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1.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445670

RESUMO

While first and foremost considered a respiratory infection, COVID-19 can result in complications affecting multiple organs. Immune responses in COVID-19 can both protect against the disease as well as drive it. Insights into these responses, and specifically the targets being recognised by the immune system, are of vital importance in understanding the side effects of COVID-19 and associated pathologies. The body's adaptive immunity recognises and responds against specific targets (antigens) expressed by foreign pathogens, but not usually to target self-antigens. However, if the immune system becomes dysfunctional, adaptive immune cells can react to self-antigens, which can result in autoimmune disease. Viral infections are well reported to be associated with, or exacerbate, autoimmune diseases such as multiple sclerosis (MS) and systemic lupus erythematosus (SLE). In COVID-19 patients, both new onset MS and SLE, as well as the occurrence of other autoimmune-like pathologies, have been reported. Additionally, the presence of autoantibodies, both with and without known associations to autoimmune diseases, have been found. Herein we describe the mechanisms of virally induced autoimmunity and summarise some of the emerging reports on the autoimmune-like diseases and autoreactivity that is reported to be associated with SARS-CoV-2 infection.


Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/virologia , COVID-19/imunologia , Imunidade Adaptativa , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Autoimunidade , COVID-19/virologia , Humanos , Lúpus Eritematoso Sistêmico/imunologia , SARS-CoV-2/imunologia
2.
Nat Commun ; 12(1): 4813, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376664

RESUMO

Differences in immune responses to viruses and autoimmune diseases such as systemic lupus erythematosus (SLE) can show sexual dimorphism. Age-associated B cells (ABC) are a population of CD11c+T-bet+ B cells critical for antiviral responses and autoimmune disorders. Absence of DEF6 and SWAP-70, two homologous guanine exchange factors, in double-knock-out (DKO) mice leads to a lupus-like syndrome in females marked by accumulation of ABCs. Here we demonstrate that DKO ABCs show sex-specific differences in cell number, upregulation of an ISG signature, and further differentiation. DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c+ and CD11c- effector B cell populations with pathogenic and pro-inflammatory function as demonstrated by BCR sequencing and fate-mapping experiments. Tlr7 duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs, resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function and differentiation of ABCs that accompanies TLR7-driven immunopathogenesis.


Assuntos
Envelhecimento/imunologia , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fatores Etários , Envelhecimento/genética , Animais , Linfócitos B/citologia , Linfócitos B/metabolismo , Antígeno CD11c/imunologia , Antígeno CD11c/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Estimativa de Kaplan-Meier , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , Antígenos de Histocompatibilidade Menor/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Proteínas Nucleares/metabolismo , Fatores Sexuais , Proteínas com Domínio T/imunologia , Proteínas com Domínio T/metabolismo
3.
Pharmacol Res Perspect ; 9(5): e00842, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34414672

RESUMO

This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of enpatoran (formerly named M5049), a new toll-like receptor (TLR) 7 and 8 dual antagonist, and the effect of food on a single dose in healthy participants. In this single phase 1, randomized (3:1), double-blind, placebo-controlled study, 96 participants received single and multiple ascending oral doses of enpatoran. Participants in single-dose cohorts received one dose of enpatoran (1, 3, 9, 25, 50, 100, or 200 mg) or placebo using a sentinel dosing strategy. Multiple-dose cohorts received enpatoran (9, 25, or 200 mg once daily, or 25 or 50 mg twice daily) or placebo for 14 days. Safety, tolerability, PK, and PD (ex vivo-stimulated cytokine secretion) were assessed in both parts. The effect of food was assessed in an open-label, one-way crossover study in the 25 mg single-dose cohort. Single- and multiple-oral doses of enpatoran up to 200 mg were well tolerated and no significant dose-limiting adverse events or safety signals were observed under fasting or fed conditions. PK parameters were linear and dose-proportional across the dose range evaluated, with a slightly delayed absorption and lower peak concentration observed at 25 mg with food. Exposure-dependent inhibition of ex vivo-stimulated interleukin-6 secretion was observed, with maximum inhibition at 200 mg. Enpatoran was well tolerated at doses up to 200 mg. Further investigation of enpatoran is warranted as a potential treatment for diseases driven by TLR7/8 overactivation, such as systemic lupus erythematosus and COVID-19 pneumonia.


