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1.
Clin Immunol ; 210: 108316, 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31770611

RESUMO

Germline STAT3 gain-of-function (GOF) mutations have been linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance. Here we studied the impact of 17 different STAT3 GOF mutations on the canonical STAT3 signaling pathway and correlated the molecular results with clinical manifestations. The mutations clustered in three groups. Group 1 mutants showed altered STAT3 phosphorylation kinetics and strong basal transcriptional activity. They were associated with the highest penetrance of lymphoproliferation and autoimmunity. Group 2 mutants showed a strongly inducible transcriptional reporter activity and were clinically less penetrant. Group 3 mutants were mostly located in the DNA binding domain and showed the strongest DNA binding affinity despite a poor transcriptional reporter response. Thus, the GOF effect of STAT3 mutations is determined by a heterogeneous response pattern at the molecular level. The correlation of response pattern and clinical penetrance indicates a significant contribution of mutation-determined effects on disease manifestations.

2.
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.
Cell ; 171(2): 385-397.e11, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28919076

RESUMO

T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation-cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses.


Assuntos
Antígenos CD28/metabolismo , Ativação Linfocitária , Mitocôndrias/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Carnitina O-Palmitoiltransferase , Inibidores Enzimáticos/farmacologia , Compostos de Epóxi/farmacologia , Humanos , Interleucina-15/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/metabolismo , Estresse Fisiológico , Linfócitos T/metabolismo
5.
Clin Immunol ; 180: 97-99, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28478106

RESUMO

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


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Imunoglobulina G/imunologia , Adulto , Síndrome Linfoproliferativa Autoimune/sangue , Síndrome Linfoproliferativa Autoimune/patologia , Humanos , Hipergamaglobulinemia/imunologia , Imunoglobulina G/sangue , Linfonodos/patologia , Transtornos Linfoproliferativos/imunologia , Masculino , Pâncreas/patologia
6.
Front Immunol ; 8: 449, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28507545

RESUMO

Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility, and pulmonary or liver fibrosis. In more severe cases, immune deficiency and recurring infections can add to disease severity. RTEL1 deficiency has recently been described as a major genetic etiology, but the molecular basis and clinical consequences of RTEL1-associated DC are incompletely characterized. We report our observations in a cohort of six patients: five with novel biallelic RTEL1 mutations p.Trp456Cys, p.Ile425Thr, p.Cys1244ProfsX17, p.Pro884_Gln885ins53X13, and one with novel heterozygous mutation p.Val796AlafsX4. The most unifying features were hypocellular BMF in 6/6 and B-/NK-cell lymphopenia in 5/6 patients. In addition, three patients with homozygous mutations p.Trp456Cys or p.Ile425Thr also suffered from immunodeficiency, cerebellar hypoplasia, and enteropathy, consistent with Hoyeraal-Hreidarsson syndrome. Chromosomal breakage resembling a homologous recombination defect was detected in patient-derived fibroblasts but not in hematopoietic compartment. Notably, in both cellular compartments, differential expression of 1243aa and 1219/1300aa RTEL1 isoforms was observed. In fibroblasts, response to ionizing irradiation and non-homologous end joining were not impaired. Telomeric circles did not accumulate in patient-derived primary cells and lymphoblastoid cell lines, implying alternative pathomechanisms for telomeric loss. Overall, RTEL1-deficient cells exhibited a phenotype of replicative exhaustion, spontaneous apoptosis and senescence. Specifically, CD34+ cells failed to expand in vitro, B-cell development was compromised, and T-cells did not proliferate in long-term culture. Finally, we report on the natural history and outcome of our patients. While two patients died from infections, hematopoietic stem cell transplantation (HSCT) resulted in sustained engraftment in two patients. Whether chemotherapy negatively impacts on the course and onset of other DC-related symptoms remains open at present. Early-onset lung disease occurred in one of our patients after HSCT. In conclusion, RTEL deficiency can show a heterogeneous clinical picture ranging from mild hypocellular BMF with B/NK cell lymphopenia to early-onset, very severe, and rapidly progressing cellular deficiency.

