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1.
Haematologica ; 103(3): 540-549, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29242293

RESUMO

In patients with dysfunctions of the Ca2+ channel ORAI1, stromal interaction molecule 1 (STIM1) or integrin-regulating kindlin-3 (FERMT3), severe immunodeficiency is frequently linked to abnormal platelet activity. In this paper, we studied platelet responsiveness by multiparameter assessment of whole blood thrombus formation under high-shear flow conditions in 9 patients, including relatives, with confirmed rare genetic mutations of ORAI1, STIM1 or FERMT3. In platelets isolated from 5 out of 6 patients with ORAI1 or STIM1 mutations, store-operated Ca2+ entry (SOCE) was either completely or partially defective compared to control platelets. Parameters of platelet adhesion and aggregation on collagen microspots were impaired for 4 out of 6 patients, in part related to a low platelet count. For 4 patients, platelet adhesion/aggregation and procoagulant activity on von Willebrand Factor (VWF)/rhodocytin and VWF/fibrinogen microspots were impaired independently of platelet count, and were partly correlated with SOCE deficiency. Measurement of thrombus formation at low shear rate confirmed a greater impairment of platelet functionality in the ORAI1 patients than in the STIM1 patient. For 3 patients/relatives with a FERMT3 mutation, all parameters of thrombus formation were strongly reduced regardless of the microspot. Bone marrow transplantation, required by 2 patients, resulted in overall improvement of platelet function. We concluded that multiparameter assessment of whole blood thrombus formation in a surface-dependent way can detect: i) additive effects of low platelet count and impaired platelet functionality; ii) aberrant ORAI1-mediated Ca2+ entry; iii) differences in platelet activation between patients carrying the same ORAI1 mutation; iv) severe platelet function impairment linked to a FERMT3 mutation and bleeding history.


Assuntos
Síndromes de Imunodeficiência/sangue , Ativação Plaquetária/genética , Cálcio/metabolismo , Humanos , Síndromes de Imunodeficiência/genética , Proteínas de Membrana/genética , Mutação , Proteínas de Neoplasias/genética , Proteína ORAI1/genética , Adesividade Plaquetária , Agregação Plaquetária , Testes de Função Plaquetária , Molécula 1 de Interação Estromal/genética , Trombose/etiologia
2.
J Allergy Clin Immunol ; 142(4): 1297-1310.e11, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29155098

RESUMO

BACKGROUND: Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ channels is an essential signaling pathway in many cell types. Ca2+ release-activated Ca2+ channels are formed by ORAI1, ORAI2, and ORAI3 proteins and activated by stromal interaction molecule (STIM) 1 and STIM2. Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms. OBJECTIVE: We performed molecular and immunologic analysis of patients with CID, anhidrosis, and ectodermal dysplasia of unknown etiology. METHODS: We performed DNA sequencing of the ORAI1 gene, modeling of mutations on ORAI1 crystal structure, analysis of ORAI1 mRNA and protein expression, SOCE measurements, immunologic analysis of peripheral blood lymphocyte populations by using flow cytometry, and histologic and ultrastructural analysis of patient tissues. RESULTS: We identified 3 novel autosomal recessive mutations in ORAI1 in unrelated kindreds with CID, autoimmunity, ectodermal dysplasia with anhidrosis, and muscular dysplasia. The patients were homozygous for p.V181SfsX8, p.L194P, and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein expression and SOCE in the patients' lymphocytes and fibroblasts. In addition to impaired T-cell cytokine production, ORAI1 mutations were associated with strongly reduced numbers of invariant natural killer T and regulatory T (Treg) cells and altered composition of γδ T-cell and natural killer cell subsets. CONCLUSION: ORAI1 null mutations are associated with reduced numbers of invariant natural killer T and Treg cells that likely contribute to the patients' immunodeficiency and autoimmunity. ORAI1-deficient patients have dental enamel defects and anhidrosis, representing a new form of anhidrotic ectodermal dysplasia with immunodeficiency that is distinct from previously reported patients with anhidrotic ectodermal dysplasia with immunodeficiency caused by mutations in the nuclear factor κB signaling pathway (IKBKG and NFKBIA).