Assuntos
Fatores Imunológicos/farmacologia , Receptor 7 Toll-Like/antagonistas & inibidores , Receptor 8 Toll-Like/antagonistas & inibidores , Administração Oral , Adulto , COVID-19/tratamento farmacológico , COVID-19/imunologia , Método Duplo-Cego , Feminino , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Masculino , SARS-CoV-2
4.
Nat Immunol ; 22(9): 1107-1117, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34385713

RESUMO

The linkage between neutrophil death and the development of autoimmunity has not been thoroughly explored. Here, we show that neutrophils from either lupus-prone mice or patients with systemic lupus erythematosus (SLE) undergo ferroptosis. Mechanistically, autoantibodies and interferon-α present in the serum induce neutrophil ferroptosis through enhanced binding of the transcriptional repressor CREMα to the glutathione peroxidase 4 (Gpx4, the key ferroptosis regulator) promoter, which leads to suppressed expression of Gpx4 and subsequent elevation of lipid-reactive oxygen species. Moreover, the findings that mice with neutrophil-specific Gpx4 haploinsufficiency recapitulate key clinical features of human SLE, including autoantibodies, neutropenia, skin lesions and proteinuria, and that the treatment with a specific ferroptosis inhibitor significantly ameliorates disease severity in lupus-prone mice reveal the role of neutrophil ferroptosis in lupus pathogenesis. Together, our data demonstrate that neutrophil ferroptosis is an important driver of neutropenia in SLE and heavily contributes to disease manifestations.


Assuntos
Ferroptose/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Neutropenia/patologia , Neutrófilos/imunologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Autoanticorpos/imunologia , Autoimunidade/imunologia , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Humanos , Interferon-alfa/imunologia , Camundongos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Regiões Promotoras Genéticas/genética , Espécies Reativas de Oxigênio/metabolismo
6.
Arterioscler Thromb Vasc Biol ; 41(9): 2417-2430, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34320837

RESUMO

Objective: Systemic lupus erythematosus (SLE) is associated to boosted atherosclerosis development and a higher cardiovascular disease risk. This study aimed to delineate the role of anti-double stranded DNA (anti-dsDNA) antibodies on the molecular profile and the activity of immune and vascular cells, as well as on their enhanced cardiovascular risk. Approach and Results: Eighty SLE patients were included. Extensive clinical/analytical evaluation was performed, including cardiovascular disease parameters (endothelial function, proatherogenic dyslipidemia, and carotid intima-media thickness). Gene and protein expression profiles were evaluated in monocytes from patients diagnosed positive or negative for anti-dsDNA antibodies by using NanoString and cytokine arrays, respectively. NETosis and circulating inflammatory profile was assessed in both neutrophils and plasma. Positivity and persistence of anti-dsDNA antibodies in SLE patients were associated to endothelial dysfunction, proatherogenic dyslipidemia, and accelerated atherosclerosis. In parallel, anti-dsDNA antibodies were linked to the aberrant activation of innate immune cells, so that anti-dsDNA(+) SLE monocytes showed distinctive gene and protein expression/activity profiles, and neutrophils were more prone to suffer NETosis in comparison with anti-dsDNA(−) patients. Anti-dsDNA(+) patients further displayed altered levels of numerous circulating mediators related to inflammation, NETosis, and cardiovascular risk. In vitro, Ig-dsDNA promoted NETosis on neutrophils, apoptosis on monocytes, modulated the expression of inflammation and thrombosis-related molecules, and induced endothelial activation, at least partially, by FcR (Fc receptor)-binding mechanisms. Conclusions: Anti-dsDNA antibodies increase the cardiovascular risk of SLE patients by altering key molecular processes that drive a distinctive and coordinated immune and vascular activation, representing a potential tool in the management of this comorbidity.


