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3.
J Clin Immunol ; 38(5): 558-568, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29911256

RESUMO

The autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant and non-infectious uncontrolled proliferation of lymphocytes accompanied by autoimmune cytopenia. The genetic etiology of the ALPS was described in 1995 by the discovery of the FAS gene mutations. The related apoptosis defect accounts for the accumulation of autoreactive lymphocytes as well as for specific clinical and biological features that distinguish the ALPS-FAS from other monogenic defects of this apoptosis pathway, such as FADD and CASPASE 8 deficiencies. The ALPS-FAS was the first description of a monogenic cause of autoimmunity, but its non-Mendelian expression remained elusive until the description of somatic and germline mutations in ALPS patients. The recognition of these genetic diseases brought new information on the role of this apoptotic pathway in controlling the adaptive immune response in humans.


Assuntos
Síndrome Linfoproliferativa Autoimune/etiologia , Síndrome Linfoproliferativa Autoimune/metabolismo , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Receptor fas/genética , Receptor fas/metabolismo , Alelos , Animais , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/terapia , Gerenciamento Clínico , Suscetibilidade a Doenças , Estudos de Associação Genética , Genótipo , Humanos , Mutação , Fenótipo , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo
5.
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
6.
Int Immunopharmacol ; 52: 136-142, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28898770

RESUMO

Immunoglobulin therapy is the administration of human polyvalent IgG and represents the most effective treatment to prevent recurrent infections in antibody deficiency patients. Primary antibody deficiency represents the main indication of immunoglobulin replacement therapy and includes a wide range of disorders characterized by impaired antibody production in response to pathogens and recurrent infections. However, not all primary antibody deficiency patients require immunoglobulin replacement. Indeed, immunoglobulin preparations are expensive and, once prescribed, usually result in lifelong therapy. Moreover, many patients significantly benefit from a long-term antibiotic prophylaxis and a prompt begin of antibiotic therapy in case of infectious events. Even more controversial is the decision to initiate immunoglobulin replacement therapy in secondary antibody deficiency, a heterogeneous and expanding group including B-cell lymphoproliferative syndromes, protein losing states and therapeutic agents. This review seeks to define the indication to immunoglobulin replacement in primary and secondary antibody deficiency disorders, distinguishing those in which the beginning of immunoglobulin therapy is always indicated at the same time as the diagnosis has been made, from those lacking of defined indication to replacement therapy. In addition, we propose a clinical approach, mainly based on the evaluation of infectious history, vaccine response and bronchiectasis finding, to support the decision to initiate immunoglobulin therapy in an individual patient.


Assuntos
Síndrome Linfoproliferativa Autoimune/terapia , Imunoglobulina G/uso terapêutico , Síndromes de Imunodeficiência/terapia , Imunoterapia/métodos , Vacinas/imunologia , Antibioticoprofilaxia , Bronquiectasia , Humanos , Imunidade Heteróloga , Seleção de Pacientes
7.
Allergy Asthma Proc ; 38(4): 317-321, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28668112

RESUMO

A case of autoimmune lymphoproliferative syndrome (ALPS) was presented, followed by a discussion of the clinical characteristics, pathophysiology, diagnosis, and management of this disease. Clinical pearls and pitfalls are emphasized for the use of the practicing allergist and the fellow in-training. The diagnosis of ALPS was guided by published criteria. A careful history and workup were needed to exclude other possible etiologies for the patient's symptoms and physical findings. ALPS often carries significant morbidity and is best managed through a multidisciplinary approach.


Assuntos
Doenças Autoimunes/diagnóstico , Síndrome Linfoproliferativa Autoimune/diagnóstico , Doenças Autoimunes/epidemiologia , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/imunologia , Síndrome Linfoproliferativa Autoimune/terapia , Análise Mutacional de DNA , Diagnóstico Diferencial , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Fenótipo , Valor Preditivo dos Testes , Adulto Jovem , Receptor fas/genética
8.
Clin Rev Allergy Immunol ; 50(1): 55-63, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25663566

