Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.787
Filtrar
1.
Nat Immunol ; 20(7): 902-914, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209404

RESUMO

Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.


Assuntos
Rim/imunologia , Nefrite Lúpica/imunologia , Biomarcadores , Biópsia , Análise por Conglomerados , Biologia Computacional/métodos , Células Epiteliais/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imunofenotipagem , Interferons/metabolismo , Rim/metabolismo , Rim/patologia , Leucócitos/imunologia , Leucócitos/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Linfócitos/imunologia , Linfócitos/metabolismo , Anotação de Sequência Molecular , Células Mieloides/imunologia , Células Mieloides/metabolismo , Análise de Célula Única , Transcriptoma
2.
Nat Commun ; 10(1): 2498, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175312

RESUMO

Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c+ dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c+DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c+DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c+DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c+DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs.


Assuntos
Antígenos CD1/imunologia , Células Dendríticas/imunologia , Glicoproteínas/imunologia , Tolerância Imunológica/imunologia , Lúpus Eritematoso Sistêmico/terapia , Proteínas de Membrana/imunologia , Transplante de Células-Tronco Mesenquimais , Adulto , Antígenos CD1/metabolismo , Estudos de Casos e Controles , Células Dendríticas/metabolismo , Feminino , Glicoproteínas/metabolismo , Humanos , Interferon gama/farmacologia , Janus Quinases/efeitos dos fármacos , Janus Quinases/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/terapia , Masculino , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Fatores de Transcrição STAT/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Homólogo , Adulto Jovem
3.
PLoS Med ; 16(5): e1002800, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31067237

RESUMO

BACKGROUND: Treatment decision-making regarding immunosuppressive therapy is challenging for individuals with lupus. We assessed the effectiveness of a decision aid for immunosuppressive therapy in lupus nephritis. METHODS AND FINDINGS: In a United States multicenter, open-label, randomized controlled trial (RCT), adult women with lupus nephritis, mostly from racial/ethnic minority backgrounds with low socioeconomic status (SES), seen in in- or outpatient settings, were randomized to an individualized, culturally tailored, computerized decision aid versus American College of Rheumatology (ACR) lupus pamphlet (1:1 ratio), using computer-generated randomization. We hypothesized that the co-primary outcomes of decisional conflict and informed choice regarding immunosuppressive medications would improve more in the decision aid group. Of 301 randomized women, 298 were analyzed; 47% were African-American, 26% Hispanic, and 15% white. Mean age (standard deviation [SD]) was 37 (12) years, 57% had annual income of <$40,000, and 36% had a high school education or less. Compared with the provision of the ACR lupus pamphlet (n = 147), participants randomized to the decision aid (n = 151) had (1) a clinically meaningful and statistically significant reduction in decisional conflict, 21.8 (standard error [SE], 2.5) versus 12.7 (SE, 2.0; p = 0.005) and (2) no difference in informed choice in the main analysis, 41% versus 31% (p = 0.08), but clinically meaningful and statistically significant difference in sensitivity analysis (net values for immunosuppressives positive [in favor] versus negative [against]), 50% versus 35% (p = 0.006). Unresolved decisional conflict was lower in the decision aid versus pamphlet groups, 22% versus 44% (p < 0.001). Significantly more patients in the decision aid versus pamphlet group rated information to be excellent for understanding lupus nephritis (49% versus 33%), risk factors (43% versus 27%), medication options (50% versus 33%; p ≤ 0.003 for all); and the ease of use of materials was higher in the decision aid versus pamphlet groups (51% versus 38%; p = 0.006). Key study limitations were the exclusion of men, short follow-up, and the lack of clinical outcomes, including medication adherence. CONCLUSIONS: An individualized decision aid was more effective than usual care in reducing decisional conflict for choice of immunosuppressive medications in women with lupus nephritis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02319525.


Assuntos
Técnicas de Apoio para a Decisão , Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Educação de Pacientes como Assunto , Participação do Paciente , Adulto , Comportamento de Escolha , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Alfabetização em Saúde , Humanos , Imunossupressores/efeitos adversos , Nefrite Lúpica/etnologia , Nefrite Lúpica/imunologia , Pessoa de Meia-Idade , Folhetos , Resultado do Tratamento , Estados Unidos/epidemiologia
4.
Clin Nephrol ; 91(6): 325-333, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30900983