Assuntos
Anticorpos Antinucleares/sangue , Doenças Cardiovasculares/imunologia , DNA/imunologia , Células Endoteliais/imunologia , Imunoglobulina G/sangue , Leucócitos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Apoptose , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/genética , Células Cultivadas , Técnicas de Cocultura , Estudos Transversais , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Leucócitos/metabolismo , Lipídeos/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Estresse Oxidativo , Estudos Retrospectivos , Medição de Risco , Transdução de Sinais
7.
Nat Commun ; 12(1): 4379, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282144

RESUMO

The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional Irf5 deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors.


Assuntos
Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Animais , Autoanticorpos/imunologia , Doenças Autoimunes , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Imunoglobulina G , Fatores Reguladores de Interferon/efeitos dos fármacos , Rim/patologia , Lúpus Eritematoso Sistêmico/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Interferon alfa e beta , Transdução de Sinais , Fatores de Transcrição , Quinases da Família src
8.
Paediatr Drugs ; 23(4): 331-347, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34244988

RESUMO

Childhood-onset systemic lupus erythematosus (cSLE) is a prototype of a multisystemic, inflammatory, heterogeneous autoimmune condition. This disease is characterized by simultaneous or sequential organ and system involvement, with unpredictable flare and high levels of morbidity and mortality. Racial/ethnic background, socioeconomic status, cost of medications, difficulty accessing health care, and poor adherence seem to impact lupus outcomes and treatment response. In this article, the management of cSLE patients is updated. Regarding pathogenesis, a number of potential targets for drugs have been studied. However, most treatments in pediatric patients are off-label drugs with recommendations based on inadequately powered studies, therapeutic consensus guidelines, or case series. Management practices for cSLE patients include evaluations of disease activity and cumulative damage scores, routine non-live vaccinations, physical activity, and addressing mental health issues. Antimalarials and glucocorticoids are still the most common drugs used to treat cSLE, and hydroxychloroquine is recommended for nearly all cSLE patients. Disease-modifying antirheumatic drugs (DMARDs) should be standardized for each patient, based on disease flare and cSLE severity. Mycophenolate mofetil or intravenous cyclophosphamide is suggested as induction therapy for lupus nephritis classes III and IV. Calcineurin inhibitors (cyclosporine, tacrolimus, voclosporin) appear to be another good option for cSLE patients with lupus nephritis. Regarding B-cell-targeting biologic agents, rituximab may be used for refractory lupus nephritis patients in combination with another DMARD, and belimumab was recently approved by the US Food and Drug Administration for cSLE treatment in children aged > 5 years. New therapies targeting CD20, such as atacicept and telitacicept, seem to be promising drugs for SLE patients. Anti-interferon therapies (sifalimumab and anifrolumab) have shown beneficial results in phase II randomized control trials in adult SLE patients, as have some Janus kinase inhibitors, and these could be alternative treatments for pediatric patients with severe interferon-mediated inflammatory disease in the future. In addition, strict control of proteinuria and blood pressure is required in cSLE, especially with angiotensin-converting enzyme inhibitor and angiotensin receptor blocker use.


Assuntos
Gerenciamento Clínico , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Idade de Início , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Criança , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Imunoterapia/métodos , Lúpus Eritematoso Sistêmico/imunologia , Ácido Micofenólico/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281193

RESUMO

The kidney is one of the main organs affected by the autoimmune disease systemic lupus erythematosus. Lupus nephritis (LN) concerns 30-60% of adult SLE patients and it is significantly associated with an increase in the morbidity and mortality. The definitive diagnosis of LN can only be achieved by histological analysis of renal biopsies, but the invasiveness of this technique is an obstacle for early diagnosis of renal involvement and a proper follow-up of LN patients under treatment. The use of urine for the discovery of non-invasive biomarkers for renal disease in SLE patients is an attractive alternative to repeated renal biopsies, as several studies have described surrogate urinary cells or analytes reflecting the inflammatory state of the kidney, and/or the severity of the disease. Herein, we review the main findings in the field of urine immune-related biomarkers for LN patients, and discuss their prognostic and diagnostic value. This manuscript is focused on the complement system, antibodies and autoantibodies, chemokines, cytokines, and leukocytes, as they are the main effectors of LN pathogenesis.