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS), a disorder characterized by immune dysregulation due to disrupted lymphocyte homeostasis, is mainly resulted from the mutations in FAS-mediated apoptotic pathway. In addition, other mutations of the genes such as Fas-ligand (FASLG), Caspase 10 (CASP10) and Caspase 8 (CASP8), NRAS and KRAS have also been observed in a small number of patients with ALPS or ALPS-related disorders. However, approximately 20-30% of patients with ALPS have unidentified defect. Its clinical manifestations observed in multiple family members include unexplained lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias such as thrombocytopenia, neutropenia, and anemia due to excessive production of antibodies by lymphocytes, elevated number of double-negative T (DNT) cells, and increased risk of lymphoma. As a very rare disease, ALPS was first characterized in the early 1990s. More than 300 families with hereditary ALPS have been reported till now; nearly 500 patients from these families have been studied and followed worldwide over the last 20 years. ALPS has historically considered as a primary immune defect presenting in early childhood, however, recent studies have shown that it may be more common than previous thought because adult onset presentation is increasingly becoming recognized and more adult ALPS patients are diagnosed. The new genetic and biological insights have improved the understanding of ALPS and a number of targeted therapeutic strategies such as mycophenolate mofetil, sirolimus, and pentostatin have been successfully applied in ALPS patients with promising treatment efficacy. This article comprehensively reviews the clinical and laboratory manifestations, new research advances in the molecular pathogenesis, diagnosis and treatments of this disorder.


Assuntos
Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/etiologia , Síndrome Linfoproliferativa Autoimune/terapia , Animais , Síndrome Linfoproliferativa Autoimune/metabolismo , Biomarcadores , Terapia Combinada , Diagnóstico Diferencial , Humanos , Resultado do Tratamento
9.
Blood ; 123(13): 1978, 2014 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-24677399

RESUMO

In this issue of Blood, Price et al document a 20-year experience with autoimmune lymphoproliferative syndrome (ALPS) patients and healthy mutation-positive relatives, showing that defective lymphocyte apoptosis is associated with an increased incidence of lymphomas.


Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/terapia , Mutação , Receptor fas/genética , Feminino , Humanos , Masculino
10.
An. pediatr. (2003, Ed. impr.) ; 80(2): 122-122[e1-e7], feb. 2014. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-129163

RESUMO

Esta revisión tiene como objetivo discutir los recientes avances en el conocimiento, diagnóstico y manejo del síndrome linfoproliferativo autoinmune (ALPS). El ALPS consiste en una alteración en la homeostasis de los linfocitos debida a un fallo en la apoptosis. Las manifestaciones clínicas en la infancia son las citopenias recurrentes, la linfoproliferación crónica no maligna y complicaciones autoinmunes. Los recientes descubrimientos en la biología y genética de esta afección permiten un mejor conocimiento de la misma, que se traduce en cambios en los algoritmos diagnósticos y de tratamiento, con la aparición de nuevos inmunosupresores que han demostrado una mejoría en la calidad de vida de muchos pacientes (AU)


Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis. ALPS often manifest in childhood with cytopenias, chronic non-malignant lymphoproliferation and autoimmune complications. A number of new insights have improved the understanding of the genetics and biology of ALPS. The treatment of the disease has changed and mycophenolate mofetil and sirolimus have been demonstrated to have marked activity against the disease, improving quality of life for many patients. These will be discussed in this review (AU)


Assuntos
Humanos , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/terapia , Marcadores Genéticos/genética , Predisposição Genética para Doença , Transplante de Células-Tronco Hematopoéticas
11.
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
13.
Rev Esp Med Nucl Imagen Mol ; 33(2): 99-102, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23845452

RESUMO

A young patient with undefined autoimmune lymphoproliferative syndrome (ALPS-U) and low back pain underwent a CT and MRI study that showed enhancing vertebral lesions, some pulmonary nodules and diffuse latero-cervical lymphadenopathy. A (18)F-FDG-PET/CT scan showed many areas of intense (18)F-FDG uptake in multiple vertebrae, in some ribs, in the sacrum, in the liver, in both lungs, in multiple lymph nodes spread in the cervical, thoracic and abdominal chains. A bone marrow biopsy showed a "lymphomatoid granulomatosis", a rare variant of B-cell non-Hodgkin lymphoma (NHL). After the treatment, the (18)F-FDG-PET/CT scan showed a complete metabolic response.