RESUMO

"Lupus nephritis", a serious complication of systemic lupus erythematosus (SLE), is an entity of recent vintage. The term "lupus", derived from Latin for wolf, was introduced in the Middle Ages to denote nondescript erosive skin lesions which resembled wolf bites that were known theretofore by their Greek name of "herpes esthiomenos", used in the Hippocratic Corpus for the spread of the lesions like a crawling snake. The specific dermatologic features of lupus were characterized as an "erythematous" butterfly rash in 1828 and dubbed "lupus erythematosus" in 1850. Their association with systemic manifestations was described in 1872 and termed "disseminated lupus erythematosus" by the close of the century. A preference for "systemic" rather than "disseminated" was suggested in 1904 but would not prevail until the 1960s. The generic term "nephritis", denoting "inflammation of the kidnies" dating to the 1580s, was first used to describe the renal lesions of SLE in 1902. Although albuminuria and abnormal urine sediment were often noted in SLE patients, the early study of their renal changes was limited to postmortem studies. Refinements in their identification came in the late 1950s after the introduction of kidney needle biopsies and refined thereafter by immunofluorescent and electron microscopic studies. Subsequent lupus nephritis studies paralleled the emerging discipline of immunology that identified autoimmunity as the cause of SLE. The varied lesions observed were classified by glomerular changes in 1975 and refined in 2003. Advances in genetic and molecular profiling have enriched the management of lupus nephritis based on kidney biopsies.


Assuntos
Glomérulos Renais/patologia , Nefrite Lúpica/história , Terminologia como Assunto , Biópsia , História do Século XVI , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , Humanos , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia
5.
Nat Immunol ; 20(4): 503-513, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30778242

RESUMO

Two-photon excitation microscopy (TPEM) has revolutionized the understanding of adaptive immunity. However, TPEM usually requires animal models and is not amenable to the study of human disease. The recognition of antigen by T cells requires cell contact and is associated with changes in T cell shape. We postulated that by capturing these features in fixed tissue samples, we could quantify in situ adaptive immunity. Therefore, we used a deep convolutional neural network to identify fundamental distance and cell-shape features associated with cognate help (cell-distance mapping (CDM)). In mice, CDM was comparable to TPEM in discriminating cognate T cell-dendritic cell (DC) interactions from non-cognate T cell-DC interactions. In human lupus nephritis, CDM confirmed that myeloid DCs present antigen to CD4+ T cells and identified plasmacytoid DCs as an important antigen-presenting cell. These data reveal a new approach with which to study human in situ adaptive immunity broadly applicable to autoimmunity, infection, and cancer.


Assuntos
Imunidade Adaptativa , Células Dendríticas/imunologia , Microscopia de Fluorescência por Excitação Multifotônica , Linfócitos T/imunologia , Animais , Núcleo Celular/ultraestrutura , Células Dendríticas/citologia , Humanos , Nefrite Lúpica/imunologia , Camundongos , Camundongos Transgênicos , Redes Neurais (Computação) , Linfócitos T/citologia , Linfócitos T/ultraestrutura
6.
Immunity ; 50(2): 334-347.e9, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30709743

RESUMO

Elevated endogenous retrovirus (ERV) transcription and anti-ERV antibody reactivity are implicated in lupus pathogenesis. Overproduction of non-ecotropic ERV (NEERV) envelope glycoprotein gp70 and resultant nephritis occur in lupus-prone mice, but whether NEERV mis-expression contributes to lupus etiology is unclear. Here we identified suppressor of NEERV (Snerv) 1 and 2, Krüppel-associated box zinc-finger proteins (KRAB-ZFPs) that repressed NEERV by binding the NEERV long terminal repeat to recruit the transcriptional regulator KAP1. Germline Snerv1/Snerv2 deletion increased activating chromatin modifications, transcription, and gp70 expression from NEERV loci. F1 crosses of lupus-prone New Zealand Black (NZB) and 129 mice to Snerv1/Snerv2-/- mice failed to restore NEERV repression, demonstrating that loss of SNERV underlies the lupus autoantigen gp70 overproduction that promotes nephritis in susceptible mice and that SNERV encodes for Sgp3 (in NZB mice) and Gv-1 loci (in 129 mice). Increased ERV expression in lupus patients inversely correlated with three putative ERV-suppressing KRAB-ZFPs, suggesting that loss of KRAB-ZFP-mediated ERV control may contribute to human lupus pathogenesis.