Assuntos
Biomarcadores/urina , Nefrite Lúpica/imunologia , Nefrite Lúpica/urina , Autoanticorpos/imunologia , Autoanticorpos/urina , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/urina , Diagnóstico Precoce , Humanos , Cadeias Leves de Imunoglobulina/imunologia , Cadeias Leves de Imunoglobulina/urina , Inflamação/imunologia , Inflamação/urina , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/urina , Nefrite Lúpica/diagnóstico , Prognóstico
10.
Medicine (Baltimore) ; 100(25): e26499, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160465

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ damage and the production of a variety of autoantibodies. The pathogenesis of SLE has not been fully defined, and it is difficult to treat. Our study aimed to identify candidate genes that may be used as biomarkers for the screening, diagnosis, and treatment of SLE. METHODS: We used the GEO2R tool to identify the differentially expressed genes (DEGs) in SLE-related datasets retrieved from the Gene Expression Omnibus (GEO). In addition, we also identified the biological functions of the DEGs by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Additionally, we constructed protein-protein interaction (PPI) networks to identify hub genes, as well as the regulatory network of transcription factors related to DEGs. RESULTS: Two datasets were identified for use from the GEO (GSE50772, GSE4588), and 34 up-regulated genes and 4 down-regulated genes were identified by GEO2R. Pathway analysis of the DEGs revealed enrichment of the interferon alpha/beta signaling pathway; GO analysis was mainly enriched in response to interferon alpha, regulation of ribonuclease activity. PPIs were constructed through the STRING database and 14 hub genes were selected and 1 significant module (score = 12.923) was obtained from the PPI network. Additionally, 11 key transcription factors that interacted closely with the 14 hub DEGs were identified from the gene transcription factor network. CONCLUSIONS: Bioinformatic analysis is an effective tool for screening the original genomic data in the GEO database, and a large number of SLE-related DEGs were identified. The identified hub DEGs may be potential biomarkers of SLE.


Assuntos
Regulação da Expressão Gênica/imunologia , Redes Reguladoras de Genes , Lúpus Eritematoso Sistêmico/genética , Fatores de Transcrição/metabolismo , Biomarcadores/análise , Biologia Computacional , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia
11.
Pediatr Rheumatol Online J ; 19(1): 98, 2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34187503

RESUMO

BACKGROUND: Subcutaneous anakinra is an interleukin-1 inhibitor used to treat juvenile idiopathic arthritis. Recent reports suggest anakinra can be a valuable addition to the treatment of COVID-19 associated cytokine storm syndrome and the related multisystem inflammatory syndrome (MIS-C) in children. Herein, we describe our experience with intravenously administered anakinra. FINDINGS: 19 Patients (9 male) received intravenous (IV) anakinra for treatment of macrophage activation syndrome (MAS) secondary to systemic lupus erythematosus (SLE), systemic JIA (SJIA) or secondary hemophagocytic lymphohistiocytosis (sHLH). In most cases the general trend of the fibrinogen, ferritin, AST, and platelet count (Ravelli criteria) improved after initiation of IV anakinra. There were no reports of anaphylaxis or reactions associated with administration of IV anakinra. CONCLUSION: Intravenous administration of anakinra is an important therapeutic option for critically ill patients with MAS/HLH. It is also beneficial for those with thrombocytopenia, subcutaneous edema, neurological dysfunction, or very young, hospitalized patients who need multiple painful subcutaneous injections.


Assuntos
Administração Intravenosa/métodos , COVID-19/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Lúpus Eritematoso Sistêmico , Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Antirreumáticos/administração & dosagem , COVID-19/epidemiologia , COVID-19/imunologia , Criança , Criança Hospitalizada/psicologia , Estado Terminal/psicologia , Estado Terminal/terapia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/terapia , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/terapia , Síndrome de Ativação Macrofágica/sangue , Síndrome de Ativação Macrofágica/tratamento farmacológico , Síndrome de Ativação Macrofágica/etiologia , Masculino , Conforto do Paciente/métodos , Estudos Retrospectivos , SARS-CoV-2
12.
Clin Immunol ; 229: 108765, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34089859

RESUMO

Whether and how an acute immune challenge may affect DNA Damage Response (DDR) is unknown. By studying vaccinations against Influenza and SARS-CoV-2 (mRNA-based) we found acute increases of type-I interferon-inducible gene expression, oxidative stress and DNA damage accumulation in blood mononuclear cells of 9 healthy controls, coupled with effective anti-SARS-CoV-2 neutralizing antibody production in all. Increased DNA damage after SARS-CoV-2 vaccine, partly due to increased oxidative stress, was transient, whereas the inherent DNA repair capacity was found intact. In contrast, in 26 patients with Systemic Lupus Erythematosus, who served as controls in the context of chronic immune activation, we validated increased DNA damage accumulation, increased type-I interferon-inducible gene expression and induction of oxidative stress, however aberrant DDR was associated with deficiencies in nucleotide excision repair pathways. These results indicate that acute immune challenge can indeed activate DDR pathways, whereas, contrary to chronic immune challenge, successful repair of DNA lesions occurs.


Assuntos
Anticorpos Neutralizantes/fisiologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Dano ao DNA , Lúpus Eritematoso Sistêmico/imunologia , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , COVID-19/patologia , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Interferon Tipo I/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Vacinas Sintéticas/imunologia , Adulto Jovem
13.
Nat Commun ; 12(1): 3391, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099646

RESUMO

Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study's primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, -26.5), cholesterol efflux capacity (p = 0.08, CI 95%: -0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.


Assuntos
Aterosclerose/prevenção & controle , Inibidores de Janus Quinases/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Animais , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/imunologia , HDL-Colesterol/sangue , Método Duplo-Cego , Feminino , Predisposição Genética para Doença , Fatores de Risco de Doenças Cardíacas , Humanos , Inibidores de Janus Quinases/efeitos adversos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Fator de Transcrição STAT4/genética , Resultado do Tratamento , Rigidez Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Adulto Jovem
14.
Front Immunol ; 12: 625311, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33986742

RESUMO

Identification of the antigens associated with antibodies is vital to understanding immune responses in the context of infection, autoimmunity, and cancer. Discovering antigens at a proteome scale could enable broader identification of antigens that are responsible for generating an immune response or driving a disease state. Although targeted tests for known antigens can be straightforward, discovering antigens at a proteome scale using protein and peptide arrays is time consuming and expensive. We leverage Serum Epitope Repertoire Analysis (SERA), an assay based on a random bacterial display peptide library coupled with next generation sequencing (NGS), to power the development of Protein-based Immunome Wide Association Study (PIWAS). PIWAS uses proteome-based signals to discover candidate antibody-antigen epitopes that are significantly elevated in a subset of cases compared to controls. After demonstrating statistical power relative to the magnitude and prevalence of effect in synthetic data, we apply PIWAS to systemic lupus erythematosus (SLE, n=31) and observe known autoantigens, Smith and Ribosomal protein P, within the 22 highest scoring candidate protein antigens across the entire human proteome. We validate the magnitude and location of the SLE specific signal against the Smith family of proteins using a cohort of patients who are positive by predicate anti-Sm tests. To test the generalizability of the method in an additional autoimmune disease, we identified and validated autoantigenic signals to SSB, CENPA, and keratin proteins in a cohort of individuals with Sjogren's syndrome (n=91). Collectively, these results suggest that PIWAS provides a powerful new tool to discover disease-associated serological antigens within any known proteome.


Assuntos
Autoantígenos/imunologia , Autoimunidade , Epitopos Imunodominantes , Lúpus Eritematoso Sistêmico/imunologia , Proteoma , Proteômica , Síndrome de Sjogren/imunologia , Autoanticorpos/sangue , Autoantígenos/genética , Autoantígenos/metabolismo , Estudos de Casos e Controles , Simulação por Computador , Bases de Dados de Proteínas , Ensaio de Imunoadsorção Enzimática , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Biblioteca de Peptídeos , Reprodutibilidade dos Testes , Testes Sorológicos , Síndrome de Sjogren/sangue , Síndrome de Sjogren/genética
17.
Clin Immunol ; 228: 108755, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33984497

RESUMO

Platelet-bound complement activation products (PC4d) are associated with thrombosis in Systemic Lupus Erythematosus (SLE). This study investigated the effect of PC4d on platelet function, as a mechanistic link to arterial thrombosis. In a cohort of 150 SLE patients, 13 events had occurred within five years of enrollment. Patients with arterial events had higher PC4d levels (13.6 [4.4-24.0] vs. 4.0 [2.5-8.3] net MFI), with PC4d 10 being the optimal cutoff for event detection. The association of arterial events with PC4d remained significant after adjusting for antiphospholipid status, smoking, and prednisone use (p = 0.045). PC4d levels correlated with lower platelet counts (r = -0.26, p = 0.002), larger platelet volumes (r = 0.22, p = 0.009) and increased platelet aggregation: the adenosine diphosphate (ADP) concentration to achieve 50% maximal aggregation (EC50) was lower in patients with PC4d 10 compared with PC4d < 10 (1.6 vs. 3.7, p = 0.038, respectively). These results suggest that PC4d may be a mechanistic marker for vascular disease in SLE.


Assuntos
Plaquetas/metabolismo , Ativação do Complemento/imunologia , Complemento C4/imunologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/metabolismo , Ativação Plaquetária/genética , Doenças Vasculares/etiologia , Difosfato de Adenosina/metabolismo , Autoanticorpos/imunologia , Autoimunidade , Biomarcadores , Plaquetas/imunologia , Complemento C4/metabolismo , Suscetibilidade a Doenças , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Ativação Plaquetária/imunologia , Agregação Plaquetária , Contagem de Plaquetas , Trombose/etiologia , Trombose/metabolismo , Doenças Vasculares/metabolismo
18.
Medicine (Baltimore) ; 100(21): e25985, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032713

RESUMO

ABSTRACT: Cytopenias in systemic lupus erythematosus (SLE) require clinical and laboratory workup and bone marrow (BM) examination to determine the cause and for appropriate patient management. Common causes include an increase in SLE activity, immune-mediated hemolysis, iron deficiency, antiphospholipid antibody syndrome, infection, or the effect of medications. We retrospectively evaluated the clinical and laboratory findings of patients with SLE and cytopenias who had undergone BM studies to determine the indicators of malignancy.We retrospectively reviewed medical records of patients with SLE who presented with cytopenias for their disease course, medications, laboratory parameters and documented the spectrum of morphological changes in BM including CD34 expression.Twenty patients with SLE had undergone BM biopsy for evaluation of cytopenias. 14/20 (70%) of the patients had reactive BM, and the rest had hematologic malignancies involving the BM. Of these 14 patients, 8 had hypocellular marrow with loss of precursor cells (low CD34), 4 had left shift in myeloid lineage, 3 had serous atrophy, and 1had multilineage dysplasia. The 6 patients with hematologic malignancies included 2 with diffuse large B cell lymphoma, and one each of natural killer/T cell lymphoma, post-transplant lymphoproliferative disorder, Hodgkin lymphoma, and myelodysplastic syndrome evolving to acute myelogenous leukemia. The presence of autoantibodies, SLE activity, and lupus nephritis were comparable in patients with and without neoplasia. However, the duration of the use of multiple immunosuppressants, years since renal transplant (22 vs 10), multiple transplants, and the presence of other autoimmune diseases were greater in those with neoplasia. Two of the 14 patients with non-neoplastic BM and 1 with the neoplastic BM had nonhematological malignancy.Clinical and laboratory findings, the number of transplants, and the use of immunosuppressive agents can guide physicians to identify patients with a higher risk of developing hematologic malignancy. BM findings of cytopenia in SLE are often due to increased disease activity causing global cell death and dysmaturation. SLE patients presenting with cytopenias, with a history of long-term exposure to immunosuppressive drugs, should be regularly screened for hematologic and nonhematologic malignancies.


Assuntos
Neoplasias Hematológicas/epidemiologia , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Leucopenia/diagnóstico , Lúpus Eritematoso Sistêmico/complicações , Trombocitopenia/diagnóstico , Adulto , Idoso , Biópsia/estatística & dados numéricos , Medula Óssea/patologia , Exame de Medula Óssea/estatística & dados numéricos , Suscetibilidade a Doenças , Feminino , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Humanos , Transplante de Rim/estatística & dados numéricos , Leucopenia/sangue , Leucopenia/imunologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Trombocitopenia/sangue , Trombocitopenia/imunologia , Adulto Jovem
19.
Medicine (Baltimore) ; 100(18): e25591, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950936

RESUMO

INTRODUCTION: Intravenous immunoglobulin (IVIg) is currently used with considerable success for the treatment of many autoimmune diseases, including systemic lupus erythematosus (SLE). Among its various indications, IVIg has also been found to be beneficial in myocarditis, whether or not it is associated with an autoimmune disease. Nevertheless, data regarding IVIg treatment for myocarditis/cardiomyopathy in patients with SLE are sparse. The objective of this case series was to describe our experience with IVIg as a treatment for lupus myocarditis and to review the literature for IVIg for this indication. PATIENT CONCERNS: We report 5 female patients with SLE, who presented with signs of acute heart failure including pulmonary congestion and arrhythmias. DIAGNOSIS: Echocardiography demonstrated new reduced left ventricular ejection fraction of 20% to 30%. Two patients underwent coronary artery angiography, which demonstrated normal coronary arteries, supporting the diagnosis of myocarditis or nonischemic cardiomyopathy. INTERVENTIONS: High-dose IVIg treatment was initiated in all 5 patients. OUTCOMES: Following the treatment, clinical and echocardiographic improvement in cardiac function occurred within a few days to 1 month. This dramatic improvement persisted for several years. CONCLUSION: Based on our case series, we believe that IVIg has an important role in the management of lupus acute cardiomyopathy. This safe, well-tolerated optional treatment should be considered, especially in severe cases.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Imunoglobulinas Intravenosas/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Miocardite/tratamento farmacológico , Disfunção Ventricular Esquerda/tratamento farmacológico , Doença Aguda/terapia , Adulto , Angiografia Coronária , Relação Dose-Resposta a Droga , Ecocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/imunologia , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Pessoa de Meia-Idade , Miocardite/diagnóstico , Miocardite/imunologia , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/imunologia
20.
Medicine (Baltimore) ; 100(18): e25779, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950971

RESUMO

RATIONALE: Systemic lupus erythematosus (SLE) is an important cause of stroke, more than a half the cases present as acute ischemic stroke. Thrombolysis is an effective choice in most cases, but for large vessel occlusion, mechanical thrombectomy is more effective. Here we reported a case of SLE-related stroke with left middle cerebral artery (MCA) occlusion, who was successfully treated by MT and tirofiban. PATIENT CONCERN: A 38-year-old female suffered from right hemiplegia and aphasia for 8 hours. She was diagnosed with SLE 20 years ago, and neuropsychiatric SLE was considered 8 months before this onset. One month ago, glucocorticoids were discontinued by herself because of deterioration of bilateral femoral head osteonecrosis. DIAGNOSIS: Left MCA occlusion was confirmed by computed tomography perfusion. INTERVENTION: Immediate mechanical thrombectomy was performed and tirofiban was given to prevent re-occlusion of left MCA. Twenty fourhours later oral antiplatelet was given after intracranial hemorrhage was ruled out. OUTCOMES: Her neurological symptom improved several days later, and she was transferred to further rehabilitation. At 4 months follow-up she can live independently with mild hypophrasia. There was no further events of ischemic stroke in 1-year follow-up. LESSONS: Mechanical thrombectomy is a highly effective and indispensable treatment for SLE related large vessel occlusion. In addition, tirofiban may reduce vessel reocclusion in special cases such as SLE and artery stenosis.


Assuntos
Infarto da Artéria Cerebral Média/terapia , Lúpus Eritematoso Sistêmico/complicações , Trombectomia/métodos , AVC Trombótico/terapia , Tirofibana/administração & dosagem , Adulto , Feminino , Humanos , Infarto da Artéria Cerebral Média/diagnóstico , Infarto da Artéria Cerebral Média/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/cirurgia , Imagem de Perfusão , AVC Trombótico/diagnóstico , AVC Trombótico/imunologia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
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