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1.
J Autoimmun ; 144: 103183, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38401466

RESUMO

Chronic nonbacterial osteomyelitis (CNO), an autoinflammatory bone disease primarily affecting children, can cause pain, hyperostosis and fractures, affecting quality-of-life and psychomotor development. This study investigated CNO-associated variants in P2RX7, encoding for the ATP-dependent trans-membrane K+ channel P2X7, and their effects on NLRP3 inflammasome assembly. Whole exome sequencing in two related transgenerational CNO patients, and target sequencing of P2RX7 in a large CNO cohort (N = 190) were conducted. Results were compared with publicly available datasets and regional controls (N = 1873). Findings were integrated with demographic and clinical data. Patient-derived monocytes and genetically modified THP-1 cells were used to investigate potassium flux, inflammasome assembly, pyroptosis, and cytokine release. Rare presumably damaging P2RX7 variants were identified in two related CNO patients. Targeted P2RX7 sequencing identified 62 CNO patients with rare variants (32.4%), 11 of which (5.8%) carried presumably damaging variants (MAF <1%, SIFT "deleterious", Polyphen "probably damaging", CADD >20). This compared to 83 of 1873 controls (4.4%), 36 with rare and presumably damaging variants (1.9%). Across the CNO cohort, rare variants unique to one (Median: 42 versus 3.7) or more (≤11 patients) participants were over-represented when compared to 190 randomly selected controls. Patients with rare damaging variants more frequently experienced gastrointestinal symptoms and lymphadenopathy while having less spinal, joint and skin involvement (psoriasis). Monocyte-derived macrophages from patients, and genetically modified THP-1-derived macrophages reconstituted with CNO-associated P2RX7 variants exhibited altered potassium flux, inflammasome assembly, IL-1ß and IL-18 release, and pyroptosis. Damaging P2RX7 variants occur in a small subset of CNO patients, and rare P2RX7 variants may represent a CNO risk factor. Observations argue for inflammasome inhibition and/or cytokine blockade and may allow future patient stratification and individualized care.


Assuntos
Inflamassomos , Osteomielite , Humanos , Citocinas , Inflamassomos/genética , Inflamassomos/metabolismo , Osteomielite/genética , Potássio , Piroptose , Receptores Purinérgicos P2X7/genética
2.
Front Immunol ; 14: 1245876, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37662940

RESUMO

Background: Psoriasis is an autoimmune/inflammatory disorder primarily affecting the skin. Chronic joint inflammation triggers the diagnosis of psoriatic arthritis (PsA) in approximately one-third of psoriasis patients. Although joint disease typically follows the onset of skin psoriasis, in around 15% of cases it is the initial presentation, which can result in diagnostic delays. The pathophysiological mechanisms underlying psoriasis and PsA are not yet fully understood, but there is evidence pointing towards epigenetic dysregulation involving CD4+ and CD8+ T-cells. Objectives: The aim of this study was to investigate disease-associated DNA methylation patterns in CD4+ T-cells from psoriasis and PsA patients that may represent potential diagnostic and/or prognostic biomarkers. Methods: PBMCs were collected from 12 patients with chronic plaque psoriasis and 8 PsA patients, and 8 healthy controls. CD4+ T-cells were separated through FACS sorting, and DNA methylation profiling was performed (Illumina EPIC850K arrays). Bioinformatic analyses, including gene ontology (GO) and KEGG pathway analysis, were performed using R. To identify genes under the control of interferon (IFN), the Interferome database was consulted, and DNA Methylation Scores were calculated. Results: Numbers and proportions of CD4+ T-cell subsets (naïve, central memory, effector memory, CD45RA re-expressing effector memory cells) did not vary between controls, skin psoriasis and PsA patients. 883 differentially methylated positions (DMPs) affecting 548 genes were identified between controls and "all" psoriasis patients. Principal component and partial least-squares discriminant analysis separated controls from skin psoriasis and PsA patients. GO analysis considering promoter DMPs delivered hypermethylation of genes involved in "regulation of wound healing, spreading of epidermal cells", "negative regulation of cell-substrate junction organization" and "negative regulation of focal adhesion assembly". Comparing controls and "all" psoriasis, a majority of DMPs mapped to IFN-related genes (69.2%). Notably, DNA methylation profiles also distinguished skin psoriasis from PsA patients (2,949 DMPs/1,084 genes) through genes affecting "cAMP-dependent protein kinase inhibitor activity" and "cAMP-dependent protein kinase regulator activity". Treatment with cytokine inhibitors (IL-17/TNF) corrected DNA methylation patterns of IL-17/TNF-associated genes, and methylation scores correlated with skin disease activity scores (PASI). Conclusion: DNA methylation profiles in CD4+ T-cells discriminate between skin psoriasis and PsA. DNA methylation signatures may be applied for quantification of disease activity and patient stratification towards individualized treatment.


Assuntos
Artrite Psoriásica , Doenças Autoimunes , Psoríase , Humanos , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/genética , Interleucina-17 , Metilação de DNA , Linfócitos T CD8-Positivos , Psoríase/genética , Proteínas Quinases Dependentes de AMP Cíclico , Linfócitos T CD4-Positivos
3.
Clin Immunol ; 238: 108998, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35398286

RESUMO

Deciphering signaling pathways that regulate the complex interplay between inflammation and cell death is a key challenge in understanding innate immune responses. Over recent years, receptor interacting protein (RIP) kinases have been described to regulate the interplay between inflammation and cell death. Whereas RIP1 and 3, the most well described members of the RIP kinase family, play important roles in necroptosis, RIP2's involvement in regulating inflammation, cell death processes and cancer is less well described and controversially discussed. Here, we demonstrate that RIP2 exerts immune regulatory functions by regulating mitochondrial damage and mitochondrial superoxide production in response to SV40 LT-induced genotoxic stress by the induction of ULK1-phosphorylation, therefore regulating the expression of interferon stimulated genes (ISGs) and NLRP3-inflammasome dependent IL-1ß release. Because RIP2 is upregulated and/or activated in autoimmune/inflammatory disease and cancer, observations from this study promise implications of RIP kinases in human disease.


Assuntos
Inflamação , Proteína Serina-Treonina Quinase 2 de Interação com Receptor , Dano ao DNA , Homeostase , Humanos , Espécies Reativas de Oxigênio/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo
4.
Front Cell Dev Biol ; 9: 746145, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34746142

RESUMO

Background: Psoriasis is a T cell-mediated chronic autoimmune/inflammatory disease. While some patients experience disease limited to the skin (skin psoriasis), others develop joint involvement (psoriatic arthritis; PsA). In the absence of disease- and/or outcome-specific biomarkers, and as arthritis can precede skin manifestations, diagnostic and therapeutic delays are common and contribute to disease burden and damage accrual. Objective: Altered epigenetic marks, including DNA methylation, contribute to effector T cell phenotypes and altered cytokine expression in autoimmune/inflammatory diseases. This project aimed at the identification of disease-/outcome-specific DNA methylation signatures in CD8+ T cells from patients with psoriasis and PsA as compared to healthy controls. Method: Peripheral blood CD8+ T cells from nine healthy controls, 10 psoriasis, and seven PsA patients were collected to analyze DNA methylation marks using Illumina Human Methylation EPIC BeadChips (>850,000 CpGs per sample). Bioinformatic analysis was performed using R (minfi, limma, ChAMP, and DMRcate packages). Results: DNA methylation profiles in CD8+ T cells differentiate healthy controls from psoriasis patients [397 Differentially Methylated Positions (DMPs); 9 Differentially Methylated Regions (DMRs) when ≥CpGs per DMR were considered; 2 DMRs for ≥10 CpGs]. Furthermore, patients with skin psoriasis can be discriminated from PsA patients [1,861 DMPs, 20 DMRs (≥5 CpGs per region), 4 DMRs (≥10 CpGs per region)]. Gene ontology (GO) analyses considering genes with ≥1 DMP in their promoter delivered methylation defects in skin psoriasis and PsA primarily affecting the BMP signaling pathway and endopeptidase regulator activity, respectively. GO analysis of genes associated with DMRs between skin psoriasis and PsA demonstrated an enrichment of GABAergic neuron and cortex neuron development pathways. Treatment with cytokine blockers associated with DNA methylation changes [2,372 DMPs; 1,907 DMPs within promoters, 7 DMRs (≥5 CpG per regions)] affecting transforming growth factor beta receptor and transmembrane receptor protein serine/threonine kinase signaling pathways. Lastly, a methylation score including TNF and IL-17 pathway associated DMPs inverse correlates with skin disease activity scores (PASI). Conclusion: Patients with skin psoriasis exhibit DNA methylation patterns in CD8+ T cells that allow differentiation from PsA patients and healthy individuals, and reflect clinical activity of skin disease. Thus, DNA methylation profiling promises potential as diagnostic and prognostic tool to be used for molecular patient stratification toward individualized treatment.

