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1.
Clin Immunol ; 162: 27-30, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26529633

RESUMO

PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1) gain-of-function has recently been described in patients with recurrent sinopulmonary infections, chronic CMV-/EBV-infections, lymphoproliferation, and hypogammaglobulinemia. Here we report a 15-year-old boy with treatment refractory CMV lymphadenitis, severe combined immunodeficiency, microcephaly and a severe developmental defect of Th17 cells. To avoid poor outcome, hematopoietic stem cell transplantation (HSCT) was performed. Subsequently, whole exome sequencing revealed a de novo heterozygous G-to-C mutation (chr5: 5:67,589,663: G>C) at the splice donor site of the PIK3R1 gene. Our data suggest that PIK3R1 gain-of-function leads to developmental defects in helper and regulatory T-cell subsets, the latter expanding the immunological features of PIK3R1 gain-of-function. T-cell subsets play a critical role in the regulation of immune response against infectious agents and of autoimmunity and thus may be particularly accountable for the clinical phenotype of affected patients.


Assuntos
Infecções por Citomegalovirus , Linfadenite , Microcefalia , Fosfatidilinositol 3-Quinases , Infecções Respiratórias , Adolescente , Classe Ia de Fosfatidilinositol 3-Quinase , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Humanos , Linfadenite/complicações , Linfadenite/genética , Linfadenite/imunologia , Masculino , Microcefalia/complicações , Microcefalia/genética , Seios Paranasais/fisiopatologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Recidiva , Infecções Respiratórias/complicações , Infecções Respiratórias/genética , Células Th17/imunologia
2.
J Clin Immunol ; 36(7): 684-92, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27473539

RESUMO

Hereditary defects in several genes have been shown to disturb the normal immune response to EBV and to give rise to severe EBV-induced lymphoproliferation in the recent years. Nevertheless, in many patients, the molecular basis of fatal EBV infection still remains unclear. The Fanconi anemia-associated protein 24 (FAAP24) plays a dual role in DNA repair. By association with FANCM as component of the FA core complex, it recruits the FA core complex to damaged DNA. Additionally, FAAP24 has been shown to evoke ATR-mediated checkpoint responses independently of the FA core complex. By whole exome sequencing, we identified a homozygous missense mutation in the FAAP24 gene (cC635T, pT212M) in two siblings of a consanguineous Turkish family who died from an EBV-associated lymphoproliferative disease after infection with a variant EBV strain, expressing a previously unknown EBNA2 allele.In order to analyze the functionality of the variant FAAP24 allele, we used herpes virus saimiri-transformed patient T cells to test endogenous cellular FAAP24 functions that are known to be important in DNA damage control. We saw an impaired FANCD2 monoubiquitination as well as delayed checkpoint responses, especially affecting CHK1 phosphorylation in patient samples in comparison to healthy controls. The phenotype of this FAAP24 mutation might have been further accelerated by an EBV strain that harbors an EBNA2 allele with enhanced activities compared to the prototype laboratory strain B95.8. This is the first report of an FAAP24 loss of function mutation found in human patients with EBV-associated lymphoproliferation.


Assuntos
Proteínas de Ligação a DNA/genética , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/genética , Mutação , Irmãos , Substituição de Aminoácidos , Ciclo Celular , Códon , Consanguinidade , Dano ao DNA , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Proteínas de Grupos de Complementação da Anemia de Fanconi , Evolução Fatal , Feminino , Genótipo , Homozigoto , Humanos , Contagem de Linfócitos , Transtornos Linfoproliferativos/virologia , Masculino , Linhagem , Fenótipo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Troca de Cromátide Irmã , Linfócitos T/imunologia , Linfócitos T/metabolismo , Ubiquitinação , Sequenciamento do Exoma
3.
Eur J Pediatr ; 175(4): 593-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26526666

RESUMO

UNLABELLED: DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly presenting with pleuropulmonary blastoma (PPB), ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. We describe the occurrence of a Hodgkin lymphoma (HL) of the T cell phenotype in a family with DICER1 syndrome. The patient presented with PPB Type I and HL. Immunohistochemical staining of the Hodgkin and Reed-Sternberg cells revealed CD30, TGP, CD2, CD3, CD15, and IRF4 positivity and weekly positivity of PAX5. T cell receptor repertoire analysis suggested HL of T cell origin, which is in contrast to common B cell-derived HL. The mother had been diagnosed with thyroid cysts, one sister had died from a primitive neuroectodermal tumor, and a brother had died from PPB Type III. Two mutational events were revealed in all affected family members; a single bp deletion, c.5299delC, leading to a frameshift and premature stop in exon 24 and a heterozygous variant (c.4616C>T; p.Thr1539Met) located in exon 23 of the DICER1 gene. This variant is predicted to be benign by in silico analysis. CONCLUSION: Future studies looking for DICER1 mutations in HL cases of the T cell phenotype will be important to confirm its association with constitutional DICER1 syndrome. WHAT IS KNOWN: • DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly pleuropulmonary blastoma, ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. • Hodgkin lymphoma is one of the most frequent types of malignant lymphomas and typically arises sporadically. T cell-derived Hodgkin lymphomas are exceptionally rare. What is New: • DICER1 syndrome may have an even broader phenotypic spectrum and seems to be associated with rare forms of T cell Hodgkin lymphoma.


Assuntos
RNA Helicases DEAD-box/genética , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/genética , Blastoma Pulmonar/genética , Ribonuclease III/genética , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Masculino , Mutação , Linhagem
4.
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
5.
Haematologica ; 100(9): 1189-98, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26113417

RESUMO

Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20-30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon γ production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease.


Assuntos
Síndrome Linfoproliferativa Autoimune/imunologia , Códon sem Sentido , Proteína Ligante Fas/imunologia , Regulação da Expressão Gênica/imunologia , Receptores de Interleucina-12/imunologia , Transdução de Sinais/imunologia , Apoptose/genética , Apoptose/imunologia , Síndrome Linfoproliferativa Autoimune/genética , Caspase 10/genética , Caspase 10/imunologia , Caspase 8/genética , Caspase 8/imunologia , Linhagem Celular Transformada , Proteína Ligante Fas/genética , Feminino , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Masculino , Receptores de Interleucina-12/genética , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT4/imunologia , Transdução de Sinais/genética , Receptor fas/genética , Receptor fas/imunologia
6.
Clin Immunol ; 155(2): 231-7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25451160

RESUMO

We report a novel type of mutation in the death ligand FasL that was associated with a severe phenotype of the autoimmune lymphoproliferative syndrome in two patients. A frameshift mutation in the intracellular domain led to complete loss of FasL expression. Cell death signaling via its receptor and reverse signaling via its intracellular domain were completely abrogated. In vitro lymphocyte proliferation induced by weak T cell receptor stimulation could be blocked and cell death was induced by engagement of FasL in T cells derived from healthy individuals and a heterozygous carrier, but not in FasL-deficient patient derived cells. Expression of genes implicated in lymphocyte proliferation and activation (CCND1, NFATc1, NF-κB1) was increased in FasL-deficient T cells and could not be downregulated by FasL engagement as in healthy cells. Our data thus suggest, that deficiency in FasL reverse signaling may contribute to the clinical lymphoproliferative phenotype of ALPS.


Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/metabolismo , Proteína Ligante Fas/genética , Homozigoto , Mutação , Receptores de Morte Celular/metabolismo , Transdução de Sinais , Apoptose , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/imunologia , Pontos de Checagem do Ciclo Celular/genética , Criança , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Proteína Ligante Fas/metabolismo , Feminino , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Imageamento por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Irmãos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
8.
Eur J Immunol ; 40(5): 1496-503, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20201035

RESUMO

Zinc signals, i.e. a change of the intracellular concentration of free zinc ions in response to receptor stimulation, are involved in signal transduction in several immune cells. Here, the role of zinc signals in T-cell activation by IL-2 was investigated in the murine cytotoxic T-cell line CTLL-2 and in primary human T cells. Measurements with the fluorescent dyes FluoZin-3 and Zinquin showed that zinc is released from lysosomes into the cytosol in response to stimulation of the IL-2-receptor. Activation of the ERK-pathway was blocked by chelation of free zinc with N,N,N',N'-tetrakis-2(pyridyl-methyl)ethylenediamine, whereas zinc was not required for STAT5 phosphorylation. In addition, the key signaling molecules MEK and ERK were activated in response to elevated free intracellular zinc, induced by incubation with zinc and the ionophore pyrithione. Downstream of ERK activation, ERK-specific gene expression of c-fos and IL-2-induced proliferation was found to depend on zinc. Further experiments indicated that inhibition of MEK and ERK-dephosphorylating protein phosphatases is the molecular mechanism for the influence of zinc on this pathway. In conclusion, an increase of cytoplasmic free zinc is required for IL-2-induced ERK signaling and proliferation of T cells.


Assuntos
Interleucina-2/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Transdução de Sinais/fisiologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Zinco/fisiologia , Animais , Compartimento Celular/fisiologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular/efeitos dos fármacos , Quelantes/farmacologia , Citosol/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Corantes Fluorescentes/análise , Regulação da Expressão Gênica/efeitos dos fármacos , Genes fos/efeitos dos fármacos , Humanos , Transporte de Íons/fisiologia , Ionóforos/farmacologia , Lisossomos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosfoproteínas Fosfatases/fisiologia , Compostos Policíclicos/análise , Piridinas/farmacologia , Quinolonas/análise , Receptores de Interleucina-2/efeitos dos fármacos , Receptores de Interleucina-2/fisiologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Citotóxicos/citologia , Tionas/farmacologia , Compostos de Tosil/análise , Zinco/farmacologia
11.
Front Immunol ; 9: 2400, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386345

RESUMO

Serine/threonine kinase 4 (STK4) deficiency is an autosomal recessive genetic condition that leads to primary immunodeficiency (PID) typically characterized by lymphopenia, recurrent infections and Epstein Barr Virus (EBV) induced lymphoproliferation and -lymphoma. State-of-the-art treatment regimens consist of prevention or treatment of infections, immunoglobulin substitution (IVIG) and restoration of the immune system by hematopoietic stem cell transplantation. Here, we report on two patients from two consanguineous families of Turkish (patient P1) and Moroccan (patient P2) decent, with PID due to homozygous STK4 mutations. P1 harbored a previously reported frameshift (c.1103 delT, p.M368RfsX2) and P2 a novel splice donor site mutation (P2; c.525+2 T>G). Both patients presented in childhood with recurrent infections, CD4 lymphopenia and dysregulated immunoglobulin levels. Patient P1 developed a highly malignant B cell lymphoma at the age of 10 years and a second, independent Hodgkin lymphoma 5 years later. To our knowledge she is the first STK4 deficient case reported who developed lymphoma in the absence of detectable EBV or other common viruses. Lymphoma development may be due to the lacking tumor suppressive function of STK4 or the perturbed immune surveillance due to the lack of CD4+ T cells. Our data should raise physicians' awareness of [1] lymphoma proneness of STK4 deficient patients even in the absence of EBV infection and [2] possibly underlying STK4 deficiency in pediatric patients with a history of recurrent infections, CD4 lymphopenia and lymphoma and unknown genetic make-up. Patient P2 experienced recurrent otitis in childhood, but when she presented at the age of 14, she showed clinical and immunological characteristics similar to patients suffering from Autoimmune Lymphoproliferative Syndrome (ALPS): elevated DNT cell number, non-malignant lymphadenopathy and hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia. Also patient P1 presented with ALPS-like features (lymphadenopathy, elevated DNT cell number and increased Vitamin B12 levels) and both were initially clinically diagnosed as ALPS-like. Closer examination of P2, however, revealed active EBV infection and genetic testing identified a novel STK4 mutation. None of the patients harbored typically ALPS-associated mutations of the Fas receptor mediated apoptotic pathway and Fas-mediated apoptosis was not affected. The presented case reports extend the clinical spectrum of STK4 deficiency.


Assuntos
Síndrome Linfoproliferativa Autoimune/etiologia , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Síndromes de Imunodeficiência/etiologia , Linfoma/etiologia , Fenótipo , Proteínas Serina-Treonina Quinases/deficiência , Síndrome Linfoproliferativa Autoimune/diagnóstico , Estudos de Casos e Controles , Biologia Computacional/métodos , Análise Mutacional de DNA , Infecções por Vírus Epstein-Barr/virologia , Feminino , Humanos , Síndromes de Imunodeficiência/diagnóstico , Peptídeos e Proteínas de Sinalização Intracelular , Linfoma/diagnóstico , Masculino , Mutação , Linhagem , Sequenciamento do Exoma
12.
Joint Bone Spine ; 81(1): 83-5, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23928235

RESUMO

Diagnostic assessment of osteoarthritis in children and adolescents is difficult. Here, we report the sixth family with a COL2A1 mutation R275C. The index patient, her mother and her three brothers had severe coxarthrosis, in some cases requiring surgery. Only the mother was hard of hearing, and only her children had brachydactyly of the fourth digit. The index patient suffered a femoral neck fracture after minor trauma at a time when osteoarthritis was not yet radiologically detectable. Hip fracture or osteoarthritis of unclear origin in childhood should prompt genetic work-up for the purposes of correct classification and genetic counseling.


Assuntos
Colágeno Tipo II/genética , Fraturas do Colo Femoral/genética , Osteoartrite/genética , Osteocondrodisplasias/genética , Adolescente , Feminino , Fraturas do Colo Femoral/diagnóstico por imagem , Fraturas do Colo Femoral/cirurgia , Humanos , Mutação , Osteoartrite/diagnóstico por imagem , Osteocondrodisplasias/complicações , Osteocondrodisplasias/diagnóstico por imagem , Radiografia
13.
J Nutr Biochem ; 23(1): 18-26, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21333516

RESUMO

Zinc is an essential nutrient with remarkable importance for immunity, in particular for T-cell function. This is, at least in part, based on an involvement of zinc ions in immune cell signal transduction; dynamic changes of the intracellular free zinc concentration have recently been recognized as signaling events. Because the molecular targets of zinc signals remain incompletely understood, we investigated the impact of elevated intracellular free zinc on mitogen-activated protein kinase (MAPK) activity and MAPK-dependent cytokine production in human T-cells. p38 was activated by treatment with zinc and the ionophore pyrithione, whereas ERK1/2 and c-Jun N-terminal kinases were unaffected. In contrast, after T-cell receptor stimulation with antibodies against CD3, ERK1/2-phosphorylation was selectively suppressed by intracellular zinc. Mechanisms that had been shown to mediate zinc-effects in other cells, such as activation of the Src kinase Lck, inhibition of the protein tyrosine phosphatase CD45 or MAPK phosphatases and cyclic nucleotide/protein kinase A signaling were not involved. This indicates that the differential impact of zinc on the MAPK families in T-cells is mediated by mechanisms that differ from the ones observed in other cell types. Further investigation of the activation of p38 by zinc demonstrated that this MAPK is responsible for the zinc-mediated activation of CREB and mRNA expression of the Th1 cytokines interferon-gamma and interleukin-2. In conclusion, regulation of MAPK activity contributes to the impact of zinc on T-cell function.


Assuntos
Proteínas Quinases Ativadas por Mitógeno/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Zinco/farmacologia , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citocinas/genética , Citocinas/metabolismo , Ativação Enzimática , Humanos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , MAP Quinase Quinase 4/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
J Leukoc Biol ; 87(5): 833-44, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20089671

RESUMO

It was reported previously that zinc-deficient mice show impaired lymphopoiesis. At the same time, monocyte numbers in these animals are increased, indicating a negative impact of zinc on monocyte development. Here, we investigate the role of zinc homeostasis in the differentiation of myeloid precursors into monocytes. Reduced gene expression of several zinc transporters, predominantly from the Zip family, was observed during 1 alpha, 25-dihydroxyvitamin D(3) (1,25D(3))-induced differentiation of HL-60 cells. This was accompanied by a reduction of intracellular-free zinc, measured by FluoZin-3. Amplifying this reduction with the zinc chelator TPEN or zinc-depleted cell-culture medium enhanced 1,25D(3)-induced expression of monocytic surface markers CD11b and CD14 on HL-60, THP-1, and NB4 cells. In contrast, differentiation of NB4 cells to granulocytes was not zinc-sensitive, pointing toward a specific effect of zinc on monocyte differentiation. Further, monocyte functions, such as TNF-alpha secretion, phagocytosis, and oxidative burst, were also augmented by differentiation in the presence of TPEN. The second messenger cAMP promotes monocyte differentiation. We could show that zinc inhibits the cAMP-synthesizing enzyme adenylate cyclase, and chelation of zinc by TPEN increases cAMP generation after stimulation with the adenylate cyclase activator forskolin. Based on our in vitro results and the in vivo observations from the literature, we suggest a model in which the intracellular-free zinc concentration limits AC activity, and the decrease of zinc after 1,25D(3) treatment promotes differentiation by relieving AC inhibition. Thus, cellular zinc homeostasis acts as an endogenous modulator of monocyte differentiation.


Assuntos
Diferenciação Celular/fisiologia , Homeostase/fisiologia , Monócitos/citologia , Vitamina D/análogos & derivados , Zinco/metabolismo , Adenilil Ciclases/metabolismo , Animais , Proteínas de Transporte/biossíntese , Proteínas de Transporte/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Separação Celular , Citometria de Fluxo , Expressão Gênica/efeitos dos fármacos , Células HL-60 , Homeostase/efeitos dos fármacos , Humanos , Immunoblotting , Camundongos , Monócitos/imunologia , Monócitos/metabolismo , Reação em Cadeia da Polimerase , Vitamina D/metabolismo , Vitamina D/farmacologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-19519463

RESUMO

The trace element zinc is a crucial cofactor for many proteins involved in cellular processes like differentiation, proliferation and apoptosis. Zinc homeostasis is tightly regulated and disturbance of this homeostasis due to genetic defects, zinc deficiency, or supplementation influences the development and the progression of various infectious and autoimmune diseases. The immune system is strongly impaired during zinc deficiency, predominantly the cell-mediated response by T-lymphocytes. During zinc deprivation T-lymphocyte development, polarization into effector cells, and function are impaired. This leads to reduced T-cell numbers, a decreased ratio of type 1 to type 2 T-helper cells with reduced production of T-helper type 1 cytokines like interferon-gamma, and compromised T-cell mediated immune defense. Accordingly, disturbed zinc homeostasis increases the risk for infections, and zinc supplementation restores normal immune function. Furthermore, several disorders, like mycobacterial infections, asthma, diabetes, and rheumatoid arthritis are accompanied by decreased zinc levels and in some cases disease progression can be affected by zinc supplementation. On the molecular level, apoptosis of T-cell precursors is influenced by zinc via the Bcl-2/Bax ratio, and zinc ions inhibit caspases-3, -6, -7, and -8. In mature T-cells, zinc interacts with kinases involved in T-cell activation, like protein kinase C and the lymphocyte protein tyrosine kinase (Lck), while higher zinc concentrations are inhibitory, reducing the activities of the interleukin-1 receptor-associated kinase (IRAK) and calcineurin. Taken together, zinc homeostasis influences T-lymphocytes via several molecular targets, leading to a modulation of T-cell-dependent immune responses.


Assuntos
Linfócitos T/efeitos dos fármacos , Zinco/farmacologia , Animais , Apoptose/efeitos dos fármacos , Inibidores de Calcineurina , Humanos , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/fisiologia , Proteína Quinase C/metabolismo , Transdução de Sinais/fisiologia , Linfócitos T/fisiologia , Zinco/deficiência
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