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1.
Ann Rheum Dis ; 80(5): 617-625, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33277241

RESUMEN

OBJECTIVES: Systemic juvenile idiopathic arthritis (SJIA) confers high risk for macrophage activation syndrome (MAS), a life-threatening cytokine storm driven by interferon (IFN)-γ. SJIA monocytes display IFN-γ hyper-responsiveness, but the molecular basis of this remains unclear. The objective of this study is to identify circulating monocyte and bone marrow macrophage (BMM) polarisation phenotypes in SJIA including molecular features contributing to IFN response. METHODS: Bulk RNA-seq was performed on peripheral blood monocytes (n=26 SJIA patients) and single cell (sc) RNA-seq was performed on BMM (n=1). Cultured macrophages were used to define consequences of tripartite motif containing 8 (TRIM8) knockdown on IFN-γ signalling. RESULTS: Bulk RNA-seq of SJIA monocytes revealed marked transcriptional changes in patients with elevated ferritin levels. We identified substantial overlap with multiple polarisation states but little evidence of IFN-induced signature. Interestingly, among the most highly upregulated genes was TRIM8, a positive regulator of IFN-γ signalling. In contrast to PBMC from SJIA patients without MAS, scRNA-seq of BMM from a patient with SJIA and MAS identified distinct subpopulations of BMM with altered transcriptomes, including upregulated IFN-γ response pathways. These BMM also showed significantly increased expression of TRIM8. In vitro knockdown of TRIM8 in macrophages significantly reduced IFN-γ responsiveness. CONCLUSIONS: Macrophages with an 'IFN-γ response' phenotype and TRIM8 overexpression were expanded in the bone marrow from an MAS patient. TRIM8 is also upregulated in SJIA monocytes, and augments macrophage IFN-γ response in vitro, providing both a candidate molecular mechanism and potential therapeutic target for monocyte hyper-responsiveness to IFNγ in cytokine storms including MAS.


Asunto(s)
Artritis Juvenil/sangre , Proteínas Portadoras/sangre , Interferón gamma/sangre , Síndrome de Activación Macrofágica/genética , Activación de Macrófagos/genética , Proteínas del Tejido Nervioso/sangre , Artritis Juvenil/genética , Médula Ósea/metabolismo , Técnicas de Cultivo de Célula , Niño , Preescolar , Síndrome de Liberación de Citoquinas , Femenino , Ferritinas/sangre , Humanos , Leucocitos Mononucleares/metabolismo , Macrófagos/metabolismo , Masculino , Monocitos/metabolismo , Fenotipo , Análisis de Secuencia de ARN , Transducción de Señal , Transcriptoma , Regulación hacia Arriba
2.
Arthritis Rheumatol ; 76(1): 119-129, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37471469

RESUMEN

OBJECTIVE: Human leukocyte antigen (HLA)-DRB1*15:01 has been recently associated with interstitial lung disease (LD), eosinophilia, and drug reactions in systemic juvenile idiopathic arthritis (sJIA). Additionally, genetic variants in IL1RN have been linked to poor response to anakinra. We sought to reproduce these findings in a prospective cohort study of patients with new-onset sJIA treated with anakinra as first-line therapy. METHODS: HLA and IL1RN risk alleles were identified via whole-genome sequencing. Treatment responses and complications were compared between carriers versus noncarriers. RESULTS: Seventeen of 65 patients (26%) carried HLA-DRB1*15:01, comparable with the general population, and there was enrichment for HLA-DRB1*11:01, a known risk locus for sJIA. The rates of clinical inactive disease (CID) at 6 months, 1 year, and 2 years were generally high, irrespective of HLA-DRB1 or IL1RN variants, but significantly lower in carriers of an HLA-DRB1*11:01 allele. One patient, an HLA-DRB1*15:01 carrier, developed sJIA-LD. Of the three patients with severe drug reactions to biologics, one carried HLA-DRB1*15:01. The prevalence of eosinophilia did not significantly differ between HLA-DRB1*15:01 carriers and noncarriers at disease onset (6.2% vs 14.9%, P = 0.67) nor after the start of anakinra (35.3% vs 37.5% in the first 2 years of disease). CONCLUSION: We observed high rates of CID using anakinra as first-line treatment irrespective of HLA-DRB1 or IL1RN variants. Only one of the 17 HLA-DRB1*15:01 carriers developed sJIA-LD, and of the three patients with drug reactions to biologics, only one carried HLA-DRB1*15:01. Although thorough monitoring for the development of drug hypersensitivity and refractory disease courses in sJIA, including sJIA-LD, remains important, our data support the early start of biologic therapy in patients with new-onset sJIA irrespective of HLA-DRB1 background or IL1RN variants.