Assuntos
Proteínas de Transporte/imunologia , Retrovirus Endógenos/imunologia , Glicoproteínas/imunologia , Nefrite Lúpica/imunologia , Chaperonas Moleculares/imunologia , Proteínas Nucleares/imunologia , Proteínas Repressoras/imunologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Regulação da Expressão Gênica/imunologia , Predisposição Genética para Doença/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Células HEK293 , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NZB , Camundongos Knockout , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
7.
Lupus ; 28(4): 529-537, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30799679

RESUMO

INTRODUCTION: Pregnancies in women with lupus nephritis are at high-risk of complications, while scarcity of scientific knowledge on prognostic factors impedes a fair medical counseling. We aimed to identify determinants associated with maternal and fetal complications. MATERIALS: We retrospectively reviewed medical charts of pregnancies that lasted more than 22 weeks in 66 patients with pre-existing lupus nephritis between 2004 and 2013 in France. Univariate and multivariate analyses were conducted to identify determinants for maternal complications, lupus renal flare and fetal prematurity or death. RESULTS: Eighty-four pregnancies were identified. A maternal complication occurred in 31 pregnancies (36.9%): mostly preeclampsia (17 pregnancies, 20.2%) and renal flares (12 pregnancies, 14.3%). Overall fetal survival was 94.0% (79/84). Maternal pregnancy complications were independently associated with prepregnancy body mass index >25 kg/m2 (OR 3.81, 95% CI 1.03-14.09) and immunological activity (positive anti-dsDNA antibodies or Farr assay lupus) (OR 4.95, 95% CI 1.33-18.43). Renal lupus flares were independently associated with maternal age (OR 1.50, 95% CI 1.12-2.01) and prepregnancy immunological activity (OR 15.99, 95% CI 1.57-162.68) while a remission time >12 months had a protective effect (OR 0.17, 95% CI 0.04-0.68). Three parameters were associated with a higher risk of fetal prematurity or death: a prepregnancy body mass index >25 kg/m2 (HR 3.58, 95% CI 1.45-8.83), hypertension (HR 8.97, 95% CI 3.32-24.25), and immunological activity (HR 3.34, 95% CI 1.30-8.63). CONCLUSION: Maternal age, prepregnancy hypertension, body mass index >25 kg/m2 and lupus immunological activity may be considered as the main determinants for fetal and maternal complications. A remission time above 12 months for patients with lupus nephritis could be associated with a reduced risk of renal flare during pregnancy.


Assuntos
Nefrite Lúpica/epidemiologia , Sobrepeso/epidemiologia , Pré-Eclâmpsia/epidemiologia , Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Adulto , Fatores Etários , Índice de Massa Corporal , Feminino , França/epidemiologia , Humanos , Hipertensão Renal/epidemiologia , Recém-Nascido , Recém-Nascido Prematuro , Estimativa de Kaplan-Meier , Nefrite Lúpica/imunologia , Idade Materna , Análise Multivariada , Morte Perinatal/etiologia , Gravidez , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Natimorto/epidemiologia , Adulto Jovem
8.
Lupus ; 28(3): 396-405, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30760090

RESUMO

BACKGROUND: Antibodies to M-type phospholipase A2 receptor (a-PLA2R) have been identified in most patients with idiopathic membranous nephropathy, but the prevalence in membranous lupus nephritis (MLN) is still unclear. The objective of this study was to assess the prevalence of a-PLA2R antibodies in a large cohort of patients with lupus nephritis. METHODS: a-PLA2R antibodies were measured by ELISA in serum from patients with systemic lupus erythematosus ( n = 190), of whom 37 had a biopsy-proven MLN. Positive samples were confirmed by commercial ELISA kit, Western blot and immunohistochemistry in renal tissue. RESULTS: A total of 10 from 190 patients (5.3%) with systemic lupus erythematosus had circulating a-PLA2R measured by in-house ELISA assay. The antibodies were detected in 7 patients with MLN (18.9%) and 3 patients with non-renal lupus disease (3.2%). PLA2R staining was detected in the kidney biopsy of 5 of the 7 (71.4%) patients with MLN. a-PLA2R levels were associated with active disease but not proteinuria levels. Presence of a-PLA2R antibodies at baseline was associated with worse remission rates and longer time to remission compared to those patients serologically negative. CONCLUSIONS: a-PLA2R antibodies can be detected with low prevalence in MLN patients, but their detection is associated with a worse renal prognosis.