5.
J Immunol ; 207(1): 55-64, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34135066

RESUMO

Effector CD4+ T lymphocytes contribute to inflammation and tissue damage in psoriasis, but the underlying molecular mechanisms remain poorly understood. The transcription factor CREMα controls effector T cell function in people with systemic autoimmune diseases. The inhibitory surface coreceptor PD-1 plays a key role in the control of effector T cell function and its therapeutic inhibition in patients with cancer can cause psoriasis. In this study, we show that CD4+ T cells from patients with psoriasis and psoriatic arthritis exhibit increased production of IL-17 but decreased expression of IL-2 and PD-1. In genetically modified mice and Jurkat T cells CREMα expression was linked to low PD-1 levels. We demonstrate that CREMα is recruited to the proximal promoter of PDCD1 in which it trans-represses gene expression and corecruits DNMT3a-mediating DNA methylation. As keratinocytes limit inflammation by PD-1 ligand expression and, in this study, reported reduced expression of PD-1 on CD4+ T cells is linked to low IL-2 and high IL-17A production, our studies reveal a molecular pathway in T cells from people with psoriasis that can deserve clinical exploitation.


Assuntos
Artrite Psoriásica/imunologia , Linfócitos T CD4-Positivos/imunologia , Modulador de Elemento de Resposta do AMP Cíclico/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL
6.
Cell Rep ; 30(8): 2501-2511.e5, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32101731

RESUMO

Pro-inflammatory caspase-1 is a key player in innate immunity. Caspase-1 processes interleukin (IL)-1ß and IL-18 to their mature forms and triggers pyroptosis. These caspase-1 functions are linked to its enzymatic activity. However, loss-of-function missense mutations in CASP1 do not prevent autoinflammation in patients, despite decreased IL-1ß production. In vitro data suggest that enzymatically inactive caspase-1 drives inflammation via enhanced nuclear factor κB (NF-κB) activation, independent of IL-1ß processing. Here, we report two mouse models of enzymatically inactive caspase-1-C284A, demonstrating the relevance of this pathway in vivo. In contrast to Casp1-/- mice, caspase-1-C284A mice show pronounced hypothermia and increased levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and IL-6 when challenged with lipopolysaccharide (LPS). Caspase-1-C284A signaling is RIP2 dependent and mediated by TNF-α but independent of the NLRP3 inflammasome. LPS-stimulated whole blood from patients carrying loss-of-function missense mutations in CASP1 secretes higher amounts of TNF-α. Taken together, these results reveal non-canonical caspase-1 signaling in vivo.


Assuntos
Caspase 1/metabolismo , Inflamação/patologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Loci Gênicos , Genótipo , Células HEK293 , Heterozigoto , Humanos , Camundongos Endogâmicos C57BL , Mutação/genética , Adulto Jovem
7.
Curr Osteoporos Rep ; 15(6): 542-554, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29080202

RESUMO

PURPOSE OF REVIEW: Chronic non-bacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder. We summarize the clinical presentation, diagnostic approaches, most recent advances in understanding the pathophysiology, and available treatment options and outcomes in CNO/CRMO. RECENT FINDINGS: Though the exact molecular pathophysiology of CNO/CRMO remains somewhat elusive, it appears likely that variable defects in the TLR4/MAPK/inflammasome signaling cascade result in an imbalance between pro- and anti-inflammatory cytokine expressions in monocytes from CNO/CRMO patients. In this context, we present previously unpublished data on cytokine and chemokine expression in monocytes and tissues. CNO/CRMO is an autoinflammatory bone disorder resulting from imbalanced cytokine expression from innate immune cells. Though the exact molecular pathophysiology remains unclear, variable molecular defects appear to result in inflammasome activation and pro-inflammatory cytokine expression in monocytes from CNO/CRMO patients. Recent advances suggest signaling pathways and single molecules as biomarkers for CNO/CRMO as well as future treatment targets.


Assuntos
Citocinas/imunologia , Inflamassomos/imunologia , Proteínas Quinases Ativadas por Mitógeno/imunologia , Monócitos/imunologia , Osteomielite/imunologia , Receptor 4 Toll-Like/imunologia , Corticosteroides/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Quimiocina CCL2/imunologia , Quimiocina CCL4/imunologia , Quimiocina CCL5/imunologia , Quimiocinas/imunologia , Difosfonatos/uso terapêutico , Modelos Animais de Doenças , Humanos , Imunossupressores/uso terapêutico , Interleucina-12/imunologia , Interleucina-6/imunologia , Metotrexato/uso terapêutico , Camundongos , Osteomielite/diagnóstico , Osteomielite/terapia , Receptores de Interleucina-2/imunologia , Transdução de Sinais , Sulfassalazina/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores
8.
Clin Immunol ; 145(1): 69-76, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22940633

RESUMO

Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder of unknown origin. We previously demonstrated that monocytes from CRMO patients fail to express the immune-modulatory cytokine interleukin-10 (IL-10) in a chromatin dependent manner. Here, we demonstrate that attenuated extracellular-signal regulated kinase (ERK)1 and 2 signaling in response to TLR4 activation results in failure to induce IL-10 expression in monocytes from CRMO patients. Attenuated ERK1/2 activation results in 1) reduced levels of Sp-1, a transcription factor that induces IL-10 expression in monocytes, and 2) impaired H3S10 phosphorylation of the IL10 promoter, an activating epigenetic mark. The pro-inflammatory cytokines tumor necrosis factor (TNF)α and IL-6 are not negatively affected, resulting in an imbalance towards pro-inflammatory cytokines. Thus, impaired ERK1/2 signaling with subsequently reduced Sp-1 expression and H3S10 phosphorylation of the IL10 promoter may centrally contribute to the pathophysiology of CRMO.


Assuntos
Interleucina-10/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Osteomielite/metabolismo , Receptor 4 Toll-Like/metabolismo , Cromatina/genética , Cromatina/imunologia , Expressão Gênica , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/biossíntese , Interleucina-6/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Monócitos/imunologia , Monócitos/metabolismo , Osteomielite/genética , Osteomielite/imunologia , Fosforilação , Cultura Primária de Células , Regiões Promotoras Genéticas , Proteínas Quinases/genética , Proteínas Quinases/imunologia , Proteínas Quinases/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia
9.
Cardiol Young ; 19(5): 530-3, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19674502

RESUMO

Congenital arteriovenous malformations are rare causes of congestive cardiac failure in neonates. The most common sites are in the head and liver, but other sites include the thorax, the abdomen and the limbs. The onset of failure is usually not in the immediate neonatal period, but later on in life, albeit that lesions such as the arteriovenous malformation of the vein of Galen, and other arteriovenous malformations in different locations which produce high flow can present early. We describe here the first case, to the best of our knowledge, of prenatal detection of an intrathoracic arteriovenous malformation producing neonatal cardiac failure, which was successfully treated by surgery postnatally.


Assuntos
Fístula Arteriovenosa/complicações , Fístula Arteriovenosa/diagnóstico , Veias Braquiocefálicas , Insuficiência Cardíaca/etiologia , Artéria Subclávia , Humanos , Recém-Nascido , Masculino
10.
Mol Cell Biol ; 26(17): 6623-32, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16914744

RESUMO

Cybr (also known as Cytip, CASP, and PSCDBP) is an interleukin-12-induced gene expressed exclusively in hematopoietic cells and tissues that associates with Arf guanine nucleotide exchange factors known as cytohesins. Cybr levels are dynamically regulated during T-cell development in the thymus and upon activation of peripheral T cells. In addition, Cybr is induced in activated dendritic cells and has been reported to regulate dendritic cell (DC)-T-cell adhesion. Here we report the generation and characterization of Cybr-deficient mice. Despite the selective expression in hematopoietic cells, there was no intrinsic defect in T- or B-cell development or function in Cybr-deficient mice. The adoptive transfer of Cybr-deficient DCs showed that they migrated efficiently and stimulated proliferation and cytokine production by T cells in vivo. However, competitive stem cell repopulation experiments showed a defect in the abilities of Cybr-deficient T cells to develop in the presence of wild-type precursors. These data suggest that Cybr is not absolutely required for hematopoietic cell development or function, but stem cells lacking Cybr are at a developmental disadvantage compared to wild-type cells. Collectively, these data demonstrate that despite its selective expression in hematopoietic cells, the role of Cybr is limited or largely redundant. Previous in vitro studies using overexpression or short interfering RNA inhibition of the levels of Cybr protein appear to have overestimated its immunological role.


Assuntos
Proteínas de Transporte/metabolismo , Diferenciação Celular , Apresentação Cruzada/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Proteínas de Membrana/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Proteínas de Transporte/genética , Diferenciação Celular/efeitos dos fármacos , Citocinas/farmacologia , Células Dendríticas/efeitos dos fármacos , Éxons/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Marcação de Genes , Humanos , Imunidade Inata/imunologia , Lipopolissacarídeos/imunologia , Subpopulações de Linfócitos/imunologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Células Mieloides/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T/efeitos dos fármacos
11.
Mol Immunol ; 41(6-7): 727-37, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15220007

RESUMO

The discovery that Jak3 mutations are a significant cause of severe combined immunodeficiency (SCID), a rare inherited defect characterized by lymphopenia, has provided valuable insights into the functions of Jak3 in lymphoid development and function. The current therapy for patients suffering from Jak3 SCID is hematopoetic stem cell transplantation, although gene therapy trials have also been performed. In lieu of crystal structure data, these patient-derived mutations have aided in the elucidation of the functions of various structural components of Jak3. By virtue of its requirement for lymphoid functions, Jak3 makes a tantalizing target for immunosuppression and anti-cancer therapy. Herein, we discuss the normal actions of the gammac cytokines, the pathogenesis and treatment protocols for SCID, and finally, the production of a new, selective Jak3 inhibitor capable of preventing transplant rejection in two animal models. Further study of Jak3 will hopefully provide insights into the clinical treatment of patients suffering from immune-mediated diseases.


Assuntos
Proteínas Tirosina Quinases/deficiência , Imunodeficiência Combinada Severa/genética , Transdução de Sinais/fisiologia , Animais , Citocinas/genética , Citocinas/metabolismo , Humanos , Janus Quinase 3 , Mutação , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/metabolismo , Imunodeficiência Combinada Severa/enzimologia , Imunodeficiência Combinada Severa/imunologia , Transdução de Sinais/imunologia , Relação Estrutura-Atividade
12.
J Immunol ; 170(12): 6057-64, 2003 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-12794134

RESUMO

Janus kinase 3 (Jak3) is a nonreceptor tyrosine kinase essential for signaling via cytokine receptors that comprise the common gamma-chain (gammac), i.e., the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Jak3 is preferentially expressed in hemopoietic cells and is up-regulated upon cell differentiation and activation. Despite the importance of Jak3 in lymphoid development and immune function, the mechanisms that govern its expression have not been defined. To gain insight into this issue, we set out to characterize the Jak3 promoter. The 5'-untranslated region of the Jak3 gene is interrupted by a 3515-bp intron. Upstream of this intron and the transcription initiation site, we identified an approximately 1-kb segment that exhibited lymphoid-specific promoter activity and was responsive to TCR signals. Truncation of this fragment revealed that core promoter activity resided in a 267-bp fragment that contains putative Sp-1, AP-1, Ets, Stat, and other binding sites. Mutation of the AP-1 sites significantly diminished, whereas mutation of the Ets sites abolished, the inducibility of the promoter construct. Chromatin immunoprecipitation assays showed that histone acetylation correlates with mRNA expression and that Ets-1/2 binds this region. Thus, transcription factors that bind these sites, especially Ets family members, are likely to be important regulators of Jak3 expression.


Assuntos
Regiões 5' não Traduzidas/química , Regiões 5' não Traduzidas/genética , Regiões Promotoras Genéticas , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/genética , Regiões 5' não Traduzidas/análise , Animais , Composição de Bases , Sequência de Bases , Células COS , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica/imunologia , Células HeLa , Humanos , Janus Quinase 3 , Células Jurkat , Ativação Linfocitária/genética , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Especificidade de Órgãos/genética , Proteínas Tirosina Quinases/análise , Proteína Proto-Oncogênica c-ets-1 , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Proto-Oncogênicas c-ets , RNA Mensageiro/análise , RNA Mensageiro/química , Receptores de Antígenos de Linfócitos T/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Fator de Transcrição AP-1/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia , Sítio de Iniciação de Transcrição
13.
Arthritis Rheum ; 46(12): 3340-8, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12483741

RESUMO

OBJECTIVE: Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome. METHODS: Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA syndrome and their available parents was screened for CIAS1 mutations by automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by real-time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum cytokine levels were assayed by enzyme-linked immunosorbent assay. Protein expression was assessed by Western blotting of lysates from plastic-adherent peripheral blood mononuclear cells. RESULTS: In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel. None of these sequence changes was observed in a panel of >900 chromosomes from healthy controls. Two distinct nucleotide changes in a single codon in unrelated patients resulted in the same amino acid change. In 4 mutation-positive children whose parental DNA was available, no mutation was found in the parental DNA, supporting the conclusion that the mutations arose de novo. Consistent with the recently discovered role of CIAS1 in the regulation of interleukin-1 (IL-1), we found evidence of increased IL-1beta, as well as tumor necrosis factor, IL-3, IL-5, and IL-6, but not transforming growth factor beta, in a mutation-positive patient compared with normal controls. CONCLUSION: Our data increase the total number of known germline mutations in CIAS1 to 20, causing a spectrum of diseases ranging from familial cold autoinflammatory syndrome to Muckle-Wells syndrome to NOMID/CINCA syndrome. Mutations in CIAS1 were only found in approximately 50% of the cases identified clinically as NOMID/CINCA syndrome, which raises the possibility of genetic heterogeneity. IL-1 regulation by CIAS1 suggests that IL-1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome.


Assuntos
Proteínas Sanguíneas/genética , Proteínas de Transporte/genética , Citocinas/metabolismo , Heterogeneidade Genética , Inflamação/genética , Inflamação/fisiopatologia , Mutação , Proteínas/metabolismo , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Proteínas do Citoesqueleto , Análise Mutacional de DNA , Feminino , Humanos , Recém-Nascido , Inflamação/diagnóstico por imagem , Inflamação/epidemiologia , Inflamação/patologia , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR , Pirina , Radiografia , Síndrome
14.
Curr Opin Allergy Clin Immunol ; 2(6): 495-506, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14752332

RESUMO

PURPOSE OF REVIEW: The development of lymphoid tissues as well as the ultimate differentiation of naïve and memory T cells are dependent on cytokines. In this review, we will focus on recent advances in the understanding of molecular mechanisms that regulate lymphoid development, homeostasis and tolerance. RECENT FINDINGS: Cytokines play a critical role in the development and differentiation of lymphoid cells. In addition, newer data indicate important roles of interleukin-7 and interleukin-15 in lymphoid homeostasis and memory. Furthermore, a new family of heterodimeric cytokines comprising interleukin-12, interleukin-23 and -27 is important for differentiation of helper T cells and cell-mediated immunity. Finally the importance of tumor necrosis factor superfamily members in the development of lymphoid organs has recently been elucidated and will be discussed in detail. SUMMARY: New cytokines and receptors continue to be identified. The discovery and characterization of cytokines, their receptors and signaling molecules will provide a more complete understanding of normal lymphoid development, differentiation and function. In addition, this knowledge should improve our understanding of the pathogenesis of immunological diseases and hopefully will provide new treatment strategies.


Assuntos
Citocinas/metabolismo , Homeostase/fisiologia , Tecido Linfoide/fisiologia , Linfócitos T Auxiliares-Indutores/fisiologia , Humanos , Memória Imunológica , Interleucina-12/metabolismo , Interleucina-23 , Subunidade p19 da Interleucina-23 , Interleucina-4/metabolismo , Interleucina-9/metabolismo , Interleucinas/metabolismo , Tecido Linfoide/imunologia , Receptores de Citocinas/análise , Receptores de Citocinas/metabolismo , Sensibilidade e Especificidade , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia , Fator de Necrose Tumoral alfa/metabolismo
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