Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 36
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Clin Exp Dermatol ; 43(8): 913-916, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29908030

RESUMO

Ras-associated autoimmune leucoproliferative disorder (RALD) is a nonmalignant syndrome associated with somatic KRAS mutations. We report a patient with RALD and cutaneous lesions, the first such case reported, to our knowledge. An 8-year-old boy presented with erythematous plaques on his face and body, along with lymphadenopathies and spleen enlargement without systemic symptoms. An increased number of monocytes were found in skin biopsy, peripheral blood and bone marrow (BM). Juvenile myelomonocytic leukaemia (JMML) was suspected. Genetic study using peripheral blood showed no mutations in the KRAS, PTPN11, NRAS, CBL or BCR-ABL genes, but bone marrow analysis revealed a mutation (p-G12S/c.34 G>A) in the KRAS gene. The karyotype was normal. No KRAS mutations were found using molecular analysis of saliva. The diagnosis of RALD was proposed. The differential diagnosis between RALD and JMML is challenging because there are no established criteria to differentiate between them. The clinical course of RALD is uncertain, so long-term follow-up is recommended.


Assuntos
Síndrome Linfoproliferativa Autoimune/diagnóstico , Proteínas Proto-Oncogênicas p21(ras) , Dermatopatias/etiologia , Pele/patologia , Síndrome Linfoproliferativa Autoimune/complicações , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/patologia , Biópsia , Criança , Análise Mutacional de DNA , Diagnóstico Diferencial , Genes ras , Humanos , Leucemia Mielomonocítica Juvenil/diagnóstico , Masculino , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética
3.
J Pediatr Hematol Oncol ; 40(5): e305-e308, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28991130

RESUMO

We present a case of a 2-year-old female presenting with diffuse lymphadenopathy 2 years following orthotopic heart transplant. Initially, she was diagnosed with posttransplant lymphoproliferative disease based on clinical presentation and pathology and she was treated accordingly. Because of persistent lymphadenopathy following the completion of chemotherapy and new onset of autoimmune cytopenias, repeat flow of the lymph node showed an elevated double negative T-cell population prompting evaluation for autoimmune lymphoproliferative syndrome (ALPS). A complete workup was confirmative of a germline Fas mutation consistent with ALPS-FAS. This case emphasizes the importance of considering ALPS-FAS in a patient with lymphadenopathy of unknown cause.


Assuntos
Síndrome Linfoproliferativa Autoimune/diagnóstico , Transplante de Coração , Linfadenopatia/diagnóstico , Síndrome Linfoproliferativa Autoimune/imunologia , Síndrome Linfoproliferativa Autoimune/patologia , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Linfadenopatia/imunologia , Linfadenopatia/patologia
4.
Front Immunol ; 9: 2767, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30692987

RESUMO

Adenosine deaminase 2 (ADA2) deficiency is an auto-inflammatory disease due to mutations in cat eye syndrome chromosome region candidate 1 (CECR1) gene, currently named ADA2. The disease has a wide clinical spectrum encompassing early-onset vasculopathy (targeting skin, gut and central nervous system), recurrent fever, immunodeficiency and bone marrow dysfunction. Different therapeutic options have been proposed in literature, but only steroids and anti-cytokine monoclonal antibodies (such as tumor necrosis factor inhibitor) proved to be effective. If a suitable donor is available, hematopoietic stem cell transplantation (HSCT) could be curative. Here we describe a case of ADA2 deficiency in a 4-year-old Caucasian girl. The patient was initially classified as autoimmune neutropenia and then she evolved toward an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. The diagnosis of ALPS became uncertain due to atypical clinical features and normal FAS-induced apoptosis test. She was treated with G-CSF first and subsequently with immunosuppressive drugs without improvement. Only HSCT from a 9/10 HLA-matched unrelated donor, following myeloablative conditioning, completely solved the clinical signs related to ADA2 deficiency. Early diagnosis in cases presenting with hematological manifestations, rather than classical vasculopathy, allows the patients to promptly undergo HSCT and avoid more severe evolution. Finally, in similar cases highly suspicious for genetic disease, it is desirable to obtain molecular diagnosis before performing HSCT, since it can influence the transplant procedure. However, if HSCT has to be performed without delay for clinical indication, related donors should be excluded to avoid the risk of relapse or partial benefit due to a hereditary genetic defect.