Assuntos
Autoanticorpos/imunologia , Nefrite Lúpica/imunologia , Receptores da Fosfolipase A2/imunologia , Adulto , Autoanticorpos/sangue , Biomarcadores/sangue , Western Blotting , Estudos de Casos e Controles , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Glomerulonefrite Membranosa/diagnóstico , Humanos , Rim/imunologia , Estudos Longitudinais , Nefrite Lúpica/classificação , Nefrite Lúpica/diagnóstico , Masculino , Valor Preditivo dos Testes , Proteinúria , Receptores da Fosfolipase A2/sangue , Estudos Retrospectivos
9.
J Am Soc Nephrol ; 30(2): 244-259, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30622154

RESUMO

BACKGROUND: In people with SLE and in the MRL-Faslpr lupus mouse model, macrophages and autoantibodies are central to lupus nephritis. IL-34 mediates macrophage survival and proliferation, is expressed by tubular epithelial cells (TECs), and binds to the cFMS receptor on macrophages and to a newly identified second receptor, PTPRZ. METHODS: To investigate whether IL-34-dependent intrarenal and systemic mechanisms promote lupus nephritis, we compared lupus nephritis and systemic illness in MRL-Faslpr mice expressing IL-34 and IL-34 knockout (KO) MRL-Faslpr mice. We also assessed expression of IL-34 and the cFMS and PTPRZ receptors in patients with lupus nephritis. RESULTS: Intrarenal IL-34 and its two receptors increase during lupus nephritis in MRL-Faslpr mice. In knockout mice lacking IL-34, nephritis and systemic illness are suppressed. IL-34 fosters intrarenal macrophage accumulation via monocyte proliferation in bone marrow (which increases circulating monocytes that are recruited by chemokines into the kidney) and via intrarenal macrophage proliferation. This accumulation leads to macrophage-mediated TEC apoptosis. We also found suppression of circulating autoantibodies and glomerular antibody deposits in the knockout mice. This is consistent with fewer activated and proliferating intrarenal and splenic B cells in mice lacking IL-34, and with our novel discovery that PTPRZ is expressed by macrophages, B and T cells. These findings appear translatable to human patients with lupus nephritis, whose expression of IL-34, cFMS, and PTPRZ is similar to that seen in the MRL-Faslpr lupus mouse model. Moreover, expression of IL-34 in TECs correlates with disease activity. CONCLUSIONS: IL-34 is a promising novel therapeutic target for patients with lupus nephritis.


Assuntos
Morte Celular/genética , Sobrevivência Celular/genética , Interleucinas/genética , Nefrite Lúpica/patologia , Terapia de Alvo Molecular/métodos , Monócitos/citologia , Animais , Morte Celular/imunologia , Proliferação de Células/genética , Células Cultivadas , Quimiocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica , Interleucinas/imunologia , Interleucinas/metabolismo , Túbulos Renais/patologia , Túbulos Renais/fisiopatologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Monócitos/fisiologia , Medição de Risco , Especificidade da Espécie
10.
Life Sci ; 208: 26-32, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30146016

RESUMO

AIMS: Lupus nephritis (LN) is a kidney inflammatory disease caused by systemic lupus erythematosus (SLE). Both NF-κB activation and NLRP3 inflammasome activation are implicated in LN pathogenesis, suggesting they are potential targets for LN treatment. Icariin, which is isolated from Chinese medicine Horny Goat Weed (Ying Yang Huo), has been shown to have anti-inflammation activity, and inhibit activations of both NF-κB and NLRP3 inflammasome. In present study, the effects of icariin on LN were evaluated in MRL/lpr mice. MAIN METHODS: We treated MRL/lpr mice with icariin for 8 weeks and then analyzed the renal function and kidney pathology. We monitored the levels of anti-dsDNA antibody and the deposition of immune complex after icariin treatment. We also detected the macrophage infiltration, NF-κB activation, NLRP3 inflammasome activation and inflammatory cytokine TNF-α production in MRL/lpr mice after icariin treatment. KEY FINDINGS: We found that MRL/lpr mice treated with icariin displayed significantly attenuated the renal disease. Icariin-treated mice showed significantly reduced serum anti-dsDNA antibody level and immune complex deposition. Icariin inhibited NF-κB activation and TNF-α production in MRL/lpr mice. Icariin inhibited CCL2 production and macrophage infiltration in MRL/lpr mice. Finally, icariin suppressed NLRP3 inflammasome activation and IL-1ß production in MRL/lpr mice. SIGNIFICANCE: Icariin alleviated murine lupus nephritis via inhibiting NF-κB activation and NLRP3 inflammasome activation.


