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1.
Yonsei Med J ; 61(11): 951-957, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33107238

RESUMO

PURPOSE: To compare the clinical characteristics and renal outcomes between patients who initially had lupus nephritis (LN) at the onset of systemic lupus erythematosus (SLE) (initial-onset LN) and those who developed LN within 5 years after SLE onset (early-onset LN). MATERIALS AND METHODS: SLE patients with biopsy-proven LN were retrospectively reviewed. The clinical parameters and renal outcomes were compared between initial-onset and early-onset LN groups. We used Cox regression analysis to estimate risk of worse renal outcomes according to the onset time of LN. RESULTS: Of all 136 LN patients, 92 (67.6%) and 44 (32.4%) patients were classified into the initial-onset and early-onset LN groups, respectively. The initial-onset LN group had higher prevalences of class IV LN (54.3% vs. 34.1%, p=0.027), impaired renal function (34.8% vs. 11.4%, p=0.004), microscopic hematuria (73.9% vs. 54.5%, p=0.024), and higher urine protein/creatinine ratio [4626.1 (2180.0-6788.3) mg/g vs. 2410.0 (1265.0-5168.5) mg/g, p=0.006] at LN diagnosis. Renal relapse (46.3% vs. 25.7%, p=0.039) and progression to chronic kidney disease (CKD) or end-stage renal disease (ESRD) were more common (24.4% vs. 8.3%, p=0.042) in the initial-onset LN group. In Cox regression analysis, the initial-onset LN group had higher risks of renal relapse [adjusted hazard ratio (HR) 3.56, 95% confidence interval (CI) 1.51-8.35, p=0.004] and progression to CKD or ESRD (adjusted HR 4.57, 95% CI 1.03-20.17, p=0.045), compared with the early-onset LN group. CONCLUSION: Patients with LN at SLE onset may have more severe renal presentations and experience worse renal outcomes than those who develop LN within 5 years.


Assuntos
Falência Renal Crônica/etiologia , Rim/fisiopatologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/patologia , Adulto , Biópsia , Progressão da Doença , Feminino , Humanos , Lúpus Eritematoso Sistêmico/terapia , Nefrite Lúpica/complicações , Nefrite Lúpica/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Adulto Jovem
2.
Medicine (Baltimore) ; 99(31): e21467, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756168

RESUMO

BACKGROUND: This study aimed to evaluate the scleral thickness and corneal parameters of patients with systemic lupus erythematosus (SLE). METHODS: Forty-seven eyes of 47 SLE patients and 44 eyes of healthy controls were included in this cross-sectional study. Anterior segment optical coherence tomography (AS-OCT) was used to measure the corneal and scleral thickness. Scleral thickness (ST) was measured based upon the segmentation at 1000 to 5000 µm from the scleral spur. Pentacam HR was used to measure corneal parameters. RESULTS: There was no statistically significant difference between SLE group and control group according to age and sex (P > .05). The ST measurements at all distances from scleral spur were found to be thicker in patients with SLE (P < .05). Central corneal thickness (CCT), cornea volume (CV), corneal densitometry (CD), and peripheral corneal thickness (PCT) measurements were similar between the groups (P > .05). CONCLUSION: ST was thicker in SLE patients compared with healthy controls. AS-OCT seems helpful in selecting optimal sites for pharmaceutical or surgical intervention in SLE patients, since it shows thickness variations in anterior sclera.


Assuntos
Córnea/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/complicações , Esclera/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Adulto , Estudos de Casos e Controles , Córnea/patologia , Paquimetria Corneana/métodos , Estudos Transversais , Densitometria , Feminino , Voluntários Saudáveis , Humanos , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Esclera/patologia , Turquia/epidemiologia
3.
PLoS One ; 15(6): e0234813, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555638