Assuntos
Adenosina Desaminase/deficiência , Síndrome Linfoproliferativa Autoimune/terapia , Transplante de Células-Tronco Hematopoéticas , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Condicionamento Pré-Transplante , Doadores não Relacionados , Adenosina Desaminase/imunologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Síndrome Linfoproliferativa Autoimune/enzimologia , Síndrome Linfoproliferativa Autoimune/imunologia , Síndrome Linfoproliferativa Autoimune/patologia , Pré-Escolar , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Neutropenia/enzimologia , Neutropenia/imunologia , Neutropenia/patologia , Neutropenia/terapia , Transplante Homólogo , Receptor fas/imunologia
5.
Clin Immunol ; 180: 97-99, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28478106

RESUMO

A patient with autoimmune lymphoproliferative disorder (ALPS) developed IgG4-related disease. In retrospect, he had high levels of serum IgG4 for several years prior to presenting with IgG4-related pancreatitis. These high IgG4 levels were masked by hypergammaglobulinemia, a common feature of ALPS. We next screened 18 ALPS patients; four of them displayed increased levels of IgG4. Hence, IgG4-related disease should be considered in ALPS patients, especially in those manifesting lymphocytic organ infiltration or excessive hypergammaglobulinaemia. Screening of IgG4-related disease patients for ALPS-associated mutations would provide further information on whether this disease could be a late-onset atypical presentation of ALPS.


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Imunoglobulina G/imunologia , Adulto , Síndrome Linfoproliferativa Autoimune/sangue , Síndrome Linfoproliferativa Autoimune/patologia , Humanos , Hipergamaglobulinemia/imunologia , Imunoglobulina G/sangue , Linfonodos/patologia , Transtornos Linfoproliferativos/imunologia , Masculino , Pâncreas/patologia
6.
Scand J Immunol ; 85(6): 406-416, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28349581

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is an incurable disease, which is characterized by non-malignant autoimmune lymphoproliferation. TCF1 is a key effector in the canonical Wnt/ß-catenin pathway, regulating the development, activation and function of T cells. In this study, we aimed to explore the potential role of TCF1 in the development of ALPS-like phenotypes of lpr/lpr mice. We acquired TCF1-/- lpr/lpr double mutant mice by crossing TCF1 deficiency mice with lpr/lpr mice. Splenocyte compositions, serum cytokines levels, antidsDNA antibody production and kidney pathology were examined in the TCF1-/- lpr/lpr mice. With these examinations, we revealed that TCF1 deficiency relieved most manifestations of ALPS-like phenotype, which were caused by Fas mutation in TCF1-/- lpr/lpr mice. Splenocyte total numbers and compositions were downregulated to the similar levels with wildtype mice. TE and TEM cells were decreased in TCF1-/- lpr/lpr compared with lpr/lpr mice. The levels of autoantibodies and proinflammatory factors in serum, and the histopathology changes and the relative mRNA levels of proinflammatory factors in kidney all displayed parallel tendency in TCF1-/- lpr/lpr mice. Our study demonstrated that TCF1 deficiency ameliorated the ALPS-like phenotypes of TCF1-/- lpr/lpr mice, which might indicate a potential therapeutic direction for ALPS.


Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Mutação , Receptor fas/genética , Animais , Autoanticorpos/sangue , Síndrome Linfoproliferativa Autoimune/metabolismo , Síndrome Linfoproliferativa Autoimune/patologia , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Expressão Gênica , Predisposição Genética para Doença/genética , Genótipo , Fator 1-alfa Nuclear de Hepatócito/deficiência , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Rim/patologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Microscopia de Fluorescência , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/metabolismo , Baço/patologia , Receptor fas/metabolismo
7.
Mamm Genome ; 28(1-2): 47-55, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27770190

RESUMO

British shorthair (BSH) kittens in multiple litters died as a result of a severe non-neoplastic lymphoproliferative disease that showed many similarities with human autoimmune lymphoproliferative syndrome (ALPS). Human ALPS is caused by inherited defects in FAS-mediated lymphocyte apoptosis and the possibility of similar defects was investigated in BSH cats. The whole genomes of two affected kittens were sequenced and compared to 82 existing cat genomes. Both BSH kittens had homozygous insertions of an adenine within exon 3 of the FAS-ligand gene. The resultant frameshift and premature stop codon were predicted to result in a severely truncated protein that is unlikely to be able to activate FAS. Three additional affected BSH kittens were homozygous for the variant, while 11 of 16 unaffected, but closely related, BSH cats were heterozygous for the variant. All BSH cats in the study were from a population with significant inbreeding. The variant was not identified in a further survey of 510 non-BSH cats. Identification of a genetic defect in the FAS-mediated apoptosis pathway confirms that the lymphoproliferative disease in BSH cats fulfills the diagnostic criteria for ALPS in humans. These results will enable the development of a genetic test to detect BSH carrier animals.