Assuntos
Flavonoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamassomos/antagonistas & inibidores , Nefropatias/prevenção & controle , Nefrite Lúpica/prevenção & controle , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Animais , Feminino , Nefropatias/imunologia , Nefropatias/metabolismo , Nefropatias/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Transdução de Sinais/efeitos dos fármacos
11.
Med Sci Monit ; 24: 5384-5390, 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30072685

RESUMO

BACKGROUND Patients with systemic lupus erythematosus (SLE), especially with lupus nephritis (LN), undergo vascular damage and repair during the course of the disease. Since the recently identified angiogenic T cells (Tang) are involved in endothelial repair coupled with endothelial progenitor cells (EPCs), this study investigated the circulating Tang cells in LN patients and their potential correlations with disease features. MATERIAL AND METHODS Circulating Tang cells and EPCs were assessed by flow cytometry in peripheral blood samples from 67 SLE patients; of these, 32 had LN and 30 were matched healthy controls (HCs). The plasma levels of interleukin IL-17, IL-8, and vascular endothelial growth factor (VEGF) were quantified by immunoassays. RESULTS The percentage of circulating Tang cells in LN patients was significantly increased as compared to the non-LN patients and HCs, and they were positively correlated with the level of EPC and VEGF. Additionally, circulating Tang cell percentages were positively correlated with the extent of proteinuria in LN patients. CONCLUSIONS The increased levels of circulating Tang cells in LN patients might play a role in the balance of endothelium dysfunction in these patients.


Assuntos
Indutores da Angiogênese/imunologia , Nefrite Lúpica/imunologia , Linfócitos T/fisiologia , Adulto , Células Endoteliais/metabolismo , Feminino , Citometria de Fluxo , Humanos , Interleucina-17/sangue , Interleucina-8/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Fator A de Crescimento do Endotélio Vascular/sangue
12.
Autoimmun Rev ; 17(9): 890-899, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30009962

RESUMO

Lupus nephritis (LN) is one of the most frequent and severe manifestations of systemic lupus erythematosus (SLE), considered as the major predictor of poor prognosis. An early diagnosis of LN is a real challenge in the management of SLE and has an important implication in guiding treatments. In clinical practice, conventional parameters still lack sensitivity and specificity for detecting ongoing disease activity in lupus kidneys and early relapse of nephritis. LN is characterized by glomerular kidney injury, essentially due to deposition of immune complexes involving autoantibodies against cellular components and circulating proteins. One of the possible mechanisms of induction of autoantibodies in SLE is a defect in apoptotic cells clearance and subsequent release of intracellular autoantigens. Autoantibodies against soluble protective molecules involved in the uptake of dying cells, including complement proteins and pentraxins, have been described. In this review, we present the main autoantibodies found in LN, with a focus on the antibodies against these protective molecules. We also discuss their pathogenic role and conclude with their potential interest as serological biomarkers in LN.


Assuntos
Biomarcadores/sangue , Glomérulos Renais/anormalidades , Rim/patologia , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/imunologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/patologia , Masculino
13.
Ultrastruct Pathol ; 42(4): 365-368, 2018 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30019987

RESUMO

AIM: To identify the underlying diseases with TRI-positive kidney biopsies, and describe the histological pattern and spectrum of TRI-positive kidney biopsies. METHODS: A retrospective analysis of all patients' chart that underwent renal biopsy at King Saud University Medical City between 2012 and 2017 was done. Kidney biopsies that indicated a positive result for tubuloreticular inclusions (TRI's) on electron microscopy were reviewed and the underlying disease and histological pattern was extracted. RESULTS: Of 1,473 native kidney biopsies reviewed, 96 (6.5%) were TRI-positive. Of the 96 TRI-positive kidney biopsies, 87 (90.6%) were TRI-positive lupus nephritis (LN); of which 10 (11.5%) were Class V, 49 (56.3%) were active LN, and 28 (32.2%) were inactive LN. The underlying diseases of the nine non-LN TRI-positive cases included diabetic nephropathy, connective tissue disorders, immune complex mediated Glomerulonephritis (GN), acute thrombotic microangiopathy, rhabdomyolysis, and Wegener's disease. CONCLUSION: LN is a very common finding in TRI-positive kidney biopsies. Active LN and chronic LN are the more common classes of TRI-positive LN kidney biopsies, than pure membranous (Class V) LN. TRI positive kidney biopsies without LN are commonly found in diabetic nephropathy, connective tissue disorders and immune mediated GN's. This study highlights this finding in our patients cohort in opposition to what has been reported in the literature.


