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1.
Orv Hetil ; 161(31): 1293-1301, 2020 08.
Artigo em Húngaro | MEDLINE | ID: mdl-32750018

RESUMO

INTRODUCTION: Lupus nephritis is the most severe complication of systemic lupus erythematosus (SLE), its development and the effectiveness of immunosuppressive therapy substantially influence patients' quality of life and survival. AIM: In this retrospective observational investigation, the long term-outcome of patients with lupus nephritis, followed at the St. Margit Hospital Immunonephrological Outpatient Clinic, was evaluated. RESULTS: Between 1997 December 1 and 2019 April 30, 73 patients (age 33.7 ± 15 years, 82% female, 18% male) were under care with median observation of 119 [between 3-264] months. At diagnosis, eGFR showed 68 [7-120] ml/min, proteinuria was 2800 [23-16812] mg/day; 10 patients needed dialysis treatment acutely. Renal biopsy, performed in 68 patients, proved proliferative lupus nephritis in 55 and pure membranous lupus nephritis in 6 patients. Administering combined immunosuppressive therapy, complete remission was achieved in 50 and partial remission in 21 cases; one or repeated relapses developed in 28 subjects. Two patients, by the time they got under our care, had already required chronic dialysis, and in the long term, three more patients progressed to end-stage renal disease requiring renal replacement therapy. Renal function stabilized in all other participants, clinical activity of SLE, SLEDAI score, complement levels and immunserology results improved significantly. CONCLUSIONS: Lupus nephritis can be effectively treated by combined induction and prolonged maintenance immunosuppression, but to prevent progression of the disease, long-term care is necessary by co-operation of nephrologist and immunologist. To provide adequate prevention and therapy of the SLE's multiorgan involvement and also the potential complications of immunosuppression, multidisciplinary team is needed with all specialists who may facilitate these patients' complex care. For the long-term management of patients with lupus nephritis, the nephrologists have to be responsible, and the multidisciplinary teams also have to be under their direction. Orv Hetil. 2020; 161(31): 1293-1301.


Assuntos
Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Imunossupressores/administração & dosagem , Assistência de Longa Duração , Nefrite Lúpica/imunologia , Nefrite Lúpica/psicologia , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Estudos Retrospectivos , Resultado do Tratamento
2.
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
3.
PLoS One ; 15(5): e0233138, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32421738

RESUMO

Naringenin is flavonoid mainly found in citrus fruits which has shown several biological properties. In this work, we evaluated the therapeutic potential of the flavonoid Naringenin. Five-month-old B6.MRL-Faslpr/J lupus-prone mice were administered daily orally with Naringenin for seven months. We showed that Naringenin treatment at 50 or 100 mg/kg inhibited the splenomegaly and decreased the levels of anti-nuclear and anti-dsDNA autoantibodies. Furthermore, a reduction in serum concentration of TNF-α, IFN-γ and IL-6 was observed in the mice provided with Naringenin. Interestingly, serum levels of IL-10 increased. Naringenin decreased the frequency and absolute numbers of splenic effector memory T cells. Additionally, in order to be able to evaluate whether Naringenin prevented kidney damage, twelve-week-old MRL/MpJ-Faslpr/J mice, an accelerated lupus model, were orally administered with Naringenin at 100 mg/kg for six weeks. Surprisingly, Naringenin treatment prevented kidney damage and reduced the development of fibrosis similar to cyclophosphamide group. Moreover, Naringenin treatment increased the percentage of regulatory T cells in this aggressive model of lupus. Together, these results suggest a potential ability of Naringenin to reduce the autoimmunity in lupus-prone mice by modulation of T-cell subsets and cytokines profile that mitigate the development of important lupus clinical manifestations.