Assuntos
Apoptose/genética , Síndrome Linfoproliferativa Autoimune/genética , Proteína Ligante Fas/genética , Receptor fas/genética , Animais , Síndrome Linfoproliferativa Autoimune/patologia , Gatos , Códon sem Sentido/genética , Mutação da Fase de Leitura/genética , Genoma , Humanos , Linfócitos/patologia , Mutação , Sequenciamento Completo do Genoma
8.
Haematologica ; 102(2): e52-e56, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27789675
9.
Haematologica ; 102(2): 364-372, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27846610

RESUMO

Autoimmune lymphoproliferative syndrome is a rare genetic disorder characterized by defective FAS-mediated apoptosis, autoimmune disease, accumulation of mature T-cell receptor alpha/beta positive, CD4 and CD8 double-negative T cells and increased risk of lymphoma. Despite frequent hematologic abnormalities, literature is scarce regarding the bone marrow pathology in autoimmune lymphoproliferative syndrome. We retrospectively reviewed 3l bone marrow biopsies from a cohort of 240 patients with germline FAS mutations. All biopsies were performed for the evaluation of cytopenias or to rule out lymphoma. Clinical information was collected and morphological, immunohistochemical, flow cytometric and molecular studies were performed. Bone marrow lymphocytosis was the predominant feature, present in 74% (23/31) of biopsies. The lymphoid cells showed several different patterns of infiltration, most often forming aggregates comprising T cells in 15 cases, B cells in one and a mixture of T and B cells in the other seven cases. Double-negative T cells were detected by immunohistochemistry in the minority of cases (10/31; 32%); significantly, all but one of these cases had prominent double-negative T-lymphoid aggregates, which in four cases diffusely replaced the marrow space. One case showed features of Rosai-Dorfman disease, containing scattered S-100+ cells with emperipolesis and double-negative T cells. No clonal B or T cells were detected by polymerase chain reaction in any evaluated cases. Classical Hodgkin lymphoma was identified in three cases. Our results demonstrate that infiltrates of T cells, or rarely B cells, can be extensive in patients with autoimmune lymphoproliferative syndrome, mimicking lymphoma. A multi-modality approach, integrating clinical, histological, immunohistochemical as well as other ancillary tests, can help avoid this diagnostic pitfall. This study is registered at Clinicaltrials.gov ID # NCT00001350.


Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Células da Medula Óssea/metabolismo , Mutação em Linhagem Germinativa , Receptor fas/genética , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/metabolismo , Síndrome Linfoproliferativa Autoimune/patologia , Biomarcadores , Biópsia , Medula Óssea/patologia , Células da Medula Óssea/patologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Imunofenotipagem , Lactente , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Avaliação de Resultados da Assistência ao Paciente , Fenótipo , Prognóstico , Adulto Jovem , Receptor fas/metabolismo
10.
Blood ; 128(2): 227-38, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27099149

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαß(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/imunologia , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/patologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lectinas Tipo C/imunologia , Antígenos Comuns de Leucócito/imunologia , Masculino , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transativadores/imunologia
11.
Immunobiology ; 221(1): 40-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26323380

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency caused by impaired Fas/FasL-mediated apoptosis of lymphocytes and is characterized by chronic nonmalignant or benign lymphoproliferation, autoimmune manifestations and expansion of double negative (DN) T-cells (TCRαß+CD4-CD8-). Most cases of ALPS are associated with germline (ALPS-FAS) or somatic (ALPS-sFAS) heterozygous FAS mutations or a combination of both. Here we report three unrelated patients with ALPS-sFAS. Only one of them showed impaired Fas function in PHA-activated T-cells. In this patient, the genetic analysis of the caspase-10 gene (CASP10) identified a heterozygous germline change in exon 9 (c.1337A>G) causing Y446C substitution in the caspase-10 protein. In addition, this patient had a dysregulated T- and B-cell phenotype; circulating lymphocytes showed expansion of T effector memory CD45RA+ (TEMRA) CD4 T-cells, effector memory CD8 T-cells, CD21(low) B-cells and reduced memory switched B-cells. Additionally, this patient showed altered expression in T-cells of several molecules that change during differentiation from naïve to effector cells (CD27, CD95, CD57 and perforin). Molecular alterations in genes of the Fas pathway are necessary for the development of ALPS and this syndrome could be influenced by the concurrent effect of other mutations hitting different genes involved in Fas or related pathways.


Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Caspase 10/genética , Receptor fas/genética , Adolescente , Antígenos CD/genética , Antígenos CD/imunologia , Síndrome Linfoproliferativa Autoimune/imunologia , Síndrome Linfoproliferativa Autoimune/patologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Caspase 10/imunologia , Éxons , Feminino , Expressão Gênica , Humanos , Memória Imunológica , Doenças Linfáticas/genética , Doenças Linfáticas/imunologia , Doenças Linfáticas/patologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mutação , Perforina/genética , Perforina/imunologia , Fito-Hemaglutininas/farmacologia , Cultura Primária de Células , Esplenomegalia/genética , Esplenomegalia/imunologia , Esplenomegalia/patologia , Receptor fas/imunologia
13.
J Immunol ; 195(2): 695-705, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26034173

RESUMO

Linker for activation of T cells (LAT) is a transmembrane adaptor protein that is highly tyrosine phosphorylated upon engagement of the TCR. Phosphorylated LAT binds Grb2, Gads, and phospholipase C (PLC)γ1 to mediate T cell activation, proliferation, and cytokine production. T cells from mice harboring a mutation at the PLCγ1 binding site of LAT (Y136F) have impaired calcium flux and Erk activation. Interestingly, these T cells are highly activated, resulting in the development of a lymphoproliferative syndrome in these mice. CD4(+) T cells in LATY136F mice are Th2 skewed, producing large amounts of IL-4. In this study, we showed that the LATY136F T cells could also overproduce IL-6 due to activated NF-κB, AKT, and p38 pathways. By crossing LATY136F mice with IL-6-deficient mice, we demonstrated that IL-6 is required for uncontrolled T cell expansion during the early stage of disease development. Reduced CD4(+) T cell expansion was not due to a further block in thymocyte development or an increase in the number of regulatory T cells, but was caused by reduction in cell survival. In aged IL-6(-/-) LATY136F mice, CD4(+) T cells began to hyperproliferate and induced splenomegaly; however, isotype switching and autoantibody production were diminished. Our data indicated that the LAT-PLCγ1 interaction is important for controlling IL-6 production by T cells and demonstrated a critical role of IL-6 in the development of this lymphoproliferative syndrome.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Síndrome Linfoproliferativa Autoimune/imunologia , Interleucina-6/imunologia , Proteínas de Membrana/imunologia , Fosfolipase C gama/imunologia , Fosfoproteínas/imunologia , Esplenomegalia/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/patologia , Autoimunidade , Sítios de Ligação , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Cálcio/imunologia , Cálcio/metabolismo , Proliferação de Células , Sobrevivência Celular , Regulação da Expressão Gênica , Interleucina-6/genética , Transporte de Íons , Ativação Linfocitária , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/imunologia , Fosfolipase C gama/genética , Fosfoproteínas/genética , Cultura Primária de Células , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Transdução de Sinais , Esplenomegalia/genética , Esplenomegalia/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
14.
J Allergy Clin Immunol ; 135(3): 762-70, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25174872