Assuntos
Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/terapia , Fluordesoxiglucose F18 , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/terapia , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X , Adulto , Humanos , Masculino
14.
Zhonghua Er Ke Za Zhi ; 52(12): 923-6, 2014 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-25619350

RESUMO

OBJECTIVE: To summarize the clinical characteristics, diagnosis and treatment of a case with autoimmune lymphoproliferative syndrome (ALPS) . METHOD: The patient was diagnosed as autoimmune lymphoproliferactive syndrome (ALPS) after being admitted to the Department of Rheumatism and Immunology of Tianjin Children's Hospital in February 20, 2014. The clinical characteristics, physical examination, laboratory tests, gene tests, and treatment process were analyzed and related literature was reviewed. RESULT: The patient was a 16-month- old boy.Since the first month of life, he started to have repeatedly fever, diarrhea, shortness of breath, lymphadenopathy, hepatosplenomegaly, anemia (HGBmin 50 g/L) and thrombocytopenia (min 35 × 109/L) . But multiple exams showed a normal peripheral blood leukocyte count, hypergammaglobulinemia (IgG 19 800 mg/L, IgA 1 710 mg/L, IgM 2 590 mg/L) and significantly increased serum vitamin B12. Flow cytometric measures showed that CD3⁺ CD4⁻ CD8⁻ T lymphocytes significantly increased ( > 10%) at four times. The count of CD3⁺ TCRαß⁺ CD4⁻ CD8⁻T lymphocytes (double negative T cells; DNTs) >3% twice. The genetic test showed that 309th FAS gene area showed heterozygous mutations, the boy was diagnosed as ALPS. Added examinations of lymphocytes apoptosis induced by FAS was positive. He was treated with prednisone 15 mg once daily and immunomodulator 150 mg three times a day, while in maintaining period with normal levels of hemoglobin and platelet, the dose of prednisone was reduced gradually. Till now, the patient has been treated and observed for 8 months. We retrieved the reports of ALPS in the databases at home and abroad published in recent 10 years, more than 400 cases reported from foreign countries, but there were only 5 domestic cases. Among those, 4 had onset in infancy and 1 at 6-years of age. All the cases presented servere lymphadenopathy and hepatosplenomegaly with anemia (4 of them with hemolytic anemia) and thrombocytopenia. Three cases had a history of frequent infection, one of them had glomerulonephritis. All patient with significant high level of serum immunoglobulin ( > 1.5 times upper limit of normal range), in 3 of them serum vitamin B12 was > 1.5 pg/L (the other 2 cases missed the exam). In 5 cases CD3⁺ CD4⁻ CD8⁻T cells > 10%, and in 2 case DNTs were 8.9% and 15.7% respectively (the other 3 cases missed the exam). Three cases were clearly detected with FAS mutations. All patients were treated with corticosteroid, 2 of them were added with mycophenolate mofetil. The therapy presented effective result in early 1-3 months, but no long-term follow-up reports were available. CONCLUSION: ALPS is a disorder of disrupted lymphocyte homeostasis caused by defective Fas-mediated apoptosis, and it is one of the primary immunodeficiency diseases. The onset of the disease occurs during infancy mainly. Clinical lymphoid hyperplasia and autoimmune phenomena are outstanding signs, which can be associated with frequent infections and allergies. The level of serum vitamin B12 > 1.5 pg/L and the count of CD3⁺ CD4⁻ CD8⁻ T cell show important significance. Exact diagnosis should depend on detecting DNTs and FAS gene.


Assuntos
Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/terapia , Contagem de Células , Humanos , Lactente , Masculino , Subpopulações de Linfócitos T , Vitamina B 12/sangue , Receptor fas
15.
An Pediatr (Barc) ; 80(2): 122.e1-7, 2014 Feb.
Artigo em Espanhol | MEDLINE | ID: mdl-24055319

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis. ALPS often manifest in childhood with cytopenias, chronic non-malignant lymphoproliferation and autoimmune complications. A number of new insights have improved the understanding of the genetics and biology of ALPS. The treatment of the disease has changed and mycophenolate mofetil and sirolimus have been demonstrated to have marked activity against the disease, improving quality of life for many patients. These will be discussed in this review.