Assuntos
Citocinas/imunologia , Flavanonas/farmacologia , Memória Imunológica/efeitos dos fármacos , Nefrite Lúpica/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Animais , Modelos Animais de Doenças , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Masculino , Camundongos , Linfócitos T Reguladores/patologia
4.
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
5.
Transplant Proc ; 52(2): 614-618, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32057496

RESUMO

Renal transplantation is an ever-growing therapeutic option for patients with end-stage renal disease due to lupus nephritis. Outcomes for these patients are comparable to those of patients receiving renal transplantation for other causes. A known complication for these patients is recurrence of lupus nephritis in the renal graft (recurrent lupus nephritis [RLN]). Although disease severity at the time of recurrence is usually milder, a small number of cases have been reported to progress to allograft failure. There is a trend toward preemptive renal transplantation in patients with lupus nephritis, as more favorable outcomes have been observed with this treatment modality. While clinicians usually seek clinical remission of lupus prior to proceeding with renal transplantation, no guidelines are established regarding how often to check for serologic activity of lupus in patients with end-stage renal disease due to lupus nephritis and whether these serologic markers should be taken into account when deciding on the timing of transplantation. We present a case of early RLN co-occurring with acute cellular rejection 15 days after renal transplantation. The patient had been in clinical remission for more than 5 months prior to transplantation but had a rise in anti-double-stranded DNA antibody titers and a decrease in complement C3 level at the time of surgery. Although additional studies are needed to establish the extent to which serologic markers of lupus correlate with renal graft dysfunction, this case suggests hypocomplementemia and high double-stranded DNA antibody titers may be a risk factor for early RLN.


Assuntos
Anticorpos Antinucleares/sangue , Complemento C3/metabolismo , Transplante de Rim , Nefrite Lúpica/imunologia , Nefrite Lúpica/cirurgia , Rejeição de Enxerto , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/cirurgia , Nefrite Lúpica/patologia , Masculino , Recidiva , Fatores de Risco , Transplante Homólogo , Adulto Jovem
6.
Nat Rev Nephrol ; 16(2): 112-128, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31831877

RESUMO

Advances in single-cell technologies are transforming our understanding of cellular identity. For instance, the application of single-cell RNA sequencing and mass cytometry technologies to the study of immune cell populations in blood, secondary lymphoid organs and the renal tract is helping researchers to map the complex immune landscape within the kidney, define cell ontogeny and understand the relationship of kidney-resident immune cells with their circulating counterparts. These studies also provide insights into the interactions of immune cell populations with neighbouring epithelial and endothelial cells in health, and across a range of kidney diseases and cancer. These data have translational potential and will aid the identification of drug targets and enable better prediction of off-target effects. The application of single-cell technologies to clinical renal biopsy samples, or even cells within urine, will improve diagnostic accuracy and assist with personalized prognostication for patients with various kidney diseases. A comparison of immune cell types in peripheral blood and secondary lymphoid organs in healthy individuals and in patients with systemic autoimmune diseases that affect the kidney will also help to unravel the mechanisms that underpin the breakdown in self-tolerance and propagation of autoimmune responses. Together, these immune cell atlases have the potential to transform nephrology.


Assuntos
Lesão Renal Aguda/imunologia , Doenças Autoimunes/imunologia , Sistema Imunitário/citologia , Linfócitos/metabolismo , Insuficiência Renal Crônica/imunologia , Análise de Célula Única , Lesão Renal Aguda/genética , Lesão Renal Aguda/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Citometria de Fluxo , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/metabolismo , Transplante de Rim , Leucócitos/imunologia , Leucócitos/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Nefrite Lúpica/metabolismo , Linfócitos/imunologia , Pielonefrite/genética , Pielonefrite/imunologia , Pielonefrite/metabolismo , RNA-Seq , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Análise de Sequência de RNA
7.
Arthritis Rheumatol ; 72(1): 89-99, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31342656