RESUMO

BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder of T cell homeostasis caused by mutations that impair FAS-mediated apoptosis. A defining characteristic of ALPS is the expansion of double negative T cells (DNTC). Relatively little is known about how defective FAS-driven cell death and the Bcl-2 apoptotic pathway intersect in ALPS patients. OBJECTIVE: We studied changes in Bcl-2 family member expression in ALPS to determine whether the Bcl-2 pathway might provide a therapeutic target. METHODS: We used flow cytometry to analyze the expression of pro- and anti-apoptotic Bcl-2 family members in T cells from 12 ALPS patients and determined the in vitro sensitivity of ALPS DNTC to the pro-apoptotic BH3 mimetic, ABT-737. RESULTS: The pro-apoptotic molecule, Bim, was significantly elevated in DNTC. Although no general pattern of individual anti-apoptotic Bcl-2 family members emerged, increased expression of Bim was always accompanied by increased expression of at least 1 anti-apoptotic Bcl-2 family member. Strikingly, Bim levels in DNTC correlated significantly with serum IL-10 in ALPS patients, and IL-10 was sufficient to mildly induce Bim in normal and ALPS T cells via a Janus kinase/signal transducer and activator of transcription 3-dependent mechanism. Finally, ABT-737 preferentially killed ALPS DNTC in vitro. CONCLUSION: Combined, these data show that an IL-10/Janus kinase/signal transducer and activator of transcription 3 pathway drives Bim expression in ALPS DNTC, which renders them sensitive to BH3 mimetics, uncovering a potentially novel therapeutic approach to ALPS.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Síndrome Linfoproliferativa Autoimune/genética , Interleucina-10/genética , Janus Quinase 1/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas/genética , Fator de Transcrição STAT3/genética , Adolescente , Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/imunologia , Síndrome Linfoproliferativa Autoimune/imunologia , Síndrome Linfoproliferativa Autoimune/patologia , Proteína 11 Semelhante a Bcl-2 , Compostos de Bifenilo/farmacologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica , Humanos , Lactente , Interleucina-10/imunologia , Janus Quinase 1/imunologia , Masculino , Proteínas de Membrana/imunologia , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/imunologia , Nitrofenóis/farmacologia , Piperazinas/farmacologia , Cultura Primária de Células , Proteínas Proto-Oncogênicas/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais , Sulfonamidas/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia , Proteína bcl-X/genética , Proteína bcl-X/imunologia , Receptor fas/genética , Receptor fas/imunologia
17.
Blood ; 124(6): 851-60, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-24894771

RESUMO

Accumulation of CD3(+) T-cell receptor (TCR)αß(+)CD4(-)CD8(-) double-negative T cells (DNT) is a hallmark of autoimmune lymphoproliferative syndrome (ALPS). DNT origin and differentiation pathways remain controversial. Here we show that human ALPS DNT have features of terminally differentiated effector memory T cells reexpressing CD45RA(+) (TEMRA), but are CD27(+)CD28(+)KLRG1(-) and do not express the transcription factor T-bet. This unique phenotype was also detected among CD4(+) or CD8(+) ALPS TEMRA cells. T-cell receptor ß deep sequencing revealed a significant fraction of shared CDR3 sequences between ALPS DNT and both CD4(+) and CD8(+)TEMRA cells. Moreover, in ALPS patients with a germ line FAS mutation and somatic loss of heterozygosity, in whom biallelic mutant cells can be tracked by absent Fas expression, Fas-negative T cells accumulated not only among DNT, but also among CD4(+) and CD8(+)TEMRA cells. These data indicate that in human Fas deficiency DNT cannot only derive from CD8(+), but also from CD4(+) T cells. Furthermore, defective Fas signaling leads to aberrant transcriptional programs and differentiation of subsets of CD4(+) and CD8(+) T cells. Accumulation of these cells before their double-negative state appears to be an important early event in the pathogenesis of lymphoproliferation in ALPS patients.


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Síndrome Linfoproliferativa Autoimune/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Receptor fas/deficiência , Receptor fas/genética , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/genética , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Criança , Pré-Escolar , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Humanos , Memória Imunológica , Antígenos Comuns de Leucócito/metabolismo , Perda de Heterozigosidade , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Proteínas com Domínio T/metabolismo , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem
18.
Blood ; 124(10): 1597-609, 2014 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-24970930

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) caused by impaired FAS-mediated apoptosis of lymphocytes is characterized by lymphoproliferation, autoimmunity, but also an increased risk of invasive bacterial infection, notably following splenectomy. We surveyed a cohort of 100 ALPS patients (including 33 splenectomized) and found that 12 (10 splenectomized) had experienced 23 invasive bacterial infections mainly caused by Streptococcus pneumoniae. This vulnerability was associated with evidence of defective B-cell function characterized by low serum immunoglobulin (Ig) M, low IgM antibody production in response to S pneumoniae following nonconjugated immunization, and low blood memory B-cells counts (including marginal zone [MZ] B-cell counts). This immunodeficiency strongly correlated with intensity of lymphoproliferation. Spleen sections from 9 ALPS patients revealed double-negative T-cell (DN-T) infiltration of the MZ, which was depleted of B cells. MZ in ALPS patients contained an abnormally thick layer of MAdCAM-1((+)) stromal cells and an excess of DN-Ts. DN-Ts were shown to express MAdCAM-1 ligand, the α4ß7 integrin. These observations suggest that accumulating DN-Ts are trapped within stromal cell meshwork and interfere with correct localization of MZ B cells. Similar observations were made in spleens of fas-deficient mice. Our data revealed an unexpected mechanism by which ALPS results in anti-polysaccharide IgM antibody production-specific defect. Splenectomy should be avoided.