Assuntos
Displasia Ectodérmica/genética , Síndromes de Imunodeficiência/genética , Proteína ORAI1/genética , Cálcio/metabolismo , Células Cultivadas , Pré-Escolar , Evolução Fatal , Feminino , Humanos , Lactente , Masculino , Modelos Moleculares , Mutação
3.
Blood ; 130(12): 1456-1467, 2017 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-28679735

RESUMO

X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Quinase I-kappa B/genética , Mutação/genética , Pré-Escolar , Estudos de Coortes , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Heterozigoto , Humanos , Lactente , Recém-Nascido , Inflamação/patologia , Doenças Inflamatórias Intestinais/etiologia , NF-kappa B/metabolismo , Fenótipo , Transdução de Sinais/genética , Análise de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante , Resultado do Tratamento
5.
J Allergy Clin Immunol ; 139(4): 1302-1310.e4, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27658761

RESUMO

BACKGROUND: Absent T-cell immunity resulting in life-threatening infections provides a clear rationale for hematopoetic stem cell transplantation (HSCT) in patients with severe combined immunodeficiency (SCID). Combined immunodeficiencies (CIDs) and "atypical" SCID show reduced, not absent T-cell immunity. If associated with infections or autoimmunity, they represent profound combined immunodeficiency (P-CID), for which outcome data are insufficient for unambiguous early transplant decisions. OBJECTIVES: We sought to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. METHODS: In this prospective and retrospective observational study, we recruited nontransplanted patients with P-CID aged 1 to 16 years to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. RESULTS: A total of 51 patients were recruited (median age, 9.6 years). Thirteen of 51 had a genetic diagnosis of "atypical" SCID and 14 of 51 of CID. About half of the patients had less than 10% naive T cells, reduced/absent T-cell proliferation, and at least 1 significant clinical event/year, demonstrating their profound immunodeficiency. Nineteen patients (37%) underwent transplantation within 1 year of enrolment, and 5 of 51 patients died. Analysis of the HSCT decisions revealed the anticipated heterogeneity, favoring an ongoing prospective matched-pair analysis of patients with similar disease severity with or without transplantation. Importantly, so far neither the genetic diagnosis nor basic measurements of T-cell immunity were good predictors of disease evolution. CONCLUSIONS: The P-CID study for the first time characterizes a group of patients with nontypical SCID T-cell deficiencies from a therapeutic perspective. Because genetic and basic T-cell parameters provide limited guidance, prospective data from this study will be a helpful resource for guiding the difficult HSCT decisions in patients with P-CID.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Projetos de Pesquisa
6.
Clin Immunol ; 164: 52-6, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26812624

RESUMO

NF-κB essential modulator (NEMO) deficiency causes ectodermal dysplasia with immunodeficiency in males, while manifesting as incontinentia pigmenti in heterozygous females. We report a family with NEMO deficiency, in which a female carrier displayed skewed X-inactivation favoring the mutant NEMO allele associated with symptoms of Behçet's disease. Hematopoietic stem cell transplantation of an affected boy from this donor reconstituted an immune system with retained skewed X-inactivation. After transplantation no more severe infections occurred, indicating that an active wild-type NEMO allele in only 10% of immune cells restores host defense. Yet he developed inflammatory bowel disease (IBD). While gut infiltrating immune cells stained strongly for nuclear p65 indicating restored NEMO function, this was not the case in intestinal epithelial cells - in contrast to cells from conventional IBD patients. These results extend murine observations that epithelial NEMO-deficiency suffices to cause IBD. High anti-TNF doses controlled the intestinal inflammation and symptoms of Behçet's disease.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Quinase I-kappa B , Doenças Inflamatórias Intestinais/imunologia , Alelos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Síndrome de Behçet/imunologia , Feminino , Humanos , Quinase I-kappa B/deficiência , Quinase I-kappa B/genética , Quinase I-kappa B/imunologia , Masculino , Irmãos
7.
Blood ; 126(14): 1658-69, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26289640