Assuntos
Glomerulonefrite/patologia , Corpos de Inclusão/patologia , Rim/patologia , Nefrite Lúpica/patologia , Biópsia , Humanos , Nefrite Lúpica/imunologia , Nefrectomia/métodos , Estudos Retrospectivos , Centros de Atenção Terciária
14.
Int J Rheum Dis ; 21(6): 1163-1172, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29879319

RESUMO

AIM: Membranous lupus glomerulonephritis (MLN) is associated with morbidities such as thromboembolism, peripheral edema and/or hyperlipidemia. However, treatment of MLN remains elusive. METHODS: We performed systematic searches on MEDLINE, EMBASE and Cochrane Library database up to November, 2017. Eligible studies included randomized trials or cohort studies which evaluated different immunosuppressants in adult patients with pathologically proved MLN. No language restrictions were applied. Endpoints included complete remission (CR) as the primary outcome, and CR plus partial remission (PR) and proteinuria-reducing effect as secondary outcomes. Frequentist estimation of a network meta-analysis (NMA) random-effect model was performed. RESULTS: Eight studies (206 patients) were included with a total of six immunosuppressants as an induction therapy for MLN. NMA results showed that both mycophenolate mofetil (MMF) and calcineurin inhibitors (CNI) are effective in the induction of CR and CR plus PR when compared with corticosteroids (CS) alone, but MMF and CNI are also associated with higher infection rates when compared with CS. CONCLUSION: Our NMA demonstrated that both MMF and CNI are more effective than CS for induction therapy in MLN patients. However, there are limitations due to intra- and inter-study variability.


Assuntos
Glomerulonefrite Membranosa/tratamento farmacológico , Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Adulto , Feminino , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/imunologia , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Quimioterapia de Indução , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/imunologia , Masculino , Razão de Chances , Infecções Oportunistas/induzido quimicamente , Infecções Oportunistas/imunologia , Infecções Oportunistas/microbiologia , Proteinúria/tratamento farmacológico , Proteinúria/imunologia , Indução de Remissão , Fatores de Risco , Resultado do Tratamento
15.
Medicine (Baltimore) ; 97(26): e11287, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29953010

RESUMO

The current methods of monitoring the activity of lupus nephritis (LN) may cause unnecessary hospital visits or delayed immunosuppressive therapy. We aimed to find a urinary biomarker that could be developed as a home-based test for monitoring the activity of LN.Urine samples were collected immediately before a renal biopsy from patients of suspected active LN, and also from patients with inactive LN, systemic lupus erythematous without LN or healthy controls. Biomarker search was conducted on a cytokine antibody array and confirmation was done by quantitative evaluation with enzyme-linked immunosorbent assay. The Mann-Whiney test or Student t test was used to compare the levels of 9 cytokines between different groups. The sensitivity and specificity of each cytokine for diagnosis of LN was evaluated by receiver operating characteristic curve. A rapid test based on colloidal gold immunochromatography was then developed for bedside or home use. Furthermore, an experimental e-healthcare system was constructed for recording and sharing the results of the rapid test a cloud-assisted internet of things (IoT) consisting of a sensing device, an IoT device and a cloud server.Adiponectin (Acrp30), soluble intercellular cell adhesion molecule-1 (sICAM-1), neural cell adhesion molecule 1 (NCAM-1), and CD26 were significantly higher in urine samples of active LN patients. sICAM-1 appeared more sensitive and specific among these candidates. When the cut-off value of sICAM-1 was set at 1.44 ng/mL, the sensitivity reached 98.33% with a specificity at 85.71%. The sICAM-1 strip test showed comparable sensitivity of 95% and a specificity of 83.3% for assessing the LN activity. Meanwhile, the e-healthcare system was able to conveniently digitize and share the sICAM-1 rapid test results.sICAM-1 appeared to be an excellent biomarker for monitoring LN activity. The e-healthcare system with cloud-assisted IoT could assist the digitalization and sharing of the bedside or home-based sICAM-1 test results.


Assuntos
Molécula 1 de Adesão Intercelular/urina , Nefrite Lúpica/imunologia , Nefrite Lúpica/urina , Adiponectina/imunologia , Adiponectina/urina , Adulto , Idoso , Biomarcadores , Antígeno CD56/imunologia , Antígeno CD56/urina , Dipeptidil Peptidase 4/imunologia , Dipeptidil Peptidase 4/urina , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Molécula 1 de Adesão Intercelular/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/urina , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
16.
Int J Rheum Dis ; 21(5): 1060-1067, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29878614

RESUMO

AIM: To analyze whether different hepatitis B virus (HBV) infection status influenced the prognosis of patients with lupus nephritis (LN) under immunosuppressive therapy. METHODS: A retrospective study enrolled 177 adults with active LN (Classes III, IV, V or mixed), and divided them into three groups: (i) HBV-free group (n = 93), antibodies to hepatitis B surface antigen positive only or all items negative; (ii) occult HBV infection group (n = 68), hepatitis B surface antigen (HBsAg) negative and antibody to hepatitis B core antigen positive with undetectable HBV DNA; and (iii) HBV infection group (n = 16), HBsAg-positive. The composite renal outcome was defined as a composite of progression to end-stage renal disease, 50% estimated glomerular filtration rate decrease, or death. RESULTS: The HBV infection rate was 9.04% in active LN. In the HBV infection group, a greater proportion of patients delayed immunosuppressive therapy, reduced prednisone dose, used mycophenolate mofetil in the first induction phase, received immunoglobulin pulse therapy, as well as avoided methylprednisolone pulse treatment (P < 0.05). The composite renal outcome was significantly different among the three groups: 4/93 (4.30%) of the HBV-free group, 7/68 (10.29%) of the occult HBV infection group, and 4/16 (25.00%) of HBV infection group (P = 0.018). Univariate and multivariate analyses identified three independent risk factors of composite renal outcome: active HBV carrier (odds ratio [OR] 10.342, 95% CI 2.151-66.053, P = 0.017), cycle of immunosuppression > 1 (OR 3.345, 95% CI 1.201-9.983, P = 0.025), and delayed immunosuppressive therapy (OR 3.118, 95% CI 1.207-10.662, P = 0.031). CONCLUSIONS: All these results suggested that HBV infection status might confer a worse prognosis for patients with active LN.


Assuntos
Vírus da Hepatite B/patogenicidade , Hepatite B/virologia , Imunossupressores/uso terapêutico , Rim/efeitos dos fármacos , Nefrite Lúpica/tratamento farmacológico , Adulto , Distribuição de Qui-Quadrado , DNA Viral/sangue , DNA Viral/genética , Progressão da Doença , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Hepatite B/imunologia , Hepatite B/mortalidade , Anticorpos Anti-Hepatite B/sangue , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunossupressores/efeitos adversos , Rim/imunologia , Rim/fisiopatologia , Falência Renal Crônica/imunologia , Falência Renal Crônica/mortalidade , Modelos Logísticos , Nefrite Lúpica/imunologia , Nefrite Lúpica/mortalidade , Nefrite Lúpica/fisiopatologia , Masculino , Registros Médicos , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Ativação Viral , Adulto Jovem
17.
J Immunol Res ; 2018: 1601079, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29850618

RESUMO

Type I interferons (IFN) are pathogenic in systemic lupus erythematosus (SLE) and were proposed to control the immunometabolism of dendritic cells (DCs). We previously reported that DCs from female lupus-prone mice constitutively overexpress IFN-responsive genes resembling the IFN signature found in SLE patients. As SLE has higher incidence in women than men, more so in women of reproductive age, estrogens are suggested to affect lupus pathogenesis. We investigated the effects of sex and estrogens on the IFN signature in conventional GM-CSF-bone marrow-derived DCs (cDCs), from male and female Triple Congenic B6.NZM.Sle1/Sle2/Sle3 (TCSle) lupus-prone mice or from wild-type C57BL/6 mice, generated with titrations of 17-beta-estradiol (E2). We found that cDCs from prediseased TCSle male mice express the IFN signature as female TCSle cDCs do. Estrogens are necessary but not sufficient to express this IFN signature, but high doses of E2 can compensate for other steroidal components. E2 stimulation, regardless of sex, modulates type I IFN-dependent and type I IFN-independent activation of cDCs in response to TLR stimulation. Finally, we found that TCSle cDCs from both sexes have elevated markers of immunometabolism and estrogens enhance the metabolic pathways in cDCs, suggesting a mechanistic link between estrogens, immunometabolism, and the IFN signature in lupus.


Assuntos
Células Dendríticas/imunologia , Estradiol/metabolismo , Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/metabolismo , Animais , Autoanticorpos/metabolismo , Células da Medula Óssea/citologia , Modelos Animais de Doenças , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Interferon Tipo I/genética , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transcriptoma
18.
PLoS One ; 13(5): e0196117, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29742110

RESUMO

Both a lack of biomarkers and relatively ineffective treatments constitute impediments to management of lupus nephritis (LN). Here we used gene expression microarrays to contrast the transcriptomic profiles of active SLE patients with and without LN to identify potential biomarkers for this condition. RNA isolated from whole peripheral blood of active SLE patients was used for transcriptomic profiling and the data analyzed by linear modeling, with corrections for multiple testing. Results were validated in a second cohort of SLE patients, using NanoString technology. The majority of genes demonstrating altered transcript abundance between patients with and without LN were neutrophil-related. Findings in the validation cohort confirmed this observation and showed that levels of RNA abundance in renal remission were similar to active patients without LN. In secondary analyses, RNA abundance correlated with disease activity, hematuria and proteinuria, but not renal biopsy changes. As abundance levels of the individual transcripts correlated strongly with each other, a composite neutrophil score was generated by summing all levels before examining additional correlations. There was a modest correlation between the neutrophil score and the blood neutrophil count, which was largely driven by the dose of glucocorticosteroids and not the proportion of low density and/or activated neutrophils. Analysis of longitudinal data revealed no correlation between baseline neutrophil score or changes over the first year of follow-up with subsequent renal flare or treatment outcomes, respectively. The findings argue that although the neutrophil score is associated with LN, its clinical utility as a biomarker may be limited.


