.g., autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, is associated with defective expression by medullary thymic epithelial cells of AIRE, the transcription activator that induces thymic expression of tissue-specific antigens. Analysis of AIRE expression in the thymi of 2 Omenn syndrome patients and 1 SCID patient, by real-time RT-PCR and immunohistochemistry, demonstrated a profound reduction in the levels of AIRE mRNA and protein in patients as compared with a normal control subject. Lack of AIRE was associated with normal or even increased levels of keratin and lymphotoxin-beta receptor mRNAs, while mRNAs of the self-antigens insulin, cytochrome P450 1a2, and fatty acid-binding protein were undetectable in thymi from immunodeficiency patients. These results demonstrate that deficiency of AIRE expression is observed in severe immunodeficiencies characterized by abnormal T cell development and suggest that in Omenn syndrome, the few residual T cell clones that develop may escape negative selection and thereafter expand in the periphery, causing massive autoimmune reactions.


Asunto(s)
Tracto Gastrointestinal/inmunología , Síndromes de Inmunodeficiencia/genética , Piel/inmunología , Timo/metabolismo , Factores de Transcripción/deficiencia , Animales , Células COS , Chlorocebus aethiops , Femenino , Humanos , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/patología , Lactante , Receptor beta de Linfotoxina , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/metabolismo , Linfocitos T/inmunología , Linfocitos T/fisiología , Timo/citología , Timo/patología , Proteína AIRE
10.
Curr Opin Allergy Clin Immunol ; 6(6): 443-8, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17088649

RESUMEN

PURPOSE OF REVIEW: To review indications and outcomes of haematopoietic stem cell transplantation in primary immunodeficiencies, in light of recent advances in the field. RECENT FINDINGS: Remarkable improvements in the outcome of haematopoietic stem cell transplantation in primary immunodeficiencies have recently been reported. This is a result of the successful use of alternative donors and more effective strategies to prevent and treat complications. These advances have now permitted the indications for haematopoietic stem cell transplantation to be extended in primary immunodeficiencies. SUMMARY: The optimal results of haematopoietic stem cell transplantation in primary immunodeficiencies have long been obtained with related human leukocyte antigen-identical donors, an option limited to a minority of patients. Transplantation from mismatched related donors has been used with good results mainly in infants with severe combined immune deficiency, but has been associated with significantly delayed or incomplete immune reconstitution. Recent data indicate that transplantation from matched unrelated donors and cord blood transplantation represent valid alternatives, which can be used in all forms of severe primary immunodeficiencies. This, along with careful monitoring of infections, coupled with preemptive treatment, has resulted in a significant improvement in the outcome of haematopoietic stem cell transplantation for severe forms of primary immunodeficiencies.


Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Síndromes de Inmunodeficiencia/terapia , Recuperación de la Función , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Trasplante de Células Madre de Sangre del Cordón Umbilical/mortalidad , Supervivencia sin Enfermedad , Humanos , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/mortalidad , Control de Infecciones , Infecciones/etiología , Infecciones/mortalidad , Tasa de Supervivencia , Trasplante Homólogo
11.
JAMA ; 295(5): 508-18, 2006 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-16449616

RESUMEN

CONTEXT: Bone marrow transplantation (BMT) using stem cells obtained from a family-related, HLA-identical donor (RID) is the optimal treatment for patients with severe combined immune deficiency (SCID). In the absence of an RID, HLA-mismatched related donors (MMRDs) are often used. However, compared with RIDs, use of MMRDs for BMT is associated with reduced survival and inferior long-term immune reconstitution. Use of HLA-matched unrelated donors (MUDs) represents another potential alternative for BMT. OBJECTIVE: To compare outcomes and immune reconstitution in a large cohort of patients with SCID who received RID, MUD, or MMRD BMT. DESIGN, SETTING, AND PATIENTS: Retrospective study of medical records from 94 infants diagnosed as having SCID who received BMT between 1990 and 2004 at 1 Canadian and 1 Italian pediatric referral center. Thirteen, 41, and 40 patients received RID, MUD, and MMRD BMT, respectively. MAIN OUTCOME MEASURES: Survival and graft failure, along with incidence of graft-vs-host disease, infections, and other complications; immune reconstitution was assessed in children who survived for more than 2 years after BMT. RESULTS: Survival after RID BMT was highest. Twelve (92.3%) of 13 patients who received RID BMT, 33 (80.5%) of 41 who received MUD BMT, and 21 (52.5%) of 40 patients who received MMRD BMT survived. Compared with MMRD BMT, survival was significantly higher with RID (P = .008) or with MUD (P = .03). Graft failures and need for repeat BMT were more common in patients receiving MMRD BMT than in those who underwent MUD BMT. Long-term reconstitution of a full T-cell repertoire was achieved more frequently following MUD BMT (94.7%) than after MMRD BMT (61.1%) (P = .02). Acute graft-vs-host disease was documented in 73.1% of patients following MUD BMT but in only 45% after MMRD BMT (P = .009). Conversely, interstitial pneumonitis was observed more frequently after MMRD BMT (14 [35.0%] of 40) than after MUD BMT (3 [7.3%] of 41; P = .002). CONCLUSION: Our study suggests that in the absence of a relative with identical HLA, MUD BMT may provide better engraftment, immune reconstitution, and survival for patients with SCID than MMRD BMT.


Asunto(s)
Trasplante de Médula Ósea , Histocompatibilidad , Inmunodeficiencia Combinada Grave/terapia , Trasplante de Médula Ósea/inmunología , Estudios de Cohortes , Femenino , Prueba de Histocompatibilidad , Humanos , Lactante , Masculino , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Inmunodeficiencia Combinada Grave/inmunología , Análisis de Supervivencia , Resultado del Tratamiento
12.
Curr Opin Allergy Clin Immunol ; 5(6): 519-24, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16264332

RESUMEN

PURPOSE OF REVIEW: The aim of the review is to report on recent advances in cytokine-mediated signalling, as illustrated by the study of natural human mutants. In particular, the role of cytokines and cytokine-mediated signalling in human T-cell development is analysed in detail, and currently available forms of treatment including experimental trials are described. RECENT FINDINGS: Defects of the cytokine/JAK/STAT axis have been recently described as responsible for human Severe Combined Immune Deficiency. In particular, defects in gammac, JAK3 and IL7RA have been analysed in terms of development of novel diagnostic tools as well as of new therapeutic agents for the treatment of autoimmune diseases and graft-versus-host disease. SUMMARY: Dissection of the genetic defects underlying the various forms of Severe Combined Immune Deficiency has helped develop new and more accurate diagnostic assays and novel forms of treatment.


Asunto(s)
Citocinas/genética , Inmunodeficiencia Combinada Grave/genética , Transducción de Señal/genética , Citocinas/metabolismo , Humanos , Subunidad gamma Común de Receptores de Interleucina , Janus Quinasa 3 , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Receptores de Interleucina-7/metabolismo , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/terapia
14.
Curr Opin Allergy Clin Immunol ; 4(6): 491-6, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15640689

RESUMEN

PURPOSE OF REVIEW: To review the clinical and molecular features of autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy and discuss recent advances in the function of the AIRE protein. We will summarize how AIRE contributes to immunological tolerance, and thus to the prevention of autoimmunity. RECENT FINDINGS: The organization of a well-structured thymic microenvironment and the interaction between nascent thymocytes and thymic epithelial cells have been shown to be essential for AIRE expression. AIRE is involved in the expression of ectopic proteins by medullary thymic epithelial cells. This allows the establishment of central tolerance and contributes to the prevention of organ-specific autoimmunity, as shown by findings in patients with autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (a disease caused by AIRE gene mutations) and in aire (-/-) mice. SUMMARY: Autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy represents a unique model to investigate the cellular and molecular mechanisms that govern central tolerance and help prevent autoimmunity. Recent findings indicate that the compartmentalization of AIRE and interaction with other proteins are involved in this mechanism. The disturbance of AIRE expression may also be responsible for autoimmune manifestations in disorders with disrupted thymic structure other than autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy alone.


Asunto(s)
Candidiasis/inmunología , Displasia Ectodérmica/inmunología , Tolerancia Inmunológica , Poliendocrinopatías Autoinmunes/inmunología , Factores de Transcripción/inmunología , Candidiasis/genética , Candidiasis/metabolismo , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Humanos , Poliendocrinopatías Autoinmunes/genética , Poliendocrinopatías Autoinmunes/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína AIRE
15.
Haematologica ; 89(4): 450-61, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15075079

RESUMEN

BACKGROUND AND OBJECTIVES: In utero transplantation of hematopoietic stem cells allows immune reconstitution of fetuses with severe combined immunodeficiency. The objective of this work was to study the quality of T-cell reconstitution following this procedure. DESIGN AND METHODS: We evaluated the kinetics and extent of T-cell reconstitution in five infants with severe combined immune deficiency (SCID), three with a B+ and two with a B- phenotype, who received haploidentical stem cell transplantation before birth. To this end, we measured the frequency of T-cell receptor excision circles (TREC) and the diversity of the T-cell repertoire. RESULTS: In utero transplantation led to engraftment of donor-derived T lymphocytes which attained normal numbers in four infants, who are in good health. In the three patients with a B+ phenotype, generation of a heterogeneous T-cell repertoire was associated with development of TREC levels comparable to those of SCID patients treated by post-natal transplantation and of healthy babies. Of the two patients with a B- phenotype, one developed mixed T-cell chimerism and a substantial number of circulating T cells, associated with a variable heterogeneity of the T-cell repertoire; TREC levels were normal soon after birth, but declined thereafter. The remaining B- patient remained lymphopenic with a skewed T-cell repertoire and very low TREC levels. This patient eventually required transplantation from a matched unrelated donor at 5 years of age, but died of EBV-related lymphoproliferative disease. INTERPRETATION AND CONCLUSIONS: These data indicate that in utero transplantation of fetuses with B+ SCID allows generation of newly diversified T lymphocytes and ensures long-term reconstitution of cell-mediated immunity.