Assuntos
Síndrome Linfoproliferativa Autoimune , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/fisiopatologia , Síndrome Linfoproliferativa Autoimune/terapia , Criança , Humanos
17.
Blood ; 118(22): 5741-51, 2011 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-21885601

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis, permitting accumulation of lymphoid mass and persistence of autoreactive cells that often manifest in childhood with chronic nonmalignant lymphadenopathy, hepatosplenomegaly, and recurring multilineage cytopenias. Cytopenias in these patients can be the result of splenic sequestration as well as autoimmune complications manifesting as autoimmune hemolytic anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia. More than 300 families with hereditary ALPS have now been described; nearly 500 patients from these families have been studied and followed worldwide over the last 20 years by our colleagues and ourselves. Some of these patients with FAS mutations affecting the intracellular portion of the FAS protein also have an increased risk of B-cell lymphoma. The best approaches to diagnosis, follow-up, and management of ALPS, its associated cytopenias, and other complications resulting from infiltrative lymphoproliferation and autoimmunity are presented.


Assuntos
Síndrome Linfoproliferativa Autoimune/terapia , Animais , Apoptose/genética , Apoptose/fisiologia , Síndrome Linfoproliferativa Autoimune/classificação , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Autoimunidade/genética , Autoimunidade/fisiologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Humanos , Linfoma/etiologia , Linfoma/genética , Modelos Biológicos , Fatores de Risco , Transdução de Sinais/genética
19.
Eur J Haematol ; 87(1): 1-9, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21447005

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis. It is characterized by non-malignant lymphoproliferation autoimmunity mostly directed toward blood cells and increased risk of lymphoma. Majority of patients with ALPS harbor heterozygous germline mutations in the gene for the TNF receptor-family member Fas (CD 95, Apo-1) which are inherited in an autosomal dominant fashion. Somatic Fas mutations are the second most common genetic etiology of ALPS. Additionally mutations in the genes encoding Fas-ligand (FASLG), caspase 10 (CASP10) and caspase 8 (CASP8), NRAS and KRAS have been identified in a small number of patients with ALPS and related disorders. Approximately one-third of patients with ALPS have yet unidentified defect. ALPS was initially thought to be a very rare disease, but recent studies have shown that it may be more common than previously thought. Testing for ALPS should therefore be considered in patients with unexplained lymphadenopathy, cytopenias, and hepatosplenomegaly. There have been significant advances in the understanding of the pathophysiology of ALPS in last few years which has resulted in the development of new diagnostic criteria and a number of targeted therapies. This review describes the clinical and laboratory manifestations found in patients with ALPS, as well as the molecular basis for the disease and new advances in treatment.


Assuntos
Síndrome Linfoproliferativa Autoimune , Apoptose , Síndrome Linfoproliferativa Autoimune/classificação , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/terapia , Autoimunidade , Proliferação de Células , Humanos , Modelos Biológicos , Mutação , Neoplasias/etiologia , Prognóstico , Fatores de Risco , Transdução de Sinais , Receptor fas/genética
20.
J Immunol ; 185(12): 7151-5, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21076068

RESUMO

A hallmark of autoimmune lymphoproliferative syndrome (ALPS), caused by mutation of the Fas death receptor, is massive lymphadenopathy from aberrant expansion of CD4(-)CD8(-) (double-negative [DN]) T cells. Eomesodermin (Eomes) is a member of the T-box family of transcription factors and plays critical roles in effector cell function and memory cell fitness of CD8(+) T lymphocytes. We provide evidence in this study that DN T cells exhibit dysregulated expression of Eomes in humans and mice with ALPS. We also find that T cell-specific deletion of Eomes prevents lymphoid hypertrophy and accumulation of DN T cells in Fas-mutant mice. Although Eomes has critical physiological roles in the function and homeostasis of CD8(+) T cells, overexpression of Eomes appears to enable pathological induction or expansion of unusual CD8-related T cell subsets. Thus, antagonism of Eomes emerges as a therapeutic target for DN T cell ablation in ALPS.


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas com Domínio T/imunologia , Subpopulações de Linfócitos T/imunologia , Receptor fas , Animais , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/patologia , Síndrome Linfoproliferativa Autoimune/terapia , Linfócitos T CD8-Positivos/patologia , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Humanos , Memória Imunológica/genética , Memória Imunológica/imunologia , Masculino , Camundongos , Camundongos Knockout , Proteínas com Domínio T/genética , Subpopulações de Linfócitos T/patologia
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