RESUMO

OBJECTIVE: Long interspersed nuclear element 1 (LINE-1) encodes 2 proteins, the RNA binding protein p40 and endonuclease and reverse transcriptase (open-reading frame 2p [ORF2p]), which are both required for LINE-1 to retrotranspose. In cells expressing LINE-1, these proteins assemble with LINE-1 RNA and additional RNA binding proteins, some of which are well-known autoantigens in patients with systemic lupus erythematosus (SLE). This study was undertaken to investigate whether SLE patients also produce autoantibodies against LINE-1 p40. METHODS: Highly purified p40 protein was used to quantitate IgG autoantibodies in serum from 172 SLE patients and from disease controls and age-matched healthy subjects by immunoblotting and enzyme-linked immunosorbent assay (ELISA). Preparations of p40 that also contained associated proteins were analyzed by immunoblotting with patient sera. RESULTS: Antibodies reactive with p40 were detected in the majority of patients and many healthy controls. Their levels were higher in patients with SLE, but not those with systemic sclerosis, compared to healthy subjects (P = 0.01). Anti-p40 reactivity was higher in patients during a flare than in patients with disease in remission (P = 0.03); correlated with the SLE Disease Activity Index score (P = 0.0002), type I interferon score (P = 0.006), decrease in complement C3 level (P = 0.0001), the presence of anti-DNA antibodies (P < 0.0001) and anti-C1q antibodies (P = 0.004), and current or past history of nephritis (P = 0.02 and P = 0.003, respectively); and correlated inversely with age (r = -0.49, P < 0.0001). SLE patient sera also reacted with p40-associated proteins. CONCLUSION: Autoantibodies reacting with LINE-1 p40 characterize a population of SLE patients with severe and active disease. These autoantibodies may represent an early immune response against LINE-1 p40 that does not yet by itself imply clinically significant autoimmunity, but may represent an early, and still reversible, step toward SLE pathogenesis.


Assuntos
Autoanticorpos/imunologia , Proteínas de Ligação a DNA/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fatores Etários , Anticorpos Antinucleares/imunologia , Estudos de Casos e Controles , Complemento C1q/imunologia , Complemento C3/imunologia , Humanos , Elementos Nucleotídeos Longos e Dispersos/imunologia , Nefrite Lúpica/imunologia , Escleroderma Sistêmico/imunologia , Índice de Gravidade de Doença
9.
Nat Rev Nephrol ; 16(4): 238-250, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31853010

RESUMO

The immune mechanisms that cause tissue injury in lupus nephritis have been challenging to define. The advent of high-dimensional cellular analyses, such as single-cell RNA sequencing, has enabled detailed characterization of the cell populations present in small biopsy samples of kidney tissue. In parallel, the development of methods that cryopreserve kidney biopsy specimens in a manner that preserves intact, viable cells, has enabled the uniform analysis of tissue samples collected at multiple sites and across many geographic areas and demographic cohorts with high-dimensional platforms. The application of these methods to kidney biopsy samples from patients with lupus nephritis has begun to define the phenotypes of both infiltrating and resident immune cells, as well as parenchymal cells, present in nephritic kidneys. The detection of similar immune cell populations in urine suggests that it might be possible to non-invasively monitor immune activation in kidneys. Once applied to large patient cohorts, these high-dimensional studies might enable patient stratification according to patterns of immune cell activation in the kidney or identify disease features that can be used as surrogate measures of efficacy in clinical trials. Applied broadly across multiple inflammatory kidney diseases, these studies promise to enormously expand our understanding of renal inflammation in the next decade.


Assuntos
Células Epiteliais/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Sequenciamento Completo do Exoma/métodos , Biópsia por Agulha , Células Epiteliais/patologia , Feminino , Humanos , Imuno-Histoquímica , Nefrite Lúpica/genética , Masculino , Biologia Molecular/métodos , Sensibilidade e Especificidade , Análise de Sequência de RNA
10.
Ren Fail ; 42(1): 19-29, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31858861

RESUMO

Renal microvascular lesions, common in lupus nephritis (LN), are associated with long-term poor outcomes. There are mainly five pathological types of renal microvascular lesions in LN: (1) vascular immune complex deposits (ICD), (2) arteriosclerosis (AS), (3) thrombotic microangiopathy (TMA), (4) non-inflammatory necrotizing vasculopathy (NNV), and (5) true renal vasculitis (TRV). The pathogenesis of renal microvascular lesions in LN remains to be elucidated. The activation and dysfunction of endothelial cells, in addition to the contribution of immune system dysfunction, especially the immune complex-induced vascular inflammation and antiphospholipid antibody-associated thrombotic events, are key mechanisms in the development of vascular lesions in LN that need to be further investigated. Alteration of the microvascular environment produces an acute immunological response that recruits immune cells, such as T cells, monocytes, and macrophages, which induces platelet aggregation with microthrombus formation. There is also increased cytotoxicity caused by cytokines produced by immune cells in the kidney. Identifying the mechanism underlying the pathogenesis of renal microvascular lesions in LN might provide potential targets for the development of novel therapies.


Assuntos
Rim/irrigação sanguínea , Nefrite Lúpica/complicações , Doenças Vasculares/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Rim/imunologia , Nefrite Lúpica/imunologia , Microvasos/imunologia , Microvasos/patologia , Literatura de Revisão como Assunto , Doenças Vasculares/patologia
11.
Clin Exp Immunol ; 199(1): 39-49, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31509231

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. One of the key factors associated with SLE pathogenesis is excessive production of type I interferons (IFNs). This could result from increased activation of type I IFN-stimulating pathways, but also from decreased activation of type I IFN-inhibitory pathways. Recently, we have identified that immunoglobulin (Ig)G immune complexes strongly inhibit type I IFN production in healthy individuals by inhibitory signaling through Fcγ receptor IIa (FcγRIIa) on dendritic cells (DCs). Because, in SLE patients, immune complexes are characteristically present, we assessed whether FcγR-induced suppression of type I IFN is functional in DCs of SLE patients. We divided the SLE patients into one group without, and one group with, previous major organ involvement, for which we chose nephritis as a prototypical example. We show that DCs of lupus nephritis patients displayed impaired FcγR-mediated type I IFN inhibition compared to SLE patients without major organ involvement or healthy controls. We verified that this impaired type I IFN inhibition was not related to differences in disease activity, medication, FcγRIIa expression or expression of IFN regulatory transcription factors (IRF)1 and IRF5. In addition, we identified that DCs of lupus nephritis patients show increased FcγR-induced interleukin (IL)-1ß production, which is another important cytokine that promotes kidney inflammation. Taken together, these data indicate that DCs of lupus nephritis patients display altered FcγR-mediated regulation of cytokine production, resulting in elevated levels of type I IFN and IL-1ß. This dysregulation may contribute to the development of nephritis in SLE patients.


Assuntos
Células Dendríticas/imunologia , Interferon Tipo I/imunologia , Interleucina-1beta/imunologia , Nefrite Lúpica/imunologia , Receptores de IgG/imunologia , Adulto , Células Dendríticas/patologia , Feminino , Humanos , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade
12.
J Immunol Res ; 2019: 5071687, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815154

RESUMO

Autophagy is an important biology process, central to the maintenance of biology process in both physiological and pathological situations. It is regarded as a "double-edged sword"-exerting both protective and/or detrimental effects. These two-way effects are observed in immune cells as well as renal resident cells, including podocytes, mesangial cells, tubular epithelial cells, and endothelial cells of the glomerular capillaries. Mounting evidence suggests that autophagy is implicated in the pathological process of various immune-related renal diseases (IRRDs) as well as the kidney that underwent transplantation. Here, we provide an overview of the pathological role of autophagy in IRRDs, including lupus nephritis, IgA nephropathy, membrane nephropathy, ANCA-associated nephritis, and diabetic nephropathy. The understanding of the pathogenesis and regulatory mechanisms of autophagy in these renal diseases may lead to the identification of new diagnostic targets and refined therapeutic modulation.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Proteínas Relacionadas à Autofagia/imunologia , Autofagia/imunologia , Nefropatias Diabéticas/imunologia , Glomerulonefrite por IGA/imunologia , Hematúria/imunologia , Nefrite Lúpica/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Anticorpos Anticitoplasma de Neutrófilos/biossíntese , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Linfócitos B/imunologia , Linfócitos B/patologia , Células Dendríticas , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Regulação da Expressão Gênica , Glomerulonefrite por IGA/genética , Glomerulonefrite por IGA/patologia , Hematúria/genética , Hematúria/patologia , Humanos , Transplante de Rim , Nefrite Lúpica/genética , Nefrite Lúpica/patologia , Macrófagos/imunologia , Macrófagos/patologia , Células Mesangiais/imunologia , Células Mesangiais/patologia , Podócitos/imunologia , Podócitos/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
13.
Int J Mol Sci ; 20(24)2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31835612

RESUMO

Abnormalities in B cells play pivotal roles in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). Breach in central and peripheral tolerance mechanisms generates autoreactive B cells which contribute to the pathogenesis of SLE and LN. Dysregulation of B cell transcription factors, cytokines and B cell-T cell interaction can result in aberrant B cell maturation and autoantibody production. These immunological abnormalities also lead to perturbations in circulating and infiltrating B cells in SLE and LN patients. Conventional and novel immunosuppressive medications confer differential effects on B cells which have important clinical implications. While cyclophosphamide and mycophenolate mofetil (MMF) showed comparable clinical efficacy in active LN, MMF induction was associated with earlier reduction in circulating plasmablasts and plasma cells. Accumulating evidence suggests that MMF maintenance is associated with lower risk of disease relapse than azathioprine, which may be explained by its more potent and selective suppression of B cell proliferation. Novel therapeutic approaches targeting the B cell repertoire include B cell depletion with monoclonal antibodies binding to cell surface markers, inhibition of B cell cytokines, and modulation of costimulatory signals in B cell-T cell interaction. These biologics, despite showing improvements in serological parameters and proteinuria, did not achieve primary endpoints when used as add-on therapy to standard treatments in active LN patients. Other emerging treatments such as calcineurin inhibitors, mammalian target of rapamycin inhibitors and proteasome inhibitors also show distinct inhibitory effects on the B cell repertoire. Advancement in the knowledge on B cell biology has fueled the development of new therapeutic strategies in SLE and LN. Modification in background treatments, study endpoints and selective recruitment of subjects showing aberrant B cells or its signaling pathways when designing future clinical trials may better elucidate the roles of these novel therapies for SLE and LN patients.


Assuntos
Linfócitos B/patologia , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Azatioprina/farmacologia , Azatioprina/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Ensaios Clínicos como Assunto , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Humanos , Imunossupressores/farmacologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico
14.
Int J Rheum Dis ; 22(12): 2185-2190, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31749332

RESUMO

BACKGROUND AND PURPOSE: The mechanism of glomerular microthrombosis (GMT) in patients with lupus nephritis (LN) is largely unknown. The aim of this study is to investigate the association between antiphospholipid antibodies (aPLs) and factor Bb in LN patients with GMT. METHODS: Patients with biopsy-proven LN hospitalized from July 2015 to July 2018 in our hospital were selected for this study. Levels of lupus anticoagulant (LAC), anticardiolipin antibodies (aCLs), anti-ß2-glycoprotein I (anti-ß2-GPI) antibodies and factor Bb were measured, and other clinical and pathological data were also obtained during the same period before renal biopsy. RESULTS: A total of 25 LN patients with GMT and 76 LN patients without GMT were included in this study. In LN patients with GMT, the presence of anti-ß2GPI and LAC were both significantly higher than in those without GMT (P < .001 and P = .039, respectively). The level of factor Bb was also higher in LN patients with GMT than in those without GMT (P = .021). In the correlation analysis, Bb level was positively correlated with serum creatinine (r = 0.28, P = .014), activity index (r = 0.24, P = .021) GMT (r = 0.65, P < .001) and IgG-anti-ß2GPI (r = 0.771, P < .001). CONCLUSIONS: Our work suggests that aPLs, especially IgG-anti-ß2GPI, may play a role in the progress of GMT, and this process might involve alternative complement activation.


Assuntos
Anticorpos Anticardiolipina/sangue , Fator B do Complemento/análise , Imunoglobulina G/sangue , Glomérulos Renais/imunologia , Inibidor de Coagulação do Lúpus/sangue , Nefrite Lúpica/imunologia , Trombose/imunologia , Microglobulina beta-2/imunologia , Adulto , Biomarcadores/sangue , Ativação do Complemento , Feminino , Humanos , Glomérulos Renais/patologia , Nefrite Lúpica/sangue , Nefrite Lúpica/diagnóstico , Masculino , Pessoa de Meia-Idade , Trombose/sangue , Trombose/diagnóstico , Adulto Jovem
15.
PLoS One ; 14(11): e0224707, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31697750

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disorder that is associated with lupus nephritis, initiated by the deposition of immune complexes in the kidney; subsequently, this induces the overexpression of cytokines. Lupus nephritis is known as one of the major clinical manifestations that affect the disease severity in SLE patients. An increased number of resident periglomerular and immune cells in the kidney has the potential to affect the equilibrium of different immune cell subsets, such as Th1, Th2, Th17, and Tregs, which may be central to the induction of tissue damage in kidney by exerting either proinflammatory or anti-inflammatory effects, or both. This equilibrium has yet to be confirmed, as new players such as IL-25 remain undiscovered. IL-25 is a cytokine of the IL-17 family, which stimulates Th2-mediated immune response when overly expressed. Thus, the aim of this research is to determine the plasma levels of IL-25 and Th2-associated cytokines (IL-4, IL-5, IL-6, IL-9, IL-10, IL-13) in SLE patients with (SLE-LN) and without lupus nephritis. Sixty-four (n = 64) SLE patients and fifteen (n = 15) healthy individuals were recruited. This study demonstrated that the IL-9, IL-10 and IL-25 had significantly increased expressions in SLE-LN, followed by SLE without LN, compared to healthy controls. Meanwhile, IL-5 and IL-6 had significantly reduced. No significant difference was observed with IL-13, while the level of IL-4 was undetectable. Furthermore, IL-9 and IL-10 were significantly correlated with the IL-25, and IL-25, IL-9 and IL-10 were positively correlated with the disease severity score, SLEDAI. In conclusion, IL-25 and its associated Th2 cytokines (IL-9 and IL-10) may be involved in SLE pathogenesis. These cytokines could be potential biomarkers in monitoring and predicting the disease severity during SLE pathogenesis.


Assuntos
Interleucina-17/sangue , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Células Th2/imunologia , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Humanos , Lúpus Eritematoso Sistêmico/sangue , Nefrite Lúpica/sangue , Índice de Gravidade de Doença
16.
Pathology ; 51(7): 727-732, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31668566

RESUMO

Tubuloreticular inclusions (TRI) are distinctive cytoplasmic structures of unknown origin that typically associate with autoimmune and viral diseases. We investigated the clinical and prognostic relevance of TRI detection in patients with lupus nephritis (LN). We conducted a single centre study of patients (n=84) with biopsy evidence of LN. Clinical variables included demographics, SLEDAI score, and autoantibody profiling; while histological evaluation included TRI presence, International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification with NIH activity and chronicity indices, immunofluorescence, and other EM findings. Patients with and without TRI were compared by non-parametric statistical methods and survival analysis for the endpoints of death and renal failure. TRI were detected in 37 patients (44%) that were younger (28.4 vs 34.3 years, p=0.02) and more often from Asian background (37.8% vs 19.1%, p=0.04) compared to patients without TRI. SLEDAI score (11 vs 12 units, p=0.36) and amount of proteinuria (370 vs 340 mg/mmol, p=0.71) were similar in both groups; however, TRI positive patients had increased frequency of anti-SSB antibodies (16% vs 2%, p=0.02), 'full house' immune complex deposition (85% vs 58%, p=0.04) and subendothelial electron dense deposits (83% vs 65%, p=0.07), but were less often anti-dsDNA Ab positive (62% vs 85%, p=0.02). Patient and renal survival were not influenced by TRI status. TRI were observed in nearly half of all LN patients and TRI positive patients more often carried anti-SSB antibodies. However, TRI had little bearing on disease presentation or outcome in LN.


Assuntos
Autoanticorpos , Corpos de Inclusão/patologia , Nefrite Lúpica/patologia , Adulto , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Biópsia , Feminino , Humanos , Corpos de Inclusão/imunologia , Rim/imunologia , Rim/patologia , Estudos Longitudinais , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/imunologia , Masculino , Prognóstico , Análise de Sobrevida
17.
Nat Commun ; 10(1): 4097, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506438

RESUMO

Phenotypic variation of quantitative traits is orchestrated by a complex interplay between the environment (e.g. diet) and genetics. However, the impact of gene-environment interactions on phenotypic traits mostly remains elusive. To address this, we feed 1154 mice of an autoimmunity-prone intercross line (AIL) three different diets. We find that diet substantially contributes to the variability of complex traits and unmasks additional genetic susceptibility quantitative trait loci (QTL). By performing whole-genome sequencing of the AIL founder strains, we resolve these QTLs to few or single candidate genes. To address whether diet can also modulate genetic predisposition towards a given trait, we set NZM2410/J mice on similar dietary regimens as AIL mice. Our data suggest that diet modifies genetic susceptibility to lupus and shifts intestinal bacterial and fungal community composition, which precedes clinical disease manifestation. Collectively, our study underlines the importance of including environmental factors in genetic association studies.


Assuntos
Cruzamentos Genéticos , Dieta , Genes , Estudos de Associação Genética , Característica Quantitativa Herdável , Animais , Animais não Endogâmicos , Anticorpos Antinucleares/genética , Bactérias/crescimento & desenvolvimento , Biodiversidade , Feminino , Fungos/crescimento & desenvolvimento , Predisposição Genética para Doença , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Masculino , Camundongos , Microbiota , Mapeamento Físico do Cromossomo , Locos de Características Quantitativas/genética , Baço/metabolismo , Transcriptoma/genética , Sequenciamento Completo do Genoma
18.
Genomics Proteomics Bioinformatics ; 17(3): 248-259, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31494269

RESUMO

Systemic lupus erythematosus (SLE) is a complex autoimmune syndrome characterized by various co-existing autoantibodies (autoAbs) in patients' blood. However, the full spectrum of autoAbs in SLE has not been comprehensively elucidated. In this study, a commercial platform bearing 9400 antigens (ProtoArray) was used to identify autoAbs that were significantly elevated in the sera of SLE patients. By comparing the autoAb profiles of SLE patients with those of healthy controls, we identified 437 IgG and 1213 IgM autoAbs that the expression levels were significantly increased in SLE (P < 0.05). Use of the ProtoArray platform uncovered over 300 novel autoAbs targeting a broad range of nuclear, cytoplasmic, and membrane antigens. Molecular interaction network analysis revealed that the antigens targeted by the autoAbs were most significantly enriched in cell death, cell cycle, and DNA repair pathways. A group of autoAbs associated with cell apoptosis and DNA repair function, including those targeting APEX1, AURKA, POLB, AGO1, HMGB1, IFIT5, MAPKAPK3, PADI4, RGS3, SRP19, UBE2S, and VRK1, were further validated by ELISA and Western blot in a larger cohort. In addition, the levels of autoAbs against APEX1, HMGB1, VRK1, AURKA, PADI4, and SRP19 were positively correlated with the level of anti-dsDNA in SLE patients. Comprehensive autoAb screening has identified novel autoAbs, which may shed light on potential pathogenic pathways leading to lupus.


Assuntos
Autoanticorpos/sangue , Reparo do DNA , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Anticorpos Antinucleares/sangue , Morte Celular , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/sangue , Feminino , Redes Reguladoras de Genes , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Nefrite Lúpica/sangue , Nefrite Lúpica/imunologia , Masculino , Reprodutibilidade dos Testes , Regulação para Cima
20.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514450

RESUMO

An imbalanced T-cell homeostasis plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Co-stimulatory and co-inhibitory molecules regulate T-cell differentiation, survival, and cytokine production. B- and T-lymphocyte attenuator (BTLA) is a co-inhibitory molecule which negatively regulates T-cell activation. The aim of this study was to investigate BTLA expression on regulatory and effector CD4+ T-cells in SLE patients with and without lupus nephritis (LN) during active and inactive disease. Therefore, peripheral blood of forty-one SLE patients and twenty-one healthy controls (HC) was phenotypically analyzed. Next, ex vivo stimulated T-cells were analyzed for the expression of BTLA on Th1-, Th2-, and Th17-effector cells by flow cytometry. Renal involvement was defined as biopsy-proven LN. Disease activity was assessed by SLE disease activity index (SLEDAI). Percentages of peripheral unstimulated BTLA+ CD4+ T-cells were significantly decreased in SLE patients with active disease. However, ex vivo stimulated Th1, Th2, and Th17 effector T-cells, expressed increased percentages of BTLA expression in active disease. In contrast, the BTLA expression on CD4+CD25++CD127- regulatory T-cells was not significantly different. BTLA seems to be an important co-inhibitory molecule in the T-cell homeostasis of patients with systemic lupus erythematosus and crucial for disease activity.


Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Receptores Imunológicos/metabolismo , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Adulto , Feminino , Humanos , Nefrite Lúpica/imunologia , Ativação Linfocitária/imunologia , Masculino , Modelos Imunológicos , Linfócitos T Reguladores/imunologia
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