RESUMO

BACKGROUND: Autoimmune conditions (AICs) and/or their treatment may alter risk of human papilloma virus (HPV) infection and females with AICs are therefore at an increased risk of cervical dysplasia. However, inclusion of these at-risk populations in cervical cancer screening and HPV-vaccination guidelines, are mostly lacking. This study aimed to determine the prevalence of cervical dysplasia in a wide range of AICs and compare that to HIV and immunocompetent controls to support the optimisation of cervical cancer preventive health measures. METHODS: Data linkage was used to match cervical screening episodes to emergency department records of females with AICs or HIV to immunocompetent controls over a 14-year period. The primary outcome was histologically confirmed high-grade cervical disease. Results, measured as rates by cytology and histology classification per 1,000 females screened, were analysed per disease group, and intergroup comparisons were performed. RESULTS: Females with inflammatory bowel disease (2,683), psoriatic and enteropathic arthropathies (1,848), multiple sclerosis (MS) (1,426), rheumatoid arthritis (1,246), systemic lupus erythematosus and/or mixed connective tissue disease (SLE/MCTD) (702), HIV (44), and 985,383 immunocompetent controls were included. SLE/MCTD and HIV groups had greater rates of high-grade histological and cytological abnormalities compared to controls. Increased rates of low-grade cytological abnormalities were detected in all females with AICs, with the exception of the MS group. CONCLUSIONS: Females with SLE/MCTD or HIV have increased rates of high-grade cervical abnormalities. The increased low-grade dysplasia rate seen in most females with AICs is consistent with increased HPV infection. These findings support expansion of cervical cancer preventative programs to include these at-risk females.


Assuntos
Doenças Autoimunes/patologia , Displasia do Colo do Útero/patologia , Adulto , Artrite Reumatoide/complicações , Artrite Reumatoide/patologia , Austrália/epidemiologia , Doenças Autoimunes/complicações , Bases de Dados Factuais , Feminino , Infecções por HIV/complicações , Infecções por HIV/patologia , Humanos , Imunocompetência , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/patologia , Pessoa de Meia-Idade , Gradação de Tumores , Prevalência , Fatores de Risco , Displasia do Colo do Útero/complicações , Displasia do Colo do Útero/epidemiologia
4.
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
5.
Ann Intern Med ; 172(11): ITC81-ITC96, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32479157

RESUMO

Systemic lupus erythematosus (lupus) is characterized by aberrant activity of the immune system, leading to variable clinical symptoms. Lupus is more prevalent in African American women and women in other ethnic minority groups. Diagnosing, treating, and identifying novel therapies for lupus is challenging because of its genetic and phenotypic heterogeneity. Lupus nephritis is the most common target-organ manifestation and requires individualized care to minimize toxicity. A multidisciplinary approach to caring for pregnant patients with lupus is essential to optimize outcomes.


Assuntos
Lúpus Eritematoso Sistêmico/diagnóstico , Diagnóstico Diferencial , Humanos , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/terapia
6.
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
7.
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
8.
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
9.
Am J Clin Pathol ; 154(2): 215-224, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32367142

RESUMO

OBJECTIVES: Kikuchi-Fujimoto disease (KFD) and systemic lupus erythematosus (SLE) are benign entities with histologic features that raise concern about malignancy and infection. We searched for a histology-independent KFD/SLE signature relying on only immunophenotype and basic clinical characteristics. METHODS: A histology-independent KFD/SLE signature was generated using 975 excised lymph nodes with flow immunophenotyping, including 16 cases of KFD/SLE. This signature was then evaluated in 1,198 fine-needle aspiration (FNA) specimens. RESULTS: The top flow cytometry discriminant for KFD/SLE was uniform CD38+ expression on CD19+ events. Immunohistochemistry demonstrated nodules of IgD+, IgM- B cells surrounding necrotizing and activated T-cell areas. A signature combining 6 flow cytometry criteria with age and sample site had a positive predictive value of 88% for KFD/SLE, which had a prevalence of 1.6%. All 4 signature-positive FNA cases with follow-up excision were KFD/SLE. At a second institution, 4 of 5 KFD/SLE cases passed the top discriminant. CONCLUSIONS: A flow cytometry signature combined with age and biopsy site identifies KFD/SLE independent of histology, suggesting a shared immune composition and independently confirming that KFD/SLE represents a distinct entity. Unexpectedly, an IgD+CD38+ small B-cell population is a distinctive feature of KFD/SLE, suggesting a possible pathologic role for anergic/autoreactive B cells.


Assuntos
Linfadenite Histiocítica Necrosante/diagnóstico , Lúpus Eritematoso Sistêmico/patologia , Linfonodos/patologia , Linfadenite/diagnóstico , Linfadenopatia/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Linfadenite Histiocítica Necrosante/patologia , Humanos , Imunofenotipagem , Linfadenite/patologia , Linfadenopatia/patologia , Masculino
10.
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
11.
Am J Physiol Renal Physiol ; 318(5): F1258-F1270, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249615

RESUMO

B lymphocyte hyperactivity plays a pathogenic role in systemic lupus erythematosus (SLE), and spliced X box-binding protein 1 (XBP1s) has been implicated in B cell maturation and differentiation. We hypothesized that blockade of the XBP1s pathway inhibits the B cell hyperactivity underlying SLE and lupus nephritis (LN) development. In the present study, we systematically evaluated the changes in B cell activation induced by the Xbp1 splicing inhibitor STF083010 in a pristane-induced lupus mouse model. The lupus mouse model was successfully established, as indicated by the presence of LN with markedly increased urine protein levels, renal deposition of Ig, and mesangial cell proliferation. In lupus mice, B cell hyperactivity was confirmed by increased CD40 and B cell-activating factor levels. B cell activation and plasma cell overproduction were determined by increases in CD40-positive and CD138-positive cells in the spleens of lupus mice by flow cytometry and further confirmed by CD45R and Ig light chain staining in the splenic tissues of lupus mice. mRNA and protein expression of XBP1s in B cells was assessed by real-time PCR, Western blot analysis, and immunofluorescence analysis and was increased in lupus mice. In addition, almost all changes were reversed by STF083010 treatment. However, the expression of XBP1s in the kidneys did not change when mice were exposed to pristane and STF083010. Taken together, these findings suggest that expression of XBP1s in B cells plays key roles in SLE and LN development. Blockade of the XBP1s pathway may be a potential strategy for SLE and LN treatment.


Assuntos
Linfócitos B/metabolismo , Rim/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/metabolismo , Ativação Linfocitária , Baço/metabolismo , Terpenos , Proteína 1 de Ligação a X-Box/metabolismo , Animais , Autoanticorpos/sangue , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Imunoglobulina G/sangue , Rim/efeitos dos fármacos , Rim/patologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Transdução de Sinais , Baço/efeitos dos fármacos , Baço/patologia , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Proteína 1 de Ligação a X-Box/antagonistas & inibidores , Proteína 1 de Ligação a X-Box/genética
12.
Medicine (Baltimore) ; 99(16): e19875, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32312013

RESUMO

INTRODUCTION: Systemic lupus erythematosus (SLE) is a multisystem, chronic, autoimmune disease which can affect any organ system including the eye. About one-third of the patients can be diagnosed with SLE-related eye involvement which is usually indicative of disease activity. Retinopathy is one of the most vision-threatening complications that can be associated with the disease. PATIENT CONCERNS: An 11-year-old girl was hospitalized with complains of repeated swelling and pain in her extremities for 1 month, chest pain for 24 days, rash for 5 days and proteinuria for 1 day. On the morning of her fourth day in hospital, she suddenly complained of sudden, painless vision loss in the left eye. The ophthalmologist found that she had obstruction of central retinal vein and artery with diffuse retinal hemorrhages and macular edema. DIAGNOSIS: The patient was diagnosed with systemic lupus erythematosus, lupus nephritis, and lupus retinopathy through her clinical manifestations and laboratory tests. INTERVENTIONS: After diagnosis, she received steroid therapy, retinal laser photocoagulation, and intravitreal injection of dexamethasone (OZURDEX, Allergan Pharmaceuticals, Dublin, Ireland) early in her course. OUTCOMES: At the latest follow-up, her vision improved partially. However, she still has the possibility of subsequent neovascular glaucoma and bleeding in the future. CONCLUSIONS: An early diagnosis and the prompt therapeutic measures are necessary to prevent sight-threatening consequences, especially in pediatric patients with SLE.


Assuntos
Lúpus Eritematoso Sistêmico/complicações , Doenças Retinianas/etiologia , Doenças Retinianas/terapia , Transtornos da Visão/etiologia , Criança , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Feminino , Glaucoma Neovascular/epidemiologia , Glaucoma Neovascular/etiologia , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Hemorragia , Humanos , Injeções Intravítreas , Fotocoagulação a Laser/métodos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/complicações , Nefrite Lúpica/diagnóstico , Edema Macular , Oclusão da Artéria Retiniana/diagnóstico , Oclusão da Artéria Retiniana/etiologia , Doenças Retinianas/patologia , Oclusão da Veia Retiniana/diagnóstico , Oclusão da Veia Retiniana/etiologia , Resultado do Tratamento
13.
Nat Rev Rheumatol ; 16(5): 255-267, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32203285

RESUMO

Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus that can lead to irreversible renal impairment. Although the prognosis of LN has improved substantially over the past 50 years, outcomes have plateaued in the USA in the past 20 years as immunosuppressive therapies have failed to reverse disease in more than half of treated patients. This failure might reflect disease complexity and heterogeneity, as well as social and economic barriers to health-care access that can delay intervention until after damage has already occurred. LN progression is still poorly understood and involves multiple cell types and both immune and non-immune mechanisms. Single-cell analysis of intrinsic renal cells and infiltrating cells from patients with LN is a new approach that will help to define the pathways of renal injury at a cellular level. Although many new immune-modulating therapies are being tested in the clinic, the development of therapies to improve regeneration of the injured kidney and to prevent fibrosis requires a better understanding of the mechanisms of LN progression. This mechanistic understanding, together with the development of clinical measures to evaluate risk and detect early disease and better access to expert health-care providers, should improve outcomes for patients with LN.


Assuntos
Rim/citologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/complicações , Biomarcadores/análise , Ensaios Clínicos como Assunto , Progressão da Doença , Diagnóstico Precoce , Fibrose/prevenção & controle , Acesso aos Serviços de Saúde/estatística & dados numéricos , Humanos , Imunossupressores/uso terapêutico , Rim/lesões , Rim/metabolismo , Rim/patologia , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/prevenção & controle , Lúpus Eritematoso Sistêmico/epidemiologia , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Prognóstico , Regeneração/efeitos dos fármacos , Regeneração/fisiologia , Fatores Socioeconômicos , Estados Unidos/epidemiologia
14.
PLoS One ; 15(3): e0229184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32182251

RESUMO

Traditional cardiovascular disease (CVD) risk factors, such as hypertension, dyslipidemia and diabetes do not explain the increased CVD burden in systemic lupus erythematosus (SLE). The oxidized-LDL receptor, LOX-1, is an inflammation-induced receptor implicated in atherosclerotic plaque formation in acute coronary syndrome, and here we evaluated its role in SLE-associated CVD. SLE patients have increased sLOX-1 levels which were associated with elevated proinflammatory HDL, oxLDL and hsCRP. Interestingly, increased sLOX-1 levels were associated with patients with early disease onset, low disease activity, increased IL-8, and normal complement and hematological measures. LOX-1 was increased on patient-derived monocytes and low-density granulocytes, and activation with oxLDL and immune-complexes increased membrane LOX-1, TACE activity, sLOX-1 release, proinflammatory cytokine production by monocytes, and triggered the formation of neutrophil extracellular traps which can promote vascular injury. In conclusion, perturbations in the lipid content in SLE patients' blood activate LOX-1 and promote inflammatory responses. Increased sLOX-1 levels may be an indicator of high CVD risk, and blockade of LOX-1 may provide a therapeutic opportunity for ameliorating atherosclerosis in SLE patients.


Assuntos
Doenças Cardiovasculares/etiologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Receptores Depuradores Classe E/fisiologia , Adulto , Aterosclerose/sangue , Aterosclerose/complicações , Doenças Cardiovasculares/sangue , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Inflamação/sangue , Inflamação/complicações , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Receptores Depuradores Classe E/sangue , Adulto Jovem
16.
Proc Natl Acad Sci U S A ; 117(10): 5409-5419, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32094169

RESUMO

Type III IFN lambdas (IFN-λ) have recently been described as important mediators of immune responses at barrier surfaces. However, their role in autoimmune diseases such as systemic lupus erythematosus (SLE), a condition characterized by aberrant type I IFN signaling, has not been determined. Here, we identify a nonredundant role for IFN-λ in immune dysregulation and tissue inflammation in a model of TLR7-induced lupus. IFN-λ protein is increased in murine lupus and IFN-λ receptor (Ifnlr1) deficiency significantly reduces immune cell activation and associated organ damage in the skin and kidneys without effects on autoantibody production. Single-cell RNA sequencing in mouse spleen and human peripheral blood revealed that only mouse neutrophils and human B cells are directly responsive to this cytokine. Rather, IFN-λ activates keratinocytes and mesangial cells to produce chemokines that induce immune cell recruitment and promote tissue inflammation. These data provide insights into the immunobiology of SLE and identify type III IFNs as important factors for tissue-specific pathology in this disease.


Assuntos
Interferons/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Animais , Linfócitos B/imunologia , Linhagem Celular , Deleção de Genes , Humanos , Imiquimode/farmacologia , Inflamação/imunologia , Inflamação/patologia , Indutores de Interferon/farmacologia , Interferon Tipo I/fisiologia , Interferons/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Queratinócitos/patologia , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/imunologia , Células Mesangiais/patologia , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Receptores de Interferon/genética , Transdução de Sinais , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/fisiologia
18.
Surg Pathol Clin ; 13(1): 165-188, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32005430

RESUMO

Patients with connective tissue diseases may have pulmonary involvement, including interstitial lung disease. Various patterns of interstitial lung disease have been classically described in certain connective tissue diseases. It is now recognized that there is significant overlap between patterns of interstitial lung disease observed in the various connective tissue diseases. Differentiating idiopathic from connective tissue disease-related interstitial lung disease is challenging but of clinical importance. New concepts in the diagnosis of connective tissue disease related interstitial lung disease may prove useful in making the diagnosis.


Assuntos
Doenças do Tecido Conjuntivo/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/patologia , Doenças do Tecido Conjuntivo/patologia , Dermatomiosite/diagnóstico , Dermatomiosite/patologia , Diagnóstico Diferencial , Humanos , Pulmão/patologia , Doenças Pulmonares Intersticiais/patologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/patologia , Doença Mista do Tecido Conjuntivo/diagnóstico , Doença Mista do Tecido Conjuntivo/patologia , Polimiosite/diagnóstico , Polimiosite/patologia , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/patologia , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/patologia
19.
Nat Med ; 26(4): 618-629, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32094927

RESUMO

Responses to vaccination and to diseases vary widely across individuals, which may be partly due to baseline immune variations. Identifying such baseline predictors of immune responses and their biological basis is of broad interest, given their potential importance for cancer immunotherapy, disease outcomes, vaccination and infection responses. Here we uncover baseline blood transcriptional signatures predictive of antibody responses to both influenza and yellow fever vaccinations in healthy subjects. These same signatures evaluated at clinical quiescence are correlated with disease activity in patients with systemic lupus erythematosus with plasmablast-associated flares. CITE-seq profiling of 82 surface proteins and transcriptomes of 53,201 single cells from healthy high and low influenza vaccination responders revealed that our signatures reflect the extent of activation in a plasmacytoid dendritic cell-type I IFN-T/B lymphocyte network. Our findings raise the prospect that modulating such immune baseline states may improve vaccine responsiveness and mitigate undesirable autoimmune disease activity.


Assuntos
Imunidade Adaptativa/genética , Formação de Anticorpos/genética , Vacinas contra Influenza/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Transcriptoma , Vacina contra Febre Amarela/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Influenza Humana/prevenção & controle , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Transcriptoma/imunologia , Vacinação , Febre Amarela/prevenção & controle , Adulto Jovem
20.
J Immunol ; 204(5): 1091-1100, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31988182

RESUMO

Almost a decade has passed since the approval of belimumab, an mAb directed against B lymphocyte stimulation and the first targeted therapy approved for systemic lupus erythematous (SLE) in over 50 y. Although well tolerated, the efficacy of belimumab remains limited and is not labeled for patients suffering from nephritis, the leading cause of patient mortality. We sought to explore alternative targets of autoreactive B lymphocytes through manipulation of affinity maturation. The BXSB/MpJ mouse, a well-established model of human SLE, develops elevated antinuclear Abs and immune complex-mediated nephritis along with other manifestations of SLE-like disease. To limit interfering with critical background genetics, we used CRISPR-Cas9 to disrupt activation-induced cytidine deaminase (AID; Aicda) directly in BXSB zygotes. Homozygous null mice demonstrated significantly prolonged survival compared with wild-type. Although mice continued to develop plasma cells, splenic follicular structure was restored, and renal pathology was reduced. Mice developed expanded germinal center B lymphocyte populations as in other models of AID deficiency as well as increased populations of CD73+ B lymphocytes. Treatment with the small molecule inhibitor of RAD51, 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid, resulted in minimal changes in disease markers in BXSB mice. The prolonged survival in AID-deficient BXSB mice appears attributed primarily to the reduced renal pathology, warranting further exploration, as current therapeutics targeting lupus nephritis are limited and, thus, in great demand.


Assuntos
Subpopulações de Linfócitos B/imunologia , Citidina Desaminase/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Animais , Subpopulações de Linfócitos B/patologia , Sistemas CRISPR-Cas , Citidina Desaminase/genética , Modelos Animais de Doenças , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Knockout
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