7.
J Allergy Clin Immunol ; 139(2): 607-620.e15, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27477328

RESUMO

BACKGROUND: Patients with heterozygous germline mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) experience autoimmunity and lymphoid hyperplasia. OBJECTIVES: Because regulation of the phosphoinositide 3-kinase (PI3K) pathway is critical for maintaining regulatory T (Treg) cell functions, we investigate Treg cells in patients with heterozygous germline PTEN mutations (PTEN hamartoma tumor syndrome [PHTS]). METHODS: Patients with PHTS were assessed for immunologic conditions, lymphocyte subsets, forkhead box P3 (FOXP3)+ Treg cell levels, and phenotype. To determine the functional importance of phosphatases that control the PI3K pathway, we assessed Treg cell induction in vitro, mitochondrial depolarization, and recruitment of PTEN to the immunologic synapse. RESULTS: Autoimmunity and peripheral lymphoid hyperplasia were found in 43% of 79 patients with PHTS. Immune dysregulation in patients with PHTS included lymphopenia, CD4+ T-cell reduction, and changes in T- and B-cell subsets. Although total CD4+FOXP3+ Treg cell numbers are reduced, frequencies are maintained in the blood and intestine. Despite pathogenic PTEN mutations, the FOXP3+ T cells are phenotypically normal. We show that the phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP) downstream of PTEN is highly expressed in normal human Treg cells and provides complementary phosphatase activity. PHLPP is indispensable for the differentiation of induced Treg cells in vitro and Treg cell mitochondrial fitness. PTEN and PHLPP form a phosphatase network that is polarized at the immunologic synapse. CONCLUSION: Heterozygous loss of function of PTEN in human subjects has a significant effect on T- and B-cell immunity. Assembly of the PTEN-PHLPP phosphatase network allows coordinated phosphatase activities at the site of T-cell receptor activation, which is important for limiting PI3K hyperactivation in Treg cells despite PTEN haploinsufficiency.


Assuntos
Linfócitos B/fisiologia , Síndrome do Hamartoma Múltiplo/imunologia , Sinapses Imunológicas/metabolismo , Subpopulações de Linfócitos/fisiologia , Proteínas Nucleares/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Linfócitos T Reguladores/fisiologia , Adolescente , Adulto , Idoso , Autoimunidade , Células Cultivadas , Criança , Fatores de Transcrição Forkhead/metabolismo , Síndrome do Hamartoma Múltiplo/genética , Humanos , Hiperplasia , Masculino , Potencial da Membrana Mitocondrial , Pessoa de Meia-Idade , Mutação/genética , PTEN Fosfo-Hidrolase/genética , Ligação Proteica , Transporte Proteico , Transdução de Sinais , Adulto Jovem
8.
Haematologica ; 102(2): e52-e56, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27789675
9.
Eur J Immunol ; 47(2): 364-373, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27925643

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome characterized by hyperactivation of lymphocytes and histiocytes. T cells play a key role in HLH pathogenesis, but their differentiation pattern is not well characterized in patients with active HLH. We compared T-cell activation patterns between patients with familial HLH (1°HLH), 2°HLH without apparent infectious trigger (2°HLH) and 2°HLH induced by a viral infection (2°V-HLH). Polyclonal CD8+ T cells are highly activated in 1°HLH and 2°V-HLH, but less in 2°HLH as assessed by HLA-DR expression and marker combination with CD45RA, CCR7, CD127, PD-1 and CD57. Absence of increased HLA-DR expression on T cells excluded active 1° HLH with high sensitivity and specificity. A high proportion of polyclonal CD127- CD4+ T cells expressing HLA-DR, CD57, and perforin is a signature of infants with 1°HLH, much less prominent in virus-associated 2°HLH. The similar pattern and extent of CD8+ T-cell activation compared to 2° V-HLH is compatible with a viral trigger of 1°HLH. However, in most 1°HLH patients no triggering infection was documented and the unique activation of cytotoxic CD4+ T cells indicates that the overall T-cell response in 1°HLH is different. This may reflect different pathways of pathogenesis of these two HLH variants.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfo-Histiocitose Hemofagocítica/imunologia , Viroses/imunologia , Antígenos CD57/metabolismo , Diferenciação Celular , Células Cultivadas , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Lactente , Recém-Nascido , Ativação Linfocitária , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Masculino , Perforina/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Viroses/complicações , Viroses/diagnóstico
10.
Blood ; 128(2): 227-38, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27099149

RESUMO

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


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/imunologia , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/patologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lectinas Tipo C/imunologia , Antígenos Comuns de Leucócito/imunologia , Masculino , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transativadores/imunologia
11.
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
12.
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
14.
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.
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
16.
Clin Immunol ; 159(1): 84-92, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25931386

RESUMO

Mutations in LPS-responsive and beige-like anchor (LRBA) gene were recently described in patients with combined immunodeficiency, enteropathy and autoimmune cytopenia. Here, we extend the clinical and immunological phenotypic spectrum of LRBA associated disorders by reporting on three patients from two unrelated families who presented with splenomegaly and lymphadenopathy, cytopenia, elevated double negative T cells and raised serum Fas ligand levels resembling autoimmune lymphoproliferative syndrome (ALPS) and one asymptomatic patient. Homozygous loss of function mutations in LRBA were identified by whole exome analysis. Similar to ALPS patients, Fas mediated apoptosis was impaired in LRBA deficient patients, while apoptosis in response to stimuli of the intrinsic mitochondria mediated apoptotic pathway was even enhanced. This manuscript illustrates the phenotypic overlap of other primary immunodeficiencies with ALPS-like disorders and strongly underlines the necessity of genetic diagnosis in order to provide early correct diagnosis and subsequent care.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Síndrome Linfoproliferativa Autoimune/genética , Apoptose/genética , Criança , Pré-Escolar , Humanos , Lactente , Masculino , Mutação , Análise de Sequência de DNA
17.
Blood ; 125(5): 753-61, 2015 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-25414442

RESUMO

Autoimmune cytopenia is a frequent manifestation of primary immunodeficiencies. Two siblings presented with Evans syndrome, viral infections, and progressive leukopenia. DNA available from one patient showed a homozygous frameshift mutation in tripeptidyl peptidase II (TPP2) abolishing protein expression. TPP2 is a serine exopeptidase involved in extralysosomal peptide degradation. Its deficiency in mice activates cell death programs and premature senescence. Similar to cells from naïve, uninfected TPP2-deficient mice, patient cells showed increased major histocompatibility complex I expression and most CD8(+) T-cells had a senescent CCR7-CD127(-)CD28(-)CD57(+) phenotype with poor proliferative responses and enhanced staurosporine-induced apoptosis. T-cells showed increased expression of the effector molecules perforin and interferon-γ with high expression of the transcription factor T-bet. Age-associated B-cells with a CD21(-) CD11c(+) phenotype expressing T-bet were increased in humans and mice, combined with antinuclear antibodies. Moreover, markers of senescence were also present in human and murine TPP2-deficient fibroblasts. Telomere lengths were normal in patient fibroblasts and granulocytes, and low normal in lymphocytes, which were compatible with activation of stress-induced rather than replicative senescence programs. TPP2 deficiency is the first primary immunodeficiency linking premature immunosenescence to severe autoimmunity. Determination of senescent lymphocytes should be part of the diagnostic evaluation of children with refractory multilineage cytopenias.


Assuntos
Envelhecimento/imunologia , Aminopeptidases/imunologia , Anemia Hemolítica Autoimune/genética , Dipeptidil Peptidases e Tripeptidil Peptidases/imunologia , Mutação da Fase de Leitura , Síndromes de Imunodeficiência/genética , Serina Endopeptidases/imunologia , Trombocitopenia/genética , Aminopeptidases/deficiência , Aminopeptidases/genética , Anemia Hemolítica Autoimune/complicações , Anemia Hemolítica Autoimune/imunologia , Anemia Hemolítica Autoimune/patologia , Animais , Apoptose , Sequência de Bases , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Consanguinidade , Dipeptidil Peptidases e Tripeptidil Peptidases/deficiência , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Expressão Gênica , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Masculino , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Perforina/genética , Perforina/imunologia , Serina Endopeptidases/deficiência , Serina Endopeptidases/genética , Irmãos , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Trombocitopenia/complicações , Trombocitopenia/imunologia , Trombocitopenia/patologia
18.
Nat Med ; 20(12): 1410-1416, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25329329

RESUMO

The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.


Assuntos
Agamaglobulinemia/genética , Doenças Autoimunes/genética , Antígeno CTLA-4/genética , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Agamaglobulinemia/imunologia , Anemia Hemolítica Autoimune/genética , Anemia Hemolítica Autoimune/imunologia , Animais , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Antígeno B7-1/metabolismo , Antígeno CTLA-4/imunologia , Criança , Códon sem Sentido , Endocitose/genética , Endocitose/imunologia , Éxons , Feminino , Granuloma/genética , Granuloma/imunologia , Heterozigoto , Humanos , Doenças do Sistema Imunitário/genética , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/imunologia , Recidiva , Infecções Respiratórias/genética , Infecções Respiratórias/imunologia , Síndrome , Adulto Jovem
19.
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
20.
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
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