Asunto(s)
Terapias Fetales , Trasplante de Células Madre Hematopoyéticas/métodos , Linfocitos T/fisiología , Adulto , Femenino , Humanos , Sistema Inmunológico/fisiología , Lactante , Embarazo , Receptores de Antígenos de Linfocitos T/genética , Regeneración , Inmunodeficiencia Combinada Grave/terapia , Timo/fisiología
16.
Rev Clin Exp Hematol ; 7(1): 84-111, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-14692236

RESUMEN

Primary immune deficiencies (PID) represent inborn errors of immunity. Over the years, detailed analysis of the clinical and laboratory features associated with these unique and rare disorders have shed light on the complex array of signals and processes that govern development and activation of the immune system. While the first examples of PID pertained to severe defects in lymphoid development, more recently a variety of gene defects have been identified in humans that do not compromize the ability to generate lymphocytes, but rather result in profound immune dysregulation. In many cases, identification of the molecular and cellular bases of PID has preceeded development of animal models by gene targeting. Finally, since the very first cases reported in humans, PID have also represented a unique tool to investigate the efficacy of novel therapeutic approaches (from molecular therapy to hematopoietic stem cell transplantation to somatic cells gene therapy), that have been applied or may apply to a variety of more common human diseases.


Asunto(s)
Inmunidad , Síndromes de Inmunodeficiencia/etiología , Citocinas/inmunología , Humanos , Síndromes de Inmunodeficiencia/terapia , Linfocitos/inmunología , Linfocitos/patología , Mutación/inmunología
18.
Blood ; 111(1): 271-4, 2008 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-17890453

RESUMEN

Hypomorphic mutations of the RAG genes in humans are associated with a spectrum of clinical and immunologic presentations that range from T(-) B(-) severe combined immune deficiency (SCID) to Omenn syndrome. In most cases, residual V(D)J recombination activity allows for development of few T-cell clones, which expand in the periphery and infiltrate target organs, resulting in tissue damage. Invariant natural killer T (iNKT) cells play an important immunoregulatory role and have been associated with protection against autoimmunity. We now report on 5 unrelated cases of combined immune deficiency due to hypomorphic RAG mutations, and demonstrate the absence of iNKT cells in all 5 patients. These findings suggest that lack of this important immunoregulatory cell population may contribute to the pathophysiology of Omenn syndrome.


Asunto(s)
Proteínas de Homeodominio/genética , Células Asesinas Naturales/patología , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/patología , Línea Celular Tumoral , Humanos , Inmunofenotipificación , Lactante , Recién Nacido , Células Asesinas Naturales/inmunología , Mutación Puntual , Inmunodeficiencia Combinada Grave/inmunología , Linfocitos T/inmunología
19.
Blood ; 111(1): 439-45, 2008 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-17901250

RESUMEN

Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency with microthrombocytopenia, eczema, recurrent infections, autoimmune disorders, and malignancies that are life-threatening in the majority of patients. In this long-term, retrospective, multicenter study, we analyzed events that occurred in 96 WAS patients who received transplants between 1979 and 2001 who survived at least 2 years following hematopoietic stem-cell transplantation (HSCT). Events included chronic graft-versus-host disease (cGVHD), autoimmunity, infections, and sequelae of before or after HSCT complications. Three patients (3%) died 2.1 to 21 years following HSCT. Overall 7-year event-free survival rate was 75%. It was lower in recipients of mismatched related donors, also in relation with an older age at HSCT and disease severity. The most striking finding was the observation of cGVHD-independent autoimmunity in 20% of patients strongly associated with a mixed/split chimerism status (P < .001), suggesting that residual-host lymphocytes can mediate autoimmune disease despite the coexistence of donor lymphocytes. Infectious complications (6%) related to splenectomy were also significant and may warrant a more restrictive approach to performing splenectomy in WAS patients. Overall, this study provides the basis for a prospective, standardized, and more in-depth detailed analysis of chimerism and events in long-term follow-up of WAS patients who receive transplants to design better-adapted therapeutic strategies.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Sistema Inmunológico/inmunología , Recuperación de la Función/inmunología , Síndrome de Wiskott-Aldrich/inmunología , Síndrome de Wiskott-Aldrich/terapia , Adolescente , Enfermedades Autoinmunes/etiología , Niño , Preescolar , Conducta Cooperativa , Supervivencia sin Enfermedad , Europa (Continente) , Enfermedad Injerto contra Huésped/etiología , Humanos , Lactante , Estudios Retrospectivos , Esplenectomía , Tasa de Supervivencia , Quimera por Trasplante , Resultado del Tratamiento , Síndrome de Wiskott-Aldrich/cirugía
20.
Expert Rev Clin Immunol ; 3(5): 813-24, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20477031

RESUMEN

Development of patient-tailored prognostic and therapeutic strategies remains a major, yet largely unmet, goal of medicine. Studies performed in patients who carry mutations in the Wiskott-Aldrich syndrome protein (WASP) gene have indicated the feasibility, but also the limitations, of this approach. In this review, we discuss the importance of specific WASP mutations, and their effects on protein expression and function in determining the spectrum of clinical phenotypes associated with WASP defects. The array of currently available and foreseeable therapeutic options is reviewed in this context as a model for other more common genetic disorders.

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