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1.
Scand J Immunol ; : e12811, 2019 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-31378960

RESUMO

Hypomorphic mutations in the gene encoding Bruton tyrosine kinase (BTK) may result in milder phenotypes and delayed diagnosis of B-cell related immunodeficiencies due to residual BTK function. Newborn screening for kappa-deleting-recombination-excision circles (KRECs) reliably identifies classical X-linked agammaglobulinaemia (XLA) patients with profound B-cell lymphopenia at birth but has not been evaluated in patients with residual BTK function. We aimed to evaluate clinical findings, BTK function and KREC copy numbers in three patients with BTK mutations presenting with impaired polysaccharide responsiveness without agammaglobulinaemia. One patient had an invasive pneumococcal infection at the age of 4 years. All three patients (two brothers) had visible tonsils, normal to slightly decreased immunoglobulin G levels, undetectable pneumococcal antibodies despite pneumococcal conjugate vaccinations, no antibody response after a diagnostic polysaccharide vaccination as well as profound B-cell lymphopenia with residual B-cell differentiation. BTK mutations were identified by Sanger sequencing. BTK staining and phosphorylation assays were performed on peripheral B cells. KREC copy numbers were determined from dried blood spots obtained within the first week of life as well as once at the age of 8, 6 and 3 years, respectively. BTK staining showed residual protein expression. Also, residual BTK activity could be demonstrated. KREC copy numbers from dried blood spots were above the threshold set for detection of patients with profound B-cell lymphopenia. Male patients with impaired polysaccharide responsiveness should be evaluated for B-cell lymphopenia followed by BTK analyses irrespective of immunoglobulin levels or tonsil size.

2.
Clin Immunol ; 203: 125-133, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31028919

RESUMO

Intestinal epithelial cells (IECs) form a fundamental mucosal barrier and actively participate in tolerance and immunity against intestinal contents. Major histocompatibility complex class II (MHC II) and invariant chain (Ii) molecules are essential for adaptive immune response. MHC II deficiency often presents with gastrointestinal disorders. Intestinal biopsy samples revealed an absence of HLA-DR, Ii, and local immunoglobulins in both hematopoietic immune cells and IECs accompanied by a lack of faecal sIgA. After successful hematopoietic stem cell transplantation (HSCT) absent HLA-DR and Ii expression persisted in IECs and faecal stool analysis indicated inflammation and high microbial activity. We describe multifaceted disturbance of adaptive mucosal immunity in MHC II deficient patients suffering from enteropathy. HLA-DR and Ii expression on enterocytes is not restored by HSCT. This may account for increased susceptibility to enteric infections and intestinal inflammation leading to prolonged enteropathy reported in MHC II deficient patients.

3.
Immunol Cell Biol ; 96(10): 1060-1071, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29790605

RESUMO

Premature T-cell immunosenescence with CD57+ CD8+ T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57+ CD8+ T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57+ CD8+ T cells from APDS patients were less differentiated with more CD27+ CD28+ effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57+ CD8+ T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57+ CD8+ T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57+ CD8+ T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.

4.
Eur J Paediatr Neurol ; 22(5): 870-877, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29843966

RESUMO

CD59 is involved in lymphocyte signal transduction and regulates complement-mediated cell lysis by inhibiting the membrane attack complex. In the cases reported so far, congenital isolated CD59 deficiency was associated with recurrent episodes of hemolytic anemia, peripheral neuropathy, and strokes. Here, we report on a patient from a consanguineous Turkish family, who had a first episode of hemolytic anemia at one month of age and presented at 14 months with acute Guillain-Barré syndrome (GBS). The child suffered repeated infection-triggered relapses leading to the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Although partly steroid-responsive, the polyneuropathy failed to be stabilized by a number of immunosuppressive agents. At the age of 6 years, he developed acute hemiparesis and showed progressive stenosis of proximal cerebral arteries, evolving into Moyamoya syndrome (MMS) with recurrent infarctions leading to death at 8 years of age. Post-mortem genetic analysis revealed a pathogenic p.(Asp49Valfs*31) mutation in CD59. Re-analysis of brain biopsy specimens showed absent CD59 expression and severe endothelial damage. Whereas strokes are a known feature of CD59 deficiency, MMS has not previously been described in this condition. Therefore, we conclude that in MMS combined with hemolysis or neuropathy CD59 deficiency should be considered. Establishing the diagnosis and targeted therapy with eculizumab might have prevented the lethal course in our patient.