Assuntos
Formação de Anticorpos , Síndrome Linfoproliferativa Autoimune/imunologia , Síndrome Linfoproliferativa Autoimune/patologia , Lipopolissacarídeos/imunologia , Baço/imunologia , Baço/patologia , Adolescente , Adulto , Animais , Síndrome Linfoproliferativa Autoimune/epidemiologia , Síndrome Linfoproliferativa Autoimune/cirurgia , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Camundongos , Camundongos Transgênicos , Baço/cirurgia , Esplenectomia/efeitos adversos , Esplenectomia/estatística & dados numéricos , Infecções Estreptocócicas/epidemiologia , Infecções Estreptocócicas/imunologia , Streptococcus pneumoniae/crescimento & desenvolvimento , Streptococcus pneumoniae/imunologia , Adulto Jovem
19.
Blood ; 123(13): 1989-99, 2014 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-24398331

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) presents in childhood with nonmalignant lymphadenopathy and splenomegaly associated with a characteristic expansion of mature CD4 and CD8 negative or double negative T-cell receptor αß(+) T lymphocytes. Patients often present with chronic multilineage cytopenias due to autoimmune peripheral destruction and/or splenic sequestration of blood cells and have an increased risk of B-cell lymphoma. Deleterious heterozygous mutations in the FAS gene are the most common cause of this condition, which is termed ALPS-FAS. We report the natural history and pathophysiology of 150 ALPS-FAS patients and 63 healthy mutation-positive relatives evaluated in our institution over the last 2 decades. Our principal findings are that FAS mutations have a clinical penetrance of <60%, elevated serum vitamin B12 is a reliable and accurate biomarker of ALPS-FAS, and the major causes of morbidity and mortality in these patients are the overwhelming postsplenectomy sepsis and development of lymphoma. With longer follow-up, we observed a significantly greater relative risk of lymphoma than previously reported. Avoiding splenectomy while controlling hypersplenism by using corticosteroid-sparing treatments improves the outcome in ALPS-FAS patients. This trial was registered at www.clinicaltrials.gov as #NCT00001350.


Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/terapia , Mutação , Receptor fas/genética , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/patologia , Proliferação de Células , Criança , Progressão da Doença , Feminino , Seguimentos , Humanos , Linfócitos/patologia , Linfócitos/fisiologia , Masculino , Pessoa de Meia-Idade , Penetrância , Adulto Jovem
20.
Blood ; 123(8): 1178-86, 2014 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-24363402

RESUMO

In autoimmune/lymphoproliferative syndrome (ALPS), defective Fas death receptor function causes lymphadenomegaly/splenomegaly, the expansion of T-cell receptor αß(+) CD4/CD8 double-negative T cells, and frequent development of hematologic autoimmunity. Dianzani autoimmune lymphoproliferative disease (DALD) has a similar phenotype but lacks the expansion of double-negative T cells. This work shows that patients with ALPS and DALD have high serum levels of interleukin 17A (IL-17A), IL-17F, and IL-17AF, which are involved in several autoimmune diseases, and that their T cells show increased secretion of these cytokines upon activation in vitro. The following data indicate that these cytokines may contribute to ALPS and DALD: (1) recombinant IL-17A and IL-17F significantly inhibit Fas-induced cell death in Fas-sensitive T cells from healthy donors; (2) this inhibitory effect is also induced by the patients' serum and is reversed by anti-IL-17A antibodies; (3) IL-17A neutralization substantially increases Fas-induced cell death in T cells from ALPS and DALD patients in vitro; and (4) treatment with anti-IL-17A antibodies ameliorates the autoimmune manifestations and, at a lesser extent, the lymphoproliferative phenotype and prolongs survival in MRLlpr/lpr mice, which are an animal model of ALPS. These data suggest that IL-17A and IL-17F could be targeted therapeutically to improve Fas function in ALPS and DALD.


Assuntos
Apoptose/imunologia , Síndrome Linfoproliferativa Autoimune/imunologia , Interleucina-17/imunologia , Linfócitos T/citologia , Animais , Anticorpos Neutralizantes/imunologia , Síndrome Linfoproliferativa Autoimune/patologia , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Imunização Passiva , Imunofenotipagem , Interleucina-17/sangue , Masculino , Camundongos , Camundongos Endogâmicos MRL lpr , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologia , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA