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1.
Medicine (Baltimore) ; 99(35): e21888, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871918

RESUMO

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with considerable genetic predisposition. Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) is crucial for the innate immunity and implicated in SLE pathogenesis. Accordingly, we conducted a case-control study to find the association of NLRP3 variations with SLE susceptibility and disease activity.Three single nucleotide polymorphisms of NLRP3 (rs3806268, rs4612666, and rs10754558) were genotyped in 400 SLE patients and 400 healthy controls; the patients were further divided into mild-to-moderate or high disease activity subgroup. Serum cytokines, complements, and autoantibodies were also detected.We found that rs4612666 TT genotype conferred a higher risk of severe disease activity with adjusted odds ratio = 2.08, P = .02 and adjusted odds ratio  = 2.34, P = .01 in the codominant and recessive model, respectively. Nevertheless, there was no association between the 3 single nucleotide polymorphisms of NLRP3 gene and SLE susceptibility. In addition, C4 decreased significantly in rs3806268 GG (P < .001) and rs4612666 TT genotype carriers (P = .03). A higher trend of interleukin-1ß and interleukin-γ release were identified in rs3806268 AA and rs10754558 CC genotype carriers, respectively.NLRP3 polymorphisms are associated with SLE disease activity and hypocomplementemia. Interleukin-1ß and interleukin-γ levels in SLE patients are correlated with NLRP3 variants as well.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Complemento C4/metabolismo , Feminino , Estudos de Associação Genética , Humanos , Subunidade gama Comum de Receptores de Interleucina/sangue , Interleucina-1beta/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
2.
Nat Commun ; 11(1): 3294, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620744

RESUMO

Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of SLE variant accessibility and gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear antibodies characteristic of SLE. Of the ~400 potential regulatory variants identified, 90% exhibit spatial proximity to genes distant in the 1D genome sequence, including variants that loop to regulate the canonical TFH genes BCL6 and CXCR5 as confirmed by genome editing. SLE 'variant-to-gene' maps also implicate genes with no known role in TFH/SLE disease biology, including the kinases HIPK1 and MINK1. Targeting these kinases in TFH inhibits production of IL-21, a cytokine crucial for class-switched B cell antibodies. These studies offer mechanistic insight into the SLE-associated regulatory architecture of the human genome.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Linfócitos T Auxiliares-Indutores/metabolismo , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Células Cultivadas , Mapeamento Cromossômico/métodos , Perfilação da Expressão Gênica/métodos , Humanos , Células Jurkat , Lúpus Eritematoso Sistêmico/imunologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Interferência de RNA , Receptores CXCR5/genética , Linfócitos T Auxiliares-Indutores/imunologia
3.
Clin Rheumatol ; 39(9): 2811-2815, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32720260

RESUMO

In the midst of the COVID-19 pandemic, further understanding of its complications points towards dysregulated immune response as a major component. Systemic lupus erythematosus (SLE) is also a disease of immune dysregulation leading to multisystem compromise. We present a case of new-onset SLE concomitantly with COVID-19 and development of antiphospholipid antibodies. An 18-year-old female that presented with hemodynamic collapse and respiratory failure, progressed to cardiac arrest, and had a pericardial tamponade drained. She then progressed to severe acute respiratory distress syndrome, severe ventricular dysfunction, and worsening renal function with proteinuria and hematuria. Further studies showed bilateral pleural effusions, positive antinuclear and antidouble-stranded DNA antibodies, lupus anticoagulant, and anticardiolipin B. C3 and C4 levels were low. SARS-Cov-2 PCR was positive after 2 negative tests. She also developed multiple deep venous thrombosis, in the setting of positive antiphospholipid antibodies and lupus anticoagulant. In terms of pathophysiology, COVID-19 is believed to cause a dysregulated cytokine response which could potentially be exacerbated by the shift in Th1 to Th2 response seen in SLE. Also, it is well documented that viral infections are an environmental factor that contributes to the development of autoimmunity; however, COVID-19 is a new entity, and it is not known if it could trigger autoimmune conditions. Additionally, it is possible that SARS-CoV-2, as it happens with other viruses, might lead to the formation of antiphospholipid antibodies, potentially contributing to the increased rates of thrombosis seen in COVID-19.


Assuntos
Síndrome Antifosfolipídica/imunologia , Infecções por Coronavirus/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Pneumonia Viral/imunologia , Adolescente , Anemia/etiologia , Anticorpos Anticardiolipina/imunologia , Anticorpos Antinucleares/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/terapia , Anuria/etiologia , Betacoronavirus , Tamponamento Cardíaco/diagnóstico por imagem , Tamponamento Cardíaco/etiologia , Tamponamento Cardíaco/terapia , Complemento C3/imunologia , Complemento C4/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , DNA/imunologia , Ecocardiografia , Evolução Fatal , Feminino , Parada Cardíaca/etiologia , Hematúria/etiologia , Humanos , Inibidor de Coagulação do Lúpus/imunologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Pandemias , Posicionamento do Paciente , Pericardiocentese , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Decúbito Ventral , Proteinúria/etiologia , Diálise Renal , Insuficiência Renal/etiologia , Insuficiência Renal/terapia , Respiração Artificial , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome do Desconforto Respiratório do Adulto/terapia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Trombocitopenia/etiologia , Trombose Venosa/etiologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia
4.
PLoS One ; 15(7): e0236664, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722684

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a severe autoimmune disease in which immune tolerance defects drive production of pathogenic anti-nuclear autoantibodies. Anergic B cells are considered a potential source of these autoantibodies due to their autoreactivity and overrepresentation in SLE patients. Studies of lupus-prone mice have shown that genetic defects mediating autoimmunity can breach B cell anergy, but how this breach occurs with regards to endogenous nuclear antigen remains unclear. We investigated whether B and T cell defects in congenic mice (c1) derived from the lupus-prone New Zealand Black strain can breach tolerance to nuclear self-antigen in the presence of knock-in genes (Vκ8/3H9; dKI) that generate a ssDNA-reactive, anergic B cell population. METHODS: Flow cytometry was used to assess splenic B and T cells from 8-month-old c1 dKI mice and serum autoantibodies were measured by ELISA. dKI B cells stimulated in vitro with anti-IgM were assessed for proliferation and activation by examining CFSE decay and CD86. Cytokine-producing T cells were identified by flow cytometry following culture of dKI splenocytes with PMA and ionomycin. dKI B cells from 6-8-week-old mice were adoptively transferred into 4-month-old wild type recipients and assessed after 7 days via flow cytometry and immunofluorescence microscopy. RESULTS: c1 dKI mice exhibited B cell proliferation indicative of impaired anergy, but had attenuated autoantibodies and germinal centres compared to wild type littermates. This attenuation appeared to stem from a decrease in PD-1hi T helper cells in the dKI strains, as c1 dKI B cells were recruited to germinal centres when adoptively transferred into c1 wild type mice. CONCLUSION: Anergic, DNA-specific autoreactive B cells only seem to drive profound autoimmunity in the presence of concomitant defects in the T cell subsets that support high-affinity plasma cell production.


Assuntos
Anticorpos Antinucleares/genética , Anticorpos Antifosfolipídeos/genética , Antígenos/imunologia , Linfócitos B/imunologia , Anergia Clonal , Lúpus Eritematoso Sistêmico/imunologia , Animais , Linfócitos B/citologia , Proliferação de Células , DNA de Cadeia Simples/imunologia , Suscetibilidade a Doenças , Técnicas de Introdução de Genes , Lúpus Eritematoso Sistêmico/genética , Camundongos
5.
J Investig Med High Impact Case Rep ; 8: 2324709620933438, 2020.
Artigo em Inglês | MEDLINE | ID: covidwho-535847

RESUMO

In this article, we present a case of a young female patient with previously diagnosed lupus pneumonitis, now with a flare and new superimposed COVID-19 infection that was treated with intravenous steroids. On computed tomography scans, she had extensive interstitial lung fibrosis in addition to a positive COVID-19 polymerase chain reaction test requiring 6 L of oxygen via nasal cannula on admission. After administration of methylprednisolone, the patient improved and was weaned off her oxygen requirements and was discharged home.


Assuntos
Infecções por Coronavirus/complicações , Lúpus Eritematoso Sistêmico/complicações , Pneumonia Viral/complicações , Pneumonia/complicações , Anticorpos Antinucleares/imunologia , Antirreumáticos/uso terapêutico , Betacoronavirus , Tamponamento Cardíaco , Complemento C3/imunologia , Complemento C4/imunologia , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , DNA , Progressão da Doença , Inibidores Enzimáticos/uso terapêutico , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Pulmão/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica , Linfopenia/etiologia , Metilprednisolona/uso terapêutico , Ácido Micofenólico/uso terapêutico , Oxigenoterapia , Pandemias , Pneumonia/diagnóstico por imagem , Pneumonia/imunologia , Pneumonia/terapia , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/terapia , Tomografia Computadorizada por Raios X , Adulto Jovem
6.
Adv Rheumatol ; 60(1): 32, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: covidwho-591986

RESUMO

Hydroxychloroquine and chloroquine, also known as antimalarial drugs, are widely used in the treatment of rheumatic diseases and have recently become the focus of attention because of the ongoing COVID-19 pandemic. Rheumatologists have been using antimalarials to manage patients with chronic immune-mediated inflammatory rheumatic diseases for decades. It is an appropriate time to review their immunomodulatory and anti-inflammatory mechanisms impact on disease activity and survival of systemic lupus erythematosus patient, including antiplatelet effect, metabolic and lipid benefits. We also discuss possible adverse effects, adding a practical and comprehensive approach to monitoring rheumatic patients during treatment with these drugs.


Assuntos
Antimaláricos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Cloroquina/farmacologia , Hidroxicloroquina/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/imunologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/imunologia , Infecções por Coronavirus/tratamento farmacológico , Erupção por Droga/etiologia , Interações Medicamentosas , Feminino , Glucose/metabolismo , Cardiopatias/induzido quimicamente , Humanos , Lipídeos/sangue , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Cutâneo/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/mortalidade , Masculino , Pandemias , Agregação Plaquetária/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Gravidez , Insuficiência Renal/prevenção & controle , Doenças Retinianas/induzido quimicamente , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/imunologia
7.
J Investig Med High Impact Case Rep ; 8: 2324709620933438, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32500773

RESUMO

In this article, we present a case of a young female patient with previously diagnosed lupus pneumonitis, now with a flare and new superimposed COVID-19 infection that was treated with intravenous steroids. On computed tomography scans, she had extensive interstitial lung fibrosis in addition to a positive COVID-19 polymerase chain reaction test requiring 6 L of oxygen via nasal cannula on admission. After administration of methylprednisolone, the patient improved and was weaned off her oxygen requirements and was discharged home.


Assuntos
Infecções por Coronavirus/complicações , Lúpus Eritematoso Sistêmico/complicações , Pneumonia Viral/complicações , Pneumonia/complicações , Anticorpos Antinucleares/imunologia , Antirreumáticos/uso terapêutico , Betacoronavirus , Tamponamento Cardíaco , Complemento C3/imunologia , Complemento C4/imunologia , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , DNA , Progressão da Doença , Inibidores Enzimáticos/uso terapêutico , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Pulmão/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica , Linfopenia/etiologia , Metilprednisolona/uso terapêutico , Ácido Micofenólico/uso terapêutico , Oxigenoterapia , Pandemias , Pneumonia/diagnóstico por imagem , Pneumonia/imunologia , Pneumonia/terapia , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/terapia , Tomografia Computadorizada por Raios X , Adulto Jovem
8.
Nat Commun ; 11(1): 2859, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503973

RESUMO

Mature double negative (DN) T cells are a population of αß T cells that lack CD4 and CD8 coreceptors and contribute to systemic lupus erythematosus (SLE). The splenic marginal zone macrophages (MZMs) are important for establishing immune tolerance, and loss of their number or function contributes to the progression of SLE. Here we show that loss of MZMs impairs the tolerogenic clearance of apoptotic cells and alters the serum cytokine profile, which in turn provokes the generation of DN T cells from self-reactive CD8+ T cells. Increased Ki67 expression, narrowed TCR V-beta repertoire usage and diluted T-cell receptor excision circles confirm that DN T cells from lupus-prone mice and patients with SLE undergo clonal proliferation and expansion in a self-antigen dependent manner, which supports the shared mechanisms for their generation. Collectively, our results provide a link between the loss of MZMs and the expansion of DN T cells, and indicate possible strategies to prevent the development of SLE.


Assuntos
Autoantígenos/imunologia , Interleucina-17/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Autoantígenos/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Tolerância Imunológica , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Subpopulações de Linfócitos T/metabolismo
9.
Autoimmun Rev ; 19(8): 102592, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32561462

RESUMO

INTRODUCTION: The aim of this narrative review is to provide an overview of the literature on the possible immunologic pathophysiology of psychiatric manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: A systematic search on PubMed was conducted. English studies with full text availability that investigated the correlation between blood-brain barrier (BBB) dysfunction, intrathecal synthesis of antibodies, antibodies, cytokines, chemokines, metalloproteinases, complement and psychiatric NPSLE manifestations in adults were included. RESULTS: Both transient BBB-dysfunction with consequent access of antibodies to the cerebrospinal fluid (CSF) and intrathecal synthesis of antibodies could occur in psychiatric NPSLE. Anti-phospholipid antibodies, anti-NMDA antibodies and anti-ribosomal protein p antibodies seem to mediate concentration dependent neuronal dysfunction. Interferon-α may induce microglial engulfment of neurons, direct neuronal damage and production of cytokines and chemokines in psychiatric NPSLE. Several cytokines, chemokines and matrix metalloproteinase-9 may contribute to the pathophysiology of psychiatric NPSLE by attracting and activating Th1-cells and B-cells. DISCUSSION: This potential pathophysiology may help understand NPSLE and may have implications for the diagnostic management and therapy of psychiatric NPSLE. However, the presented pathophysiological model is based on correlations between potential immunologic etiologies and psychiatric NPSLE that remain questionable. More research on this topic is necessary to further elucidate the pathophysiology of NPSLE.


Assuntos
Anticorpos , Barreira Hematoencefálica , Citocinas , Lúpus Eritematoso Sistêmico , Transtornos Mentais , Anticorpos/imunologia , Barreira Hematoencefálica/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Transtornos Mentais/etiologia , Transtornos Mentais/imunologia
10.
Adv Rheumatol ; 60(1): 32, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32517786

RESUMO

Hydroxychloroquine and chloroquine, also known as antimalarial drugs, are widely used in the treatment of rheumatic diseases and have recently become the focus of attention because of the ongoing COVID-19 pandemic. Rheumatologists have been using antimalarials to manage patients with chronic immune-mediated inflammatory rheumatic diseases for decades. It is an appropriate time to review their immunomodulatory and anti-inflammatory mechanisms impact on disease activity and survival of systemic lupus erythematosus patient, including antiplatelet effect, metabolic and lipid benefits. We also discuss possible adverse effects, adding a practical and comprehensive approach to monitoring rheumatic patients during treatment with these drugs.


Assuntos
Antimaláricos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Cloroquina/farmacologia , Hidroxicloroquina/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/imunologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/imunologia , Infecções por Coronavirus/tratamento farmacológico , Erupção por Droga/etiologia , Interações Medicamentosas , Feminino , Glucose/metabolismo , Cardiopatias/induzido quimicamente , Humanos , Lipídeos/sangue , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Cutâneo/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/mortalidade , Masculino , Pandemias , Agregação Plaquetária/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Gravidez , Insuficiência Renal/prevenção & controle , Doenças Retinianas/induzido quimicamente , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/imunologia
12.
Expert Opin Pharmacother ; 21(13): 1617-1628, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32511034

RESUMO

INTRODUCTION: SLE is increasingly recognized as an important risk factor for cardiovascular disease. Premature CAD and several other cardiac manifestations are resulting in significant morbidity and premature death among young and older adults. There is a considerable unmet need for developing specific guidelines toward the primary and secondary prevention of cardiovascular disease in SLE patients. AREAS COVERED: The authors describe the prevalence of various cardiovascular manifestations, associated with traditional and lupus-specific risk factors. They summarize the evidence behind various nonpharmacological and pharmacological options such as cardiac medications, antimalarials, anti-inflammatory, and immunosuppressant medications. EXPERT OPINION: There is considerable literature claiming that the traditional Framingham score used to calculate the risk in the general population would not clearly predict the 10-year risk among SLE patients as they do not include lupus-specific risk factors such as accelerated inflammation, immunometabolic changes, thrombosis, vasospasm, vasculitis, and endothelial dysfunction into account. Identifying potential risk factors among SLE patients and treating hyperlipidemia regardless of their risk scores may be the first step in reducing mortality. Blocking lupus-specific inflammatory pathways by targeting validated biomarkers of pathogenesis has great future potential and more studies are needed on their cardiovascular benefits.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antimaláricos/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Idoso , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/imunologia , Humanos , Inflamação , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Prevalência , Fatores de Risco
13.
Scand J Immunol ; 92(3): e12915, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32533866

RESUMO

Systemic lupus erythematosus is an autoimmune syndrome characterized by the development of autoantibodies to a wide range of antigens. Together with B cells, respective self-reactive T cells have an important contribution in disease progression as being responsible for inflammatory cytokines secretion, B cell activation and promoting amplification of the autoimmune response. Annexin A1 is expressed by many cell types and binds to phospholipids in a Ca2+ -dependent manner. Abnormal expression of annexin A1 was found on activated B and T cells in both murine and human autoimmunity suggesting its potential role as a therapeutic target. In the present study, we have investigated the possibility to suppress autoimmune manifestation in spontaneous mouse model of lupus using anti-annexin A1 antibody. Groups of lupus-prone MRL/lpr mice were treated with the anti-annexin A1 monoclonal antibody, and the disease activity and survival of the animals were following up. Flow cytometry, ELISA assays, and histological and immunofluorescence kidney analyses were used to determine the levels of Annexin A1 expression, cytokines, anti-dsDNA antibodies and kidney injuries. The administration of this monoclonal antibody to MRL/lpr mice resulted in suppression of IgG anti-dsDNA antibody production, modulated IL-10 secretion, decreased disease activity and prolonged survival compared with the control group.


Assuntos
Anexina A1/antagonistas & inibidores , Anexina A1/imunologia , Anticorpos Monoclonais/farmacologia , Fatores Imunológicos/farmacologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Animais , Autoanticorpos/imunologia , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Humanos , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , Proteinúria/etiologia , Proteinúria/urina , Baço/imunologia , Baço/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
14.
Medicine (Baltimore) ; 99(20): e20192, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443340

RESUMO

The aims of this study were to compare diagnostic value of anti-ribosomal P protein antibody (anti-P), anti-Smith antibody (anti-Sm), anti-double-stranded DNA antibody (anti-dsDNA), anti-nucleosome antibody (ANuA), and anti-histone antibody (AHA) for systemic lupus erythematosus (SLE) as well as explore the correlation between anti-P and SLE.A retrospective study was performed with 487 SLE patients, 235 non-SLE rheumatic diseases, and 124 healthy subjects from January 2015 to December 2018. Clinical manifestations, laboratory results and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2000 scores were analyzed between anti-P/+/ and anti-P/-/ patients. SPSS19.0 statistical software was used for data analysis.The sensitivities of anti-P, anti-Sm, anti-dsDNA, ANuA, and AHA in SLE were 31.6%, 20.7%, 45.0%, 27.9%, and 14.6%, and the specificities were 99.2%, 99.4%, 98.9%, 98.3%, and 96.7%, respectively. Only 27.9% of SLE had a single positive anti-P while the other 4 antibodies were all negative. There were significant differences in the age of onset, skin erythema, urinary protein, creatinine and serum IgG, IgM, C3, C4 between anti-P/+/ and anti-P/-/ patients (P < .05). When anti-Sjogren syndrome A antibody, anti-P were positive and anti-dsDNA was negative, the incidence of skin erythema was the highest (35.1%). Compared with anti-P/-/ patients, anti-P/+/ patients had higher SLEDAI scores (P < .001).Anti-P, anti-Sm, anti-dsDNA, ANuA, and AHA have high specificity but poor sensitivity in the diagnosis of SLE; combined detection can greatly improve the detection rate. Anti-P is more valuable in the diagnosis of SLE when other specific autoantibodies are negative. SLE patients with positive anti-P have an earlier onset age and are more prone to skin erythema, lupus nephritis as well as higher disease activity.


Assuntos
Autoanticorpos/sangue , Lúpus Eritematoso Sistêmico/imunologia , Proteínas de Membrana Transportadoras/imunologia , Proteínas Ribossômicas/imunologia , Adulto , Anticorpos Antinucleares/imunologia , DNA/antagonistas & inibidores , DNA/metabolismo , Eritema/imunologia , Eritema/patologia , Feminino , Histonas/antagonistas & inibidores , Histonas/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/imunologia , Masculino , Pessoa de Meia-Idade , Nucleossomos/metabolismo , Estudos Retrospectivos , Doenças Reumáticas/imunologia , Sensibilidade e Especificidade , Dermatopatias/epidemiologia
15.
J Nippon Med Sch ; 87(2): 100-103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32418941

RESUMO

A 39-year-old Japanese woman presented with a pruritic infiltrated erythematous plaque on the right cheek. Histopathologic analysis of the erythema showed dermal edema, separation of collagen bundles, and nodular perivascular and periadnexal infiltration of lymphocytes in the whole dermis, without epidermal changes. Alcian blue staining intensity was elevated between the collagen bundles, indicating dermal mucinosis. The nodular infiltrates consisted of CD3+ T cell clusters and CD20+ B cell clusters (ratio, approximately 3:1) and included numerous CD123+ cells, indicative of plasmacytoid dendritic cells. Blood analysis revealed serum antinuclear antibody at a titer of 1:160 (homogeneous, speckled pattern). Lupus erythematosus tumidus with pseudolymphomatous infiltrates was diagnosed. Hydroxychloroquine treatment partially improved symptoms; however, the addition of prednisolone was required for complete resolution. Lupus erythematosus tumidus is sometimes accompanied by pseudolymphomatous infiltrates. Dermal mucinosis and the presence of numerous plasmacytoid dendritic cells are useful in differentiating lupus erythematosus tumidus from pseudolymphoma.


Assuntos
Linfócitos B/patologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Pseudolinfoma/imunologia , Pseudolinfoma/patologia , Linfócitos T/patologia , Adulto , Antígenos CD20 , Linfócitos B/imunologia , Complexo CD3 , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Subunidade alfa de Receptor de Interleucina-3 , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Pseudolinfoma/tratamento farmacológico , Linfócitos T/imunologia
17.
Adv Exp Med Biol ; 1253: 185-207, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32445096

RESUMO

Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease that is characterized by dysregulated dendritic cells, T and B cells, and abundant autoantibodies. The pathogenesis of lupus remains unclear. However, increasing evidence has shown that environment factors, genetic susceptibilities, and epigenetic regulation contribute to abnormalities in the immune system. In the past decades, several risk gene loci have been identified, such as MHC and C1q. However, genetics cannot explain the high discordance of lupus incidence in homozygous twins. Environmental factor-induced epigenetic modifications on immune cells may provide some insight. Epigenetics refers to inheritable changes in a chromosome without altering DNA sequence. The primary mechanisms of epigenetics include DNA methylation, histone modifications, and non-coding RNA regulations. Increasing evidence has shown the importance of dysregulated epigenetic modifications in immune cells in pathogenesis of lupus, and has identified epigenetic changes as potential biomarkers and therapeutic targets. Environmental factors, such as drugs, diet, and pollution, may also be the triggers of epigenetic changes. Therefore, this chapter will summarize the up-to-date progress on epigenetics regulation in lupus, in order to broaden our understanding of lupus and discuss the potential roles of epigenetic regulations for clinical applications.


Assuntos
Epigênese Genética , Lúpus Eritematoso Sistêmico/genética , Autoanticorpos , Metilação de DNA , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia
18.
Scand J Immunol ; 92(4): e12894, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32428248

RESUMO

Systemic lupus erythematosus (SLE) is a heterogeneous rheumatic autoimmune disease. Genetic studies have identified up to 100 SLE risk loci. Many of these encode proteins of importance in the immune system, but the cellular and molecular mechanisms underlying these associations are still elusive. In this review, we will highlight some of the SLE risk loci where mechanistic insights have been achieved recently by linking genetic risk polymorphisms to cellular or molecular phenotypes important for the disease process.


Assuntos
Fenômenos Imunogenéticos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Humanos
19.
Clin Immunol ; 215: 108410, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-38673

RESUMO

Infection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specifically, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.


Assuntos
Infecções por Coronavirus/genética , Epigênese Genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Viremia/genética , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Antígeno CD11a/genética , Antígeno CD11a/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Citocinas/genética , Citocinas/imunologia , Metilação de DNA , Progressão da Doença , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Estresse Oxidativo/genética , Estresse Oxidativo/imunologia , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Ligação Proteica , Receptores KIR/genética , Receptores KIR/imunologia , Transdução de Sinais , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Viremia/complicações , Viremia/epidemiologia , Viremia/imunologia
20.
Scand J Immunol ; 92(1): e12884, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32243638

RESUMO

The programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an important host immunosuppression mechanism. Soluble PD-1 (sPD-1) and PD-L1 (sPD-L1) expression regulates co-inhibitory signals in autoimmune disorders. Here, we evaluated whether serum sPD-1 and sPD-L1 are involved in immune dysfunction and assessed its relationship with SLE. Blood samples were obtained from 130 patients with SLE and 44 healthy controls. Serum sPD-1 and sPD-L1 were tested by enzyme-linked immunosorbent assay (ELISA). Relevant immune parameters were analysed. Both serum sPD-1 and sPD-L1 were significantly higher in the SLE patients than in the controls. A series of severe disease clinical manifestations and laboratory features such as presence of decreased complement component 3, complement component 4 and SLEDAI >8 were associated with elevated sPD-1 and sPD-L1. Our study suggests that abnormal sPD-1 and sPD-L1 expression may be involved in the imbalance of immune regulation in SLE.


Assuntos
Antígeno B7-H1/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/patologia , Adulto , Biomarcadores/sangue , Complemento C3/análise , Complemento C4/análise , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino
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