6.
Blood ; 130(7): 875-880, 2017 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-28559357

RESUMO

We report 5 individuals in 3 unrelated families with severe thrombocytopenia progressing to trilineage bone marrow failure (BMF). Four of the children received hematopoietic stem cell transplants and all showed poor graft function with persistent severe cytopenias even after repeated transplants with different donors. Exome and targeted sequencing identified mutations in the gene encoding thrombopoietin (THPO): THPO R99W, homozygous in affected children in 2 families, and THPO R157X, homozygous in the affected child in the third family. Both mutations result in a lack of THPO in the patients' serum. For the 2 surviving patients, improvement in trilineage hematopoiesis was achieved following treatment with a THPO receptor agonist. These studies demonstrate that biallelic loss-of-function mutations in THPO cause BMF, which is unresponsive to transplant due to a hematopoietic cell-extrinsic mechanism. These studies provide further support for the critical role of the MPL-THPO pathway in hematopoiesis and highlight the importance of accurate genetic diagnosis to inform treatment decisions for BMF.


Assuntos
Transplante de Medula Óssea , Medula Óssea/patologia , Mutação/genética , Trombopoetina/genética , Sequência de Bases , Criança , Pré-Escolar , Feminino , Células HEK293 , Humanos , Lactente , Masculino , Linhagem , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Resultado do Tratamento
7.
Haematologica ; 102(2): e52-e56, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27789675
8.
Blood ; 128(5): 650-9, 2016 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-27281794

RESUMO

Repair of DNA double-strand breaks (DSBs) by the nonhomologous end-joining pathway (NHEJ) is important not only for repair of spontaneous breaks but also for breaks induced in developing lymphocytes during V(D)J (variable [V], diversity [D], and joining [J] genes) recombination of their antigen receptor loci to create a diverse repertoire. Mutations in the NHEJ factor XLF result in extreme sensitivity for ionizing radiation, microcephaly, and growth retardation comparable to mutations in LIG4 and XRCC4, which together form the NHEJ ligation complex. However, the effect on the immune system is variable (mild to severe immunodeficiency) and less prominent than that seen in deficiencies of NHEJ factors ARTEMIS and DNA-dependent protein kinase catalytic subunit, with defects in the hairpin opening step, which is crucial and unique for V(D)J recombination. Therefore, we aimed to study the role of XLF during V(D)J recombination. We obtained clinical data from 9 XLF-deficient patients and performed immune phenotyping and antigen receptor repertoire analysis of immunoglobulin (Ig) and T-cell receptor (TR) rearrangements, using next-generation sequencing in 6 patients. The results were compared with XRCC4 and LIG4 deficiency. Both Ig and TR rearrangements showed a significant decrease in the number of nontemplated (N) nucleotides inserted by terminal deoxynucleotidyl transferase, which resulted in a decrease of 2 to 3 amino acids in the CDR3. Such a reduction in the number of N-nucleotides has a great effect on the junctional diversity, and thereby on the total diversity of the Ig and TR repertoire. This shows that XLF has an important role during V(D)J recombination in creating diversity of the repertoire by stimulating N-nucleotide insertion.


Assuntos
Enzimas Reparadoras do DNA/deficiência , Proteínas de Ligação a DNA/deficiência , Nucleotídeos/metabolismo , Recombinação V(D)J/genética , Animais , Antígenos/metabolismo , Regiões Determinantes de Complementaridade/genética , DNA Nucleotidilexotransferase/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Rearranjo Gênico/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoglobulinas/genética , Camundongos , Radiação Ionizante , Receptores de Antígenos de Linfócitos T/genética
9.
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
10.
Pediatr Allergy Immunol ; 27(6): 640-4, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27116393

RESUMO

BACKGROUND: Autosomal dominant gain-of-function mutations in PIK3R1 encoding for the regulatory subunit (p85α, p55α, and p50α) of Class IA phosphoinositide 3-kinase (PI3K) result in the activated PI3Kδ syndrome (APDS) type 2 characterized by childhood-onset combined immunodeficiency, lymphoproliferation, and immune dysregulation. To improve clinical awareness and understanding of these rare diseases, we reviewed all hitherto published cases with APDS type 1 and type 2 for their clinical and immunologic symptoms and added novel clinical, immunologic, and genetic findings of two patients with APDS type 2. METHODS: Clinical, immunologic, and genetic evaluation of two new patients with APDS2 was performed followed by the systematic collection of all available previously published data of patients with APDS1 and APDS2. RESULTS: Patients with APDS type 1 (n = 49) and type 2 (n = 15) showed an indistinguishable immunologic phenotype. Overlapping clinical features shared by APDS type 1 and type 2 were observed, but our review also revealed previously unnoticed clinical differences such as remarkably high incidence of microcephaly, poor growth/short stature in patients with APDS2. Clinical management and outcome were variable and included prophylactic antibiotics, immunosuppression, immunoglobulin substitution, and hematopoietic stem cell transplantation. CONCLUSIONS: A disease-specific registry collecting prospective and long-term follow-up data of patients with APDS, as currently set up by the European Society for Immunodeficiencies, are needed to better understand the natural history and to optimize treatment concepts and thereby improving the outcome of this heterogenous patient group.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/genética , Microcefalia , Mutação/genética , Antibioticoprofilaxia , Pré-Escolar , Feminino , Genótipo , Crescimento e Desenvolvimento , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressão , Masculino , Linhagem , Fenótipo , Análise de Sequência de DNA
11.
Blood ; 127(18): 2193-202, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-26907631

RESUMO

Fas is a transmembrane receptor involved in the maintenance of tolerance and immune homeostasis. In murine models, it has been shown to be essential for deletion of autoreactive B cells in the germinal center. The role of Fas in human B-cell selection and in development of autoimmunity in patients carrying FAS mutations is unclear. We analyzed patients with either a somatic FAS mutation or a germline FAS mutation and somatic loss-of-heterozygosity, which allows comparing the fate of B cells with impaired vs normal Fas signaling within the same individual. Class-switched memory B cells showed: accumulation of FAS-mutated B cells; failure to enrich single V, D, J genes and single V-D, D-J gene combinations of the B-cell receptor variable region; increased frequency of variable regions with higher content of positively charged amino acids; and longer CDR3 and maintenance of polyreactive specificities. Importantly, Fas-deficient switched memory B cells showed increased rates of somatic hypermutation. Our data uncover a defect in B-cell selection in patients with FAS mutations, which has implications for the understanding of the pathogenesis of autoimmunity and lymphomagenesis of autoimmune lymphoproliferative syndrome.


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Subpopulações de Linfócitos B/imunologia , Seleção Clonal Mediada por Antígeno , Mutação , Receptor fas/fisiologia , Apoptose , Autoimunidade , Linhagem Celular Transformada , Transformação Celular Neoplásica , Criança , Códon sem Sentido , Feminino , Mutação da Fase de Leitura , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Memória Imunológica , Perda de Heterozigosidade , Masculino , Análise de Sequência de DNA , Hipermutação Somática de Imunoglobulina , Recombinação V(D)J , Receptor fas/deficiência , Receptor fas/genética
13.
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
15.
J Immunol ; 194(7): 3045-53, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25732729

RESUMO

The mechanisms underlying thymoma-associated immunodeficiency are largely unknown, and the significance of increased blood γδ Τ cells often remains elusive. In this study we address these questions based on an index patient with thymoma, chronic visceral leishmaniasis, myasthenia gravis, and a marked increase of rare γδ T cell subsets in the peripheral blood. This patient showed cutaneous anergy, even though he had normal numbers of peripheral blood total lymphocytes as well as CD4(+) and CD8(+) T cells. Despite his chronic infection, analyses of immunophenotypes and spectratyping of his lymphocytes revealed an unusual accumulation of naive γδ and αß T cells, suggesting a generalized T cell activation defect. Functional studies in vitro demonstrated substantially diminished IL-2 and IFN-γ production following TCR stimulation of his "untouched" naive CD4(+) T cells. Biochemical analysis revealed that his γδ and αß T cells carried an altered TCR complex with reduced amounts of the ζ-chain (CD247). No mutations were found in the CD247 gene that encodes the homodimeric ζ protein. The diminished presence of CD247 and increased numbers of γδ T cells were also observed in thymocyte populations obtained from three other thymoma patients. Thus, our findings describe a novel type of a clinically relevant acquired T cell immunodeficiency in thymoma patients that is distinct from Good's syndrome. Its characteristics are an accumulation of CD247-deficient, hyporresponsive naive γδ and αß T cells and an increased susceptibility to infections.


Assuntos
Complexo CD3/genética , Regulação da Expressão Gênica , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Timoma/genética , Timoma/imunologia , Adulto , Antígenos de Protozoários/imunologia , Complexo CD3/metabolismo , Citocinas/biossíntese , Éxons , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico , Memória Imunológica , Imunofenotipagem , Leishmania/imunologia , Contagem de Linfócitos , Masculino , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Análise de Sequência de DNA , Timoma/complicações , Timoma/diagnóstico
16.
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
17.
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
18.
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
19.
Haematologica ; 98(12): 1948-55, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23850805

RESUMO

Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3(+)TCRα/ß(+)CD4(-)CD8(-) "double negative" T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool.


Assuntos
Proteína Ligante Fas/sangue , Proteína Ligante Fas/genética , Transtornos Linfoproliferativos/sangue , Transtornos Linfoproliferativos/genética , Vitamina B 12/sangue , Adolescente , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/genética , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Transtornos Linfoproliferativos/diagnóstico , Masculino
20.
J Cell Commun Signal ; 5(2): 145-56, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21484192

RESUMO

Severe trauma and the systemic inflammatory response syndrome (SIRS) occur as a result of a cytokine storm which is in part due to ATP released from damaged tissue. This pathology also leads to increased numbers of immature antigen presenting cells (APC) sharing properties of dendritic cells (DC) or macrophages (MΦ). The occurrence of immature APC appears to coincide with the reactivation of herpes virus infections such as Epstein Barr virus (EBV). The aim of this study was the comparative analysis of the ultrastructural and functional characteristics of such immature APC. In addition, we investigated EBV infection/ reactivation and whether immature APC might be targets for natural killers (NK). Significant macroautophagy, mitochondrial degradation and multivesicular body formation together with the identification of herpes virus particles were morphological findings associated with immature APC. Exogenous stressors such as ATP further increased morphological signs of autophagy, including LC3 expression. Functional tests using fluorescent bacteria proved impaired phagolysosome fusion. However, immature APC were susceptible to NK-92-mediated cytolysis. We found evidence for EBV latency state II infection by detecting EBV-specific LMP1 and EBNA2 in immature APC and in whole blood of these patients. In summary, trauma-induced cytokine storms may induce maturation arrest of APC, promote ATP-induced autophagy, support EBV persistence and impair the degradation of phagocytozed bacteria through inefficient phagolysosome fusion. The susceptibility to NK-mediated cytolysis supports the hypothesis that NK function is likely to contribute to immune reconstitution after major trauma by regulating immature APC, and ATP-induced autophagy and survival.

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