Assuntos
Perfilação da Expressão Gênica , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Neutrófilos/metabolismo , Adulto , Contagem de Células , Feminino , Humanos , Interferons/farmacologia , Nefrite Lúpica/etiologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Adulto Jovem
19.
Int J Mol Sci ; 19(5)2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29751523

RESUMO

Annexin A1 is a protein with multifunctional roles in innate and adaptive immunity mainly devoted to the regulation of inflammatory cells and the resolution of inflammation. Most of the data regarding Annexin A1 roles in immunity derive from cell studies and from mice models lacking Annexin A1 for genetic manipulation (Annexin A1-/-); only a few studies sought to define how Annexin A1 is involved in human diseases. High levels of anti-Annexin A1 autoantibodies have been reported in systemic lupus erythematosus (SLE), suggesting this protein is implicated in auto-immunity. Here, we reviewed the evidence available for an association of anti-Annexin A1 autoantibodies and SLE manifestations, in particular in those cases complicated by lupus nephritis. New studies show that serum levels of Annexin A1 are increased in patients presenting renal complications of SLE, but this increment does not correlate with circulating anti-Annexin A1 autoantibodies. On the other hand, high circulating Annexin A1 levels cannot explain per se the development of autoantibodies since post-translational modifications are necessary to make a protein immunogenic. A hypothesis is presented here and discussed regarding the possibility that Annexin A1 undergoes post-translational modifications as a part of neutrophil extracellular traps (NETs) that are produced in response to viral, bacterial, and/or inflammatory triggers. In particular, focus is on the process of citrullination of Annexin A1, which takes place within NETs and that mimics, to some extent, other autoimmune conditions, such as rheumatoid arthritis, that are characterized by the presence of anti-citrullinated peptides in circulation. The description of pathologic pathways leading to modification of Annexin A1 as a trigger of autoimmunity is a cognitive evolution, but requires more experimental data before becoming a solid concept for explaining autoimmunity in human beings.


Assuntos
Anexina A1/metabolismo , Autoimunidade/fisiologia , Neutrófilos/metabolismo , Animais , Anexina A1/genética , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/imunologia , Nefrite Lúpica/metabolismo
20.
PLoS One ; 13(5): e0196172, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29723256

RESUMO

OBJECTIVE: We sought to evaluate the effect of antiplatelet therapy in addition to conventional immunosuppressive therapy for lupus nephritis (LN) patients positive for antiphospholipid antibodies (aPL) without definite antiphospholipid syndrome (APS). METHODS: Patients with biopsy-proven LN class III or IV were retrospectively evaluated. We selected patients positive for anticardiolipin antibody (aCL) or lupus anticoagulant (LA) who did not meet the criteria for a diagnosis of APS. The patients were divided into two subgroups according to whether antiplatelet therapy was received. The cumulative complete renal response (CR) rate, relapse-free rate, and change in estimated glomerular filtration rate (eGFR) over 3 years after induction therapy were calculated. RESULTS: We identified 17 patients who received antiplatelet therapy and 21 who did not. Baseline clinicopathological characteristics and immunosuppressive therapy did not show a significant difference between the two groups except for a higher incidence of LN class IV in the treatment group (p = 0.03). There was no difference in cumulative CR rate, relapse-free rate, or eGFR change between these subgroups. However, when data on LA-positive patients were assessed, an improvement in eGFR was found (p = 0.04) in patients receiving antiplatelet treatment. CONCLUSION: Addition of anti-platelet therapy was associated with an improvement of eGFR in LA-positive patients with LN class III or IV.


Assuntos
Anticorpos Anticardiolipina/metabolismo , Rim/efeitos dos fármacos , Rim/fisiopatologia , Inibidor de Coagulação do Lúpus/metabolismo , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/imunologia , Inibidores da Agregação de Plaquetas/farmacologia , Adulto , Síndrome Antifosfolipídica/complicações , Citoproteção/efeitos dos fármacos , Interações de Medicamentos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Imunossupressão , Rim/patologia , Nefrite Lúpica/complicações , Nefrite Lúpica/fisiopatologia , Masculino , Inibidores da Agregação de Plaquetas/uso terapêutico , Estudos Retrospectivos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA