RESUMO
Pathologic type I interferon (T1IFN) expression is a key feature in systemic lupus erythematosus (SLE) that associates with disease activity. When compared to adult-onset disease, juvenile-onset (j)SLE is characterized by increased disease activity and damage, which likely relates to increased genetic burden. To identify T1IFN-associated gene polymorphisms (TLR7, IRAK1, miR-3142/miR-146a, IRF5, IRF7, IFIH1, IRF8, TYK2, STAT4), identify long-range linkage disequilibrium and gene:gene interrelations, 319 jSLE patients were genotyped using panel sequencing. Coupling phenotypic quantitative trait loci (QTL) analysis identified 10 jSLE QTL that associated with young age at onset (<12 years; IRAK1 [rs1059702], TLR7 [rs3853839], IFIH1 [rs11891191, rs1990760, rs3747517], STAT4 [rs3021866], TYK2 [rs280501], IRF8 [rs1568391, rs6638]), global disease activity (SLEDAI-2 K >10; IFIH1 [rs1990760], STAT4 [rs3021866], IRF8 [rs903202, rs1568391, rs6638]), and mucocutaneous involvement (TLR7 [rs3853839], IFIH1 [rs11891191, rs1990760]). This study suggests T1IFN-associated polymorphisms and gene:gene interrelations in jSLE. Genotyping of jSLE patients may allow for individualized treatment and care.
Assuntos
Interferon Tipo I , Lúpus Eritematoso Sistêmico , MicroRNAs , Adulto , Humanos , Criança , Helicase IFIH1 Induzida por Interferon , Interferon Tipo I/genética , Epistasia Genética , Receptor 7 Toll-Like/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/complicações , Fatores Reguladores de Interferon/genéticaRESUMO
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-PositivosRESUMO
BACKGROUND: Hyperferritinemic syndromes are systemic inflammatory disorders characterized by a dysfunctional immune response, which leads to excessive activation of the monocyte-macrophage system with hypercytokinemia and may pursue a rapidly fatal course. CASE PRESENTATION: We describe two patients of 11 and 9 years of age with hyperferritinemic syndromes, one with impending macrophage activation syndrome (MAS) and one with overt MAS, who were refractory or intolerant to conventional therapies, but improved dramatically with canakinumab. CONCLUSIONS: Our report indicates that canakinumab may be efficacious in the management of hyperferritinemic syndromes, including MAS.
Assuntos
Corticosteroides/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Hiperferritinemia , Linfo-Histiocitose Hemofagocítica/complicações , Síndrome de Ativação Macrofágica/complicações , Antirreumáticos/administração & dosagem , Criança , Feminino , Ferritinas/análise , Humanos , Hiperferritinemia/sangue , Hiperferritinemia/diagnóstico , Hiperferritinemia/tratamento farmacológico , Hiperferritinemia/etiologia , Interleucina-1beta/antagonistas & inibidores , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/imunologia , Síndrome de Ativação Macrofágica/diagnóstico , Síndrome de Ativação Macrofágica/imunologia , Masculino , Resultado do TratamentoRESUMO
Macrophage activation syndrome (MAS) is a serious, potentially life-threatening, hyperinflammatory condition, which belongs to the spectrum of hemophagocytic lymphohistiocytosis (HLH) and can complicate several immunologic and rheumatic disorders. MAS is characterized by a dysfunctional immune response that is similar to that seen in other forms of HLH. Because MAS may pursue a rapidly fatal course, prompt recognition of its clinical and laboratory features and immediate therapeutic intervention are fundamental. Recently, a set of classification criteria for MAS complicating sJIA has been developed through a multinational collaborative effort. High-dose parenteral corticosteroids remain the mainstay of treatment of MAS.