RESUMO

Omenn syndrome (OS) is a severe immunodeficiency associated with erythroderma, lymphoproliferation, elevated IgE, and hyperactive oligoclonal T cells. A restricted T-cell repertoire caused by defective thymic T-cell development and selection, lymphopenia with homeostatic proliferation, and lack of regulatory T cells are considered key factors in OS pathogenesis. We report 2 siblings presenting with cytomegalovirus (CMV) and Pneumocystis jirovecii infections and recurrent sepsis; one developed all clinical features of OS. Both carried homozygous germline mutations in CARD11 (p.Cys150*), impairing NF-κB signaling and IL-2 production. A somatic second-site mutation reverting the stop codon to a missense mutation (p.Cys150Leu) was detected in tissue-infiltrating T cells of the OS patient. Expression of p.Cys150Leu in CARD11-deficient T cells largely reconstituted NF-κB signaling. The reversion likely occurred in a prethymic T-cell precursor, leading to a chimeric T-cell repertoire. We speculate that in our patient the functional advantage of the revertant T cells in the context of persistent CMV infection, combined with lack of regulatory T cells, may have been sufficient to favor OS. This first observation of OS in a patient with a T-cell activation defect suggests that severely defective T-cell development or homeostatic proliferation in a lymphopenic environment are not required for this severe immunopathology.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Guanilato Ciclase/genética , Ativação Linfocitária/genética , Mutação , Imunodeficiência Combinada Severa/genética , Linfócitos T Reguladores/imunologia , Animais , Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/imunologia , Feminino , Citometria de Fluxo , Guanilato Ciclase/deficiência , Guanilato Ciclase/imunologia , Humanos , Immunoblotting , Imuno-Histoquímica , Imunofenotipagem , Lactente , Ativação Linfocitária/imunologia , Masculino , Camundongos , Reação em Cadeia da Polimerase em Tempo Real , Imunodeficiência Combinada Severa/imunologia , Irmãos
8.
Clin Immunol ; 161(2): 103-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26187144

RESUMO

Autosomal recessive human ZAP70 deficiency is a rare cause of combined immunodeficiency (CID) characterized by defective CD4 T cells and profound CD8 T cell lymphopenia. Herein, we report two novel patients that extend the molecular genetics, the clinical and functional phenotypes associated with the ZAP70 deficiency. The patients presented as infant-onset CID with severe infections caused by varicella zoster virus and live vaccines. Retrospective TCR excision circle newborn screening was normal in both patients. One patient carried a novel non-sense mutation (p.A495fsX75); the other a previously described misense mutation (p.A507V). In contrast to CD4 T cells, the majority of the few CD8 T cells showed expression of the ZAP70-related tyrosine kinase SYK that correlated with residual TCR signaling including calcium flux and degranulation. Our findings highlight the differential requirements of ZAP70 and SYK during thymic development, peripheral homeostasis as well as effector functions of CD4 and CD8 T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas Tirosina Quinases/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Imunodeficiência Combinada Severa/imunologia , Proteína-Tirosina Quinase ZAP-70/deficiência , Linfócitos T CD4-Positivos/imunologia , Pré-Escolar , Humanos , Síndromes de Imunodeficiência/imunologia , Lactente , Masculino , Mutação/imunologia , Estudos Retrospectivos , Transdução de Sinais/imunologia , Quinase Syk , Proteína-Tirosina Quinase ZAP-70/imunologia
9.
Haematologica ; 100(7): 978-88, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26022711

RESUMO

Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/µL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as "lympho"-histiocytosis in these patients; and (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogeneses. This is important because of implications for therapy, in particular for protocols targeting T cells.