Asunto(s)
Artritis Juvenil , Productos Biológicos , Eosinofilia , Humanos , Artritis Juvenil/tratamiento farmacológico , Artritis Juvenil/genética , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Cadenas HLA-DRB1/genética , Estudios Prospectivos , Productos Biológicos/uso terapéutico , Eosinofilia/tratamiento farmacológico , Receptores de Interleucina-1/uso terapéutico
3.
Arthritis Care Res (Hoboken) ; 76(3): 328-339, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37691306

RESUMEN

OBJECTIVE: Systemic juvenile idiopathic arthritis-associated lung disease (SJIA-LD) is a life-threatening disease complication. Key questions remain regarding clinical course and optimal treatment approaches. The objectives of the study were to detail management strategies after SJIA-LD detection, characterize overall disease courses, and measure long-term outcomes. METHODS: This was a prospective cohort study. Clinical data were abstracted from the electronic medical record, including current clinical status and changes since diagnosis. Serum biomarkers were determined and correlated with presence of LD. RESULTS: We enrolled 41 patients with SJIA-LD, 85% with at least one episode of macrophage activation syndrome and 41% with adverse reactions to a biologic. Although 93% of patients were alive at last follow-up (median 2.9 years), 37% progressed to requiring chronic oxygen or other ventilator support, and 65% of patients had abnormal overnight oximetry studies, which changed over time. Eighty-four percent of patients carried the HLA-DRB1*15 haplotype, significantly more than patients without LD. Patients with SJIA-LD also showed markedly elevated serum interleukin-18 (IL-18), variable C-X-C motif chemokine ligand 9 (CXCL9), and significantly elevated matrix metalloproteinase 7. Treatment strategies showed variable use of anti-IL-1/6 biologics and addition of other immunomodulatory treatments and lung-directed therapies. We found a broad range of current clinical status independent of time from diagnosis or continued biologic treatment. Multidomain measures of change showed imaging features were the least likely to improve with time. CONCLUSION: Patients with SJIA-LD had highly varied courses, with lower mortality than previously reported but frequent hypoxia and requirement for respiratory support. Treatment strategies were highly varied, highlighting an urgent need for focused clinical trials.


Asunto(s)
Artritis Juvenil , Enfermedades Pulmonares , Síndrome de Activación Macrofágica , Niño , Humanos , Artritis Juvenil/complicaciones , Artritis Juvenil/diagnóstico , Artritis Juvenil/tratamiento farmacológico , Estudios Prospectivos , Pulmón , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/etiología , Síndrome de Activación Macrofágica/terapia , Progresión de la Enfermedad
4.
Biochemistry ; 52(5): 878-88, 2013 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-23311430

RESUMEN

Binding of substrate to ornithine 4,5-aminomutase (OAM) and methylmalonyl-CoA mutase (MCM) leads to the formation of an electrostatic interaction between a conserved glutamate side chain and the adenosyl ribose of the adenosylcobalamin (AdoCbl) cofactor. The contribution of this residue (Glu338 in OAM from Clostridium sticklandii and Glu392 in human MCM) to AdoCbl Co-C bond labilization and catalysis was evaluated by substituting the residue with a glutamine, aspartate, or alanine. The OAM variants, E338Q, E338D, and E338A, showed 90-, 380-, and 670-fold reductions in catalytic turnover and 20-, 60-, and 220-fold reductions in k(cat)/K(m), respectively. Likewise, the MCM variants, E392Q, E392D, and E392A, showed 16-, 330-, and 12-fold reductions in k(cat), respectively. Binding of substrate to OAM is unaffected by the single-amino acid mutation as stopped-flow absorbance spectroscopy showed that the rates of external aldimine formation in the OAM variants were similar to that of the native enzyme. The decrease in the level of catalysis is instead linked to impaired Co-C bond rupture, as UV-visible spectroscopy did not show detectable AdoCbl homolysis upon binding of the physiological substrate, d-ornithine. AdoCbl homolysis was also not detected in the MCM mutants, as it was for the native enzyme. We conclude from these results that a gradual weakening of the electrostatic energy between the protein and the ribose leads to a progressive increase in the activation energy barrier for Co-C bond homolysis, thereby pointing to a key role for the conserved polar glutamate residue in controlling the initial generation of radical species.


Asunto(s)
Clostridium sticklandii/enzimología , Cobamidas/metabolismo , Ácido Glutámico/genética , Transferasas Intramoleculares/genética , Transferasas Intramoleculares/metabolismo , Metilmalonil-CoA Mutasa/genética , Metilmalonil-CoA Mutasa/metabolismo , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Clostridium sticklandii/química , Clostridium sticklandii/genética , Clostridium sticklandii/metabolismo , Cobamidas/química , Ácido Glutámico/química , Ácido Glutámico/metabolismo , Humanos , Transferasas Intramoleculares/química , Cinética , Metilmalonil-CoA Mutasa/química , Modelos Moleculares , Datos de Secuencia Molecular , Mutación Puntual , Unión Proteica , Conformación Proteica , Alineación de Secuencia , Electricidad Estática
5.
Arthritis Rheumatol ; 73(7): 1334-1340, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33452871

RESUMEN

OBJECTIVE: Canakinumab is a human anti-interleukin-1ß (anti-IL-1ß) blocking agent that effectively neutralizes IL-1ß-mediated signaling for treatment of systemic juvenile idiopathic arthritis (JIA). While many patients have dramatic clinical response to IL-1 blockade, approximately one-third fail to respond, but there are currently no validated clinical or immunologic predictors of response. We undertook this study to characterize distinct gene signatures for treatment response and nonresponse to canakinumab in systemic JIA patients. METHODS: We performed a secondary analysis of whole-blood gene expression microarrays using blood samples obtained from healthy controls and systemic JIA patients at baseline and on day 3 after canakinumab treatment (GEO accession no. GSE80060). Patients were considered strong clinical responders if they met the ACR90 response (exhibited ≥90% improvement in the American College of Rheumatology [ACR] JIA response criteria; nonresponders were those who met ACR30 [exhibiting ≤30% improvement in the ACR JIA response criteria]). A random-effects model with patient identity as the random variable was used for differential expression analysis. RESULTS: We identified a distinct gene expression signature in patients with a strong clinical response to canakinumab treatment as compared to nonresponders, mediated by up-regulation of neutrophil- and IL-1-associated genes and characterized by increasing divergence from control transcriptomes with increasing clinical response. We also identified a signature including up-regulated CD163 expression that was associated with canakinumab nonresponse. Intriguingly, canakinumab treatment induced either up- or down-regulation of type I interferon (IFN) genes, independent of clinical response. CONCLUSION: Here, we identify a gene signature in systemic JIA patients prior to receiving treatment that distinguishes strong responders to canakinumab from nonresponders. Further prospective studies are needed to assess the utility of these insights for treatment decisions in systemic JIA and to track the association of up-regulated type I IFN signatures with systemic JIA complications.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Artritis Juvenil/tratamiento farmacológico , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Artritis Juvenil/genética , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas de Unión al Calcio/genética , Caspasas/genética , Quimiocina CXCL1/genética , Niño , Proteínas de Unión al ADN/genética , Proteínas Ligadas a GPI/genética , Ontología de Genes , Glicoproteínas/genética , Humanos , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Accesoria del Receptor de Interleucina-1/genética , Interleucina-1beta/genética , Isoantígenos/genética , Activación Neutrófila/genética , Receptores de Superficie Celular/genética , Receptores Tipo I de Interleucina-1/genética , Transducción de Señal , Receptores Toll-Like/genética , Transcriptoma , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/genética , Regulación hacia Arriba
6.
Pac Symp Biocomput ; 26: 273-284, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33691024

RESUMEN

Modeling the relationship between chemical structure and molecular activity is a key goal in drug development. Many benchmark tasks have been proposed for molecular property prediction, but these tasks are generally aimed at specific, isolated biomedical properties. In this work, we propose a new cross-modal small molecule retrieval task, designed to force a model to learn to associate the structure of a small molecule with the transcriptional change it induces. We develop this task formally as multi-view alignment problem, and present a coordinated deep learning approach that jointly optimizes representations of both chemical structure and perturbational gene expression profiles. We benchmark our results against oracle models and principled baselines, and find that cell line variability markedly influences performance in this domain. Our work establishes the feasibility of this new task, elucidates the limitations of current data and systems, and may serve to catalyze future research in small molecule representation learning.


Asunto(s)
Benchmarking , Biología Computacional , Estructura Molecular
7.
Pediatr Rheumatol Online J ; 18(Suppl 1): 53, 2020 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-32664935

RESUMEN

For reasons poorly understood, and despite the availability of biological medications blocking IL-1 and IL-6 that have markedly improved overall disease control, children with Systemic Juvenile Idiopathic Arthritis (SJIA) are now increasingly diagnosed with life-threatening chronic complications, including hepatitis and lung disease (SJIA-LD). On October 3-4, 2019, a two-day meeting, NextGen Therapies for Systemic Juvenile Idiopathic Arthritis (SJIA) & macrophage activation syndrome (MAS) organized by the Systemic JIA Foundation ( www.systemicjia.org/ ) in Washington, DC brought together scientists, clinicians, parents and FDA representatives with the objectives (1) to integrate clinical and research findings in MAS and SJIA-LD, and (2) to develop a shared understanding of this seemingly new pulmonary complication of SJIA. The current manuscript summarizes discussions and conclusions of the meeting.


Asunto(s)
Artritis Juvenil/terapia , Síndrome de Activación Macrofágica/terapia , Artritis Juvenil/diagnóstico , Artritis Juvenil/patología , Biomarcadores , Niño , Preescolar , Progresión de la Enfermedad , Humanos , Lactante , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/patología
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