Assuntos
Síndromes de Imunodeficiência/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Sistema de Registros , Adolescente , Adulto , Infecções Bacterianas/complicações , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/imunologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Europa (Continente) , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/imunologia , Fatores Imunológicos/uso terapêutico , Lactente , Recém-Nascido , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Leishmaniose/complicações , Leishmaniose/tratamento farmacológico , Leishmaniose/imunologia , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/patologia , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/imunologia , Masculino , Micoses/complicações , Micoses/tratamento farmacológico , Micoses/imunologia , Infecções Oportunistas/complicações , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/imunologia , Esteroides/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia , Terminologia como Assunto , Viroses/complicações , Viroses/tratamento farmacológico , Viroses/imunologia
10.
Eur J Immunol ; 44(10): 3129-40, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25042067

RESUMO

X-linked severe combined immunodeficiency (X-SCID) leads to a T(-) NK(-) B(+) immunophenotype and is caused by mutations in the gene encoding the IL-2 receptor γ-chain (IL2RG). IL2RG(R222C) leads to atypical SCID with a severe early onset phenotype despite largely normal NK- and T-cell numbers. To address this discrepancy, we performed a detailed analysis of T, B, and NK cells, including quantitative STAT phosphorylation and functional responses to the cytokines IL-2, IL-4, IL-15, and IL-21 in a patient with the IL2RG(R222C) mutation. Moreover, we identified nine additional unpublished patients with the same mutations, all with a full SCID phenotype, and confirmed selected immunological observations. T-cell development was variably affected, but led to borderline T-cell receptor excision circle (TREC) levels and a normal repertoire. T cells showed moderately reduced proliferation, failing enhancement by IL-2. While NK-cell development was normal, IL-2 enhancement of NK-cell degranulation and IL-15-induced cytokine production were absent. IL-2 or IL-21 failed to enhance B-cell proliferation and plasmablast differentiation. These functional alterations were reflected by a differential impact of IL2RG(R222C) on cytokine signal transduction, with a gradient IL-4

Assuntos
Linfócitos B/imunologia , Citocinas/imunologia , Subunidade gama Comum de Receptores de Interleucina/genética , Células Matadoras Naturais/imunologia , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia , Humanos , Lactente , Subunidade gama Comum de Receptores de Interleucina/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Mutação , Fenótipo , Transdução de Sinais/imunologia
11.
J Clin Immunol ; 34(6): 601-6, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24916357

RESUMO

PURPOSE: IPEX (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) is a rare X-linked recessive life-threatening disorder characterized by autoimmunity and early death. Pulmonary complication related with IPEX has not been elucidated exactly. Here, we report 4 IPEX patients, 3 of which died from severe pulmonary disease. METHODS: Clinical data and laboratory findings including autoantibodies, immunoglobulin levels as well as number of T, B and NK cells were evaluated. FOXP3 expression and T reg activity were analyzed. The FOXP3 gene was sequenced and RNA analysis was performed. RESULTS: Patient I (PI) presented with nephrotic syndrome at 3 years of age and then developed autoimmune hepatitis without eczema, enteropathy or high IgE and died at 9 years of age due to acute respiratory distress syndrome (ARDS). Two cousins of PI had the same hypomorphic splice site mutation leading to a deletion of 27 amino acids, but normal FOXP3 protein expression and normal suppressive capacity of T reg in a proliferation inhibition assay. However, they exhibited typical symptoms such as eczema, diabetes and enteropathy with eosinophilia at early age (PII, PIII) and were transplanted in infancy. One of them had severe respiratory distress right after birth (PIII). Patient IV from another family presented with chronic diarrhea without autoimmune manifestations and died due to ARDS. CONCLUSION: Lung disease related to IPEX syndrome has not been reported before and this entity could be a critical factor in disease outcome.


Assuntos
Fatores de Transcrição Forkhead/genética , Subpopulações de Linfócitos/imunologia , Síndrome do Desconforto Respiratório do Adulto/diagnóstico , Linfócitos T Reguladores/imunologia , Idade de Início , Autoanticorpos/sangue , Criança , Pré-Escolar , Análise Mutacional de DNA , Diabetes Mellitus Tipo 1/congênito , Diarreia , Evolução Fatal , Fatores de Transcrição Forkhead/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Doenças do Sistema Imunitário/congênito , Tolerância Imunológica/genética , Lactente , Masculino , Mutação/genética , Linhagem , Síndrome do Desconforto Respiratório do Adulto/epidemiologia , Síndrome do Desconforto Respiratório do Adulto/genética , Turquia
12.
J Pediatr ; 165(1): 147-153.e1, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24797953

RESUMO

OBJECTIVES: To describe characteristics of visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis (HLH) with focus on diagnostic clues and pitfalls, including the frequency of central nervous system (CNS) involvement, and to determine the efficacy of liposomal amphotericin B (L-AmB). STUDY DESIGN: We retrospectively analyzed clinical and laboratory features, diagnostic procedures, and treatment of 13 patients with HLH with imported visceral leishmaniasis, reported to the German HLH reference center (1999-2012). RESULTS: The spectrum of presentations was indistinguishable from patients with hereditary HLH or with acquired HLH because of infections with other pathogens. In 8 patients, disease onset occurred before the age of 2 years, coinciding with the typical age of manifestation of primary HLH. Two patients had mild nonspecific CNS findings. Misleading antiviral IgM (n = 6) and autoantibodies (n = 2) led to inaccurate interpretation of the etiology of HLH, sometimes with inappropriate therapeutic consequences. False negative results for Leishmania were obtained by initial bone marrow microscopy in 6/13, serology in 1/12, bone marrow culture in 2/5, and polymerase chain reaction of peripheral blood in 1/3 patients, and all bone marrow samples tested were Leishmania-positive by polymerase chain reaction (n = 7). L-AmB was administered to 12 patients, 5 of whom had no prior HLH-directed immunosuppressive therapy; sodium stibogluconate was administered to 1 patient. Persistent remission was achieved in 11 cases. Two patients required repeated or prolonged L-AmB therapy. CONCLUSIONS: Awareness of diagnostic pitfalls may save patients from unnecessary toxic treatment. CNS involvement is rare. L-AmB shows efficacy in visceral leishmaniasis-associated HLH.


Assuntos
Leishmania donovani/isolamento & purificação , Leishmaniose Visceral/complicações , Linfo-Histiocitose Hemofagocítica/etiologia , Anfotericina B/uso terapêutico , Anticorpos Antiprotozoários/sangue , Antiprotozoários/uso terapêutico , Autoanticorpos/sangue , Medula Óssea/patologia , Criança , Pré-Escolar , DNA de Protozoário/análise , Feminino , Humanos , Lactente , Leishmania donovani/genética , Leishmania donovani/imunologia , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Masculino , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Resultado do Tratamento
14.
Arthritis Res Ther ; 14(3): 213, 2012 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-22682420

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages secreting high amounts of inflammatory cytokines. It is a frequent manifestation in patients with predisposing genetic defects, but can occur secondary to various infectious, malignant, and autoimmune triggers in patients without a known genetic predisposition. Clinical hallmarks are prolonged fever, cytopenias, hepatosplenomegaly, and neurological symptoms, but atypical variants presenting with signs of chronic immunodeficiency are increasingly recognized. Impaired secretion of perforin is a key feature in several genetic forms of the disease, but not required for disease pathogenesis. Despite progress in diagnostics and therapy, mortality of patients with severe HLH is still above 40%. Reference treatment is an etoposide-based protocol, but new approaches are currently explored. Key for a favorable prognosis is the rapid identification of an underlying genetic cause, which has been facilitated by recent immunological and genetic advances. In patients with predisposing genetic disease, hematopoietic stem cell transplantation is performed increasingly with reduced intensity conditioning regimes. Current research aims at a better understanding of disease pathogenesis and evaluation of more targeted approaches to therapy, including anti-cytokine antibodies and gene therapy.


Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/terapia , Humanos
16.
Blood ; 119(12): 2754-63, 2012 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-22294731

RESUMO

Familial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening disorder of immune regulation caused by defects in lymphocyte cytotoxicity. Rapid differentiation of primary, genetic forms from secondary forms of hemophagocytic lymphohistiocytosis (HLH) is crucial for treatment decisions. We prospectively evaluated the performance of degranulation assays based on surface up-regulation of CD107a on natural killer (NK) cells and cytotoxic T lymphocytes in a cohort of 494 patients referred for evaluation for suspected HLH. Seventy-five of 77 patients (97%) with FHL3-5 and 11 of 13 patients (85%) with Griscelli syndrome type 2 or Chediak-Higashi syndrome had abnormal resting NK-cell degranulation. In contrast, NK-cell degranulation was normal in 14 of 16 patients (88%) with X-linked lymphoproliferative disease and in 8 of 14 patients (57%) with FHL2, who were identified by diminished intracellular SLAM-associated protein (SAP), X-linked inhibitor of apoptosis protein (XIAP), and perforin expression, respectively. Among 66 patients with a clinical diagnosis of secondary HLH, 13 of 59 (22%) had abnormal resting NK-cell degranulation, whereas 0 of 43 had abnormal degranulation using IL-2-activated NK cells. Active disease or immunosuppressive therapy did not impair the assay performance. Overall, resting NK-cell degranulation below 5% provided a 96% sensitivity for a genetic degranulation disorder and a specificity of 88%. Therefore, degranulation assays allow a rapid and reliable classification of patients, benefiting treatment decisions.


Assuntos
Degranulação Celular/fisiologia , Testes Imunológicos/métodos , Células Matadoras Naturais/fisiologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfócitos T Citotóxicos/fisiologia , Humanos , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/metabolismo , Proteína 1 de Membrana Associada ao Lisossomo , Estudos Prospectivos , Sensibilidade e Especificidade , Fatores de Tempo
17.
J Immunol ; 188(3): 1523-33, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22190180

RESUMO

Stromal interaction molecule 1 (STIM1) deficiency is a rare genetic disorder of store-operated calcium entry, associated with a complex syndrome including immunodeficiency and immune dysregulation. The link from the molecular defect to these clinical manifestations is incompletely understood. We report two patients with a homozygous R429C point mutation in STIM1 completely abolishing store-operated calcium entry in T cells. Immunological analysis of one patient revealed that despite the expected defect of T cell proliferation and cytokine production in vitro, significant antiviral T cell populations were generated in vivo. These T cells proliferated in response to viral Ags and showed normal antiviral cytotoxicity. However, antiviral immunity was insufficient to prevent chronic CMV and EBV infections with a possible contribution of impaired NK cell function and a lack of NKT cells. Furthermore, autoimmune cytopenia, eczema, and intermittent diarrhea suggested impaired immune regulation. FOXP3-positive regulatory T (Treg) cells were present but showed an abnormal phenotype. The suppressive function of STIM1-deficient Treg cells in vitro, however, was normal. Given these partial defects in cytotoxic and Treg cell function, impairment of other immune cell populations probably contributes more to the pathogenesis of immunodeficiency and autoimmunity in STIM1 deficiency than previously appreciated.


Assuntos
Imunidade/genética , Proteínas de Membrana/deficiência , Proteínas de Neoplasias/deficiência , Humanos , Síndromes de Imunodeficiência/etiologia , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Mutação Puntual , Molécula 1 de Interação Estromal , Linfócitos T Citotóxicos/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Vírus/imunologia
18.
Blood ; 118(17): 4620-9, 2011 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-21878672

RESUMO

Perforin-mediated cytotoxicity is important for controlling viral infections, but also for limiting immune reactions. Failure of this cytotoxic pathway leads to hemophagocytic lymphohistiocytosis (HLH), a life-threatening disorder of uncontrolled T-cell and macrophage activation. We studied susceptibility to HLH in 2 mouse strains (souris and beige(J)) and a cohort of patients with partial defects in perforin secretion resulting from different mutations in the LYST gene. Although both strains lacked NK-cell cytotoxicity, only souris mice developed all clinical and histopathologic signs of HLH after infection with lymphocytic choriomeningitis virus. The 2 strains showed subtle differences in CTL cytotoxicity in vitro that had a large impact on virus control in vivo. Whereas beige(J) CTLs eliminated lymphocytic choriomeningitis virus infection, souris CTLs failed to control the virus, which was associated with the development of HLH. In LYST-mutant patients with Chediak-Higashi syndrome, CTL cytotoxicity was reduced in patients with early-onset HLH, whereas it was retained in patients who later or never developed HLH. Thus, the risk of HLH development is set by a threshold that is determined by subtle differences in CTL cytotoxicity. Differences in the cytotoxic capacity of CTLs may be predictive for the risk of Chediak-Higashi syndrome patients to develop HLH.


Assuntos
Síndrome de Chediak-Higashi/etiologia , Síndrome de Chediak-Higashi/imunologia , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Sequência de Bases , Células Cultivadas , Síndrome de Chediak-Higashi/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Humanos , Individualidade , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Linfo-Histiocitose Hemofagocítica/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Perforina/genética , Linfócitos T Citotóxicos/fisiologia , Proteínas de Transporte Vesicular/genética
20.
Haematologica ; 95(12): 2080-7, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20823128

RESUMO

BACKGROUND: Familial hemophagocytic lymphohistiocytosis is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first two years of life and has a poor prognosis unless treated by hematopoietic stem cell transplantation. Atypical courses with later onset and prolonged survival have been described, but no detailed analysis of immunological parameters associated with typical versus atypical forms of familial hemophagocytic lymphohistiocytosis has been performed. DESIGN AND METHODS: We analyzed disease manifestations, NK-cell and T-cell cytotoxicity and degranulation, markers of T-cell activation and B-cell differentiation as well as Natural Killer T cells in 8 patients with atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2. RESULTS: All but one patient with atypical familial hemophagocytic lymphohistiocytosis carried at least one splice-site mutation in UNC13D or STXBP2. In most patients episodes of hemophagocytic lymphohistiocytosis were preceded or followed by clinical features typically associated with immunodeficiency, such as chronic active Epstein Barr virus infection, increased susceptibility to bacterial infections, granulomatous lung or liver disease, encephalitis or lymphoma. Five of 8 patients had hypogammaglobulinemia and reduced memory B cells. Most patients had a predominance of activated CD8(+) T cells and low numbers of Natural Killer T cells. When compared to patients with typical familial hemophagocytic lymphohistiocytosis, NK-cell cytotoxicity and NK-cell and CTL degranulation were impaired to a similar extent. However, in patients with an atypical course NK-cell degranulation could be partially reconstituted by interleukin-2 and cytotoxic T-cell cytotoxicity in vitro was normal. CONCLUSIONS: Clinical and immunological features of atypical familial hemophagocytic lymphohistiocytosis show an important overlap to primary immunodeficiency diseases (particularly common variable immunodeficiency and X-linked lymphoproliferative syndrome) and must, therefore, be considered in a variety of clinical presentations. We show that degranulation assays are helpful screening tests for the identification of such patients.


Assuntos
Síndromes de Imunodeficiência/complicações , Linfo-Histiocitose Hemofagocítica/genética , Proteínas de Membrana/genética , Proteínas Munc18/genética , Mutação , Adolescente , Adulto , Alelos , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Degranulação Celular/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Criança , Pré-Escolar , Citotoxicidade Imunológica/imunologia , Citometria de Fluxo , Frequência do Gene , Humanos , Imunoglobulina G/sangue , Síndromes de Imunodeficiência/imunologia , Células K562 , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/imunologia , Sítios de Splice de RNA/genética
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