RESUMO
Systemic Lupus Erythematosus (SLE) is an autoimmune disorder that causes a breakdown of immune tolerance. Current treatments mainly involve general immunosuppression, increasing the risk of infections. On the other hand, Bacillus Calmette-Guérin (BCG) has been investigated as a potential therapy for autoimmune diseases in recent years, prompting an ongoing investigation. This study aimed to evaluate the effect of BCG vaccination on early and late clinical presentation of SLE in a murine disease model. MRL/MPJ-Faslpr mice were immunized with BCG or treated with PBS as a control. The progress of the disease was evaluated at 27 days post-immunization (dpi) (early) and 56 dpi (late). Clinical parameters and proteinuria were monitored. Blood samples were collected for measurement of antinuclear antibodies (ANAs), anti-double-stranded DNA (anti-dsDNA), and cytokine determination was performed using ELISA. Samples collected from mice were analyzed by flow cytometry and histopathology. We observed a clinical improvement in BCG-treated mice, reduced proteinuria in the latter stages of the disease, and decreased TNF-α. However, BCG did not elicit significant changes in ANAs, anti-dsDNA, histopathological scores, or immune cell infiltration. BCG was only partially beneficial in an SLE mouse model, and further research is needed to determine whether the immunity induced by this vaccine can counteract lupus's autoimmune response.
Assuntos
Anticorpos Antinucleares , Vacina BCG , Modelos Animais de Doenças , Lúpus Eritematoso Sistêmico , Animais , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Camundongos , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Vacina BCG/imunologia , Feminino , Citocinas/metabolismo , Proteinúria/imunologia , Proteinúria/etiologia , Vacinação , Camundongos Endogâmicos MRL lpr , Mycobacterium bovis/imunologia , Fator de Necrose Tumoral alfa/sangueRESUMO
Macrophages are a rich source of macrophage migration inhibitory factor (MIF). It is well established that macrophages and MIF play a pathogenic role in anti-glomerular basement membrane crescentic glomerulonephritis (anti-GBM CGN). However, whether macrophages mediate anti-GBM CGN via MIF-dependent mechanism remains unexplored, which was investigated in this study by specifically deleting MIF from macrophages in MIFf/f-lysM-cre mice. We found that compared to anti-GBM CGN induced in MIFf/f control mice, conditional ablation of MIF in macrophages significantly suppressed anti-GBM CGN by inhibiting glomerular crescent formation and reducing serum creatinine and proteinuria while improving creatine clearance. Mechanistically, selective MIF depletion in macrophages largely inhibited renal macrophage and T cell recruitment, promoted the polarization of macrophage from M1 towards M2 via the CD74/NF-κB/p38MAPK-dependent mechanism. Unexpectedly, selective depletion of macrophage MIF also significantly promoted Treg while inhibiting Th1 and Th17 immune responses. In summary, MIF produced by macrophages plays a pathogenic role in anti-GBM CGN. Targeting macrophage-derived MIF may represent a novel and promising therapeutic approach for the treatment of immune-mediated kidney diseases.
Assuntos
Doença Antimembrana Basal Glomerular , Antígenos de Diferenciação de Linfócitos B , Antígenos de Histocompatibilidade Classe II , Oxirredutases Intramoleculares , Fatores Inibidores da Migração de Macrófagos , Macrófagos , Fatores Inibidores da Migração de Macrófagos/metabolismo , Animais , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Doença Antimembrana Basal Glomerular/imunologia , Doença Antimembrana Basal Glomerular/metabolismo , Oxirredutases Intramoleculares/metabolismo , Oxirredutases Intramoleculares/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Diferenciação de Linfócitos B/metabolismo , Modelos Animais de Doenças , NF-kappa B/metabolismo , Camundongos Knockout , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Camundongos Endogâmicos C57BL , Células Th17/imunologia , Células Th17/metabolismo , Proteinúria/imunologia , Transdução de SinaisRESUMO
The aetiology and progression of systemic lupus erythematosus (SLE) resulted from a complex sequence of events generated both from genetic and epigenetic processes. In the current research, the effect of methyl-supplemented nutrition on the development of SLE was studied in the pristane-induced mouse model of the disease. The results clearly demonstrated decreased anti-dsDNA antibody and proteinuria levels, modulation of cytokines and protected renal structures in the group of treated mice. An additional increase in the DNA methylation of mouse B lymphocytes was also observed. The beneficial effect of the diet is due to the methyl-containing micronutrients with possible anti-inflammatory and immunomodulating effects on cell proliferation and gene expression. Since these components are responsible for maintaining the physiological methylation level of DNA, the results point to the central role of methylation processes in environmentally triggered lupus. As nutrition represents one of the major epigenetic factors, these micronutrients may be considered novel agents with significant therapeutic outcomes.
Assuntos
Anticorpos Antinucleares , Linfócitos B , Metilação de DNA , Suplementos Nutricionais , Modelos Animais de Doenças , Lúpus Eritematoso Sistêmico , Terpenos , Animais , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Camundongos , Anticorpos Antinucleares/imunologia , Anticorpos Antinucleares/sangue , Feminino , Linfócitos B/imunologia , Linfócitos B/metabolismo , Citocinas/metabolismo , Epigênese Genética , Micronutrientes/administração & dosagem , Proteinúria/imunologia , Rim/imunologia , Rim/metabolismo , Rim/patologia , Rim/efeitos dos fármacosRESUMO
Full-dose prednisone (FP) regimen in the treatment of high-risk immunoglobulin A nephropathy (IgAN) patients, is still controversial. The pulsed intravenous methylprednisolone combined with alternative low-dose prednisone (MCALP) might have a more favorable safety profile, which has not been fully investigated. Eighty-seven biopsy-proven IgAN adult patients and proteinuria between 1 and 3.5 g/24 h after ACEI/ARB for at least 90 days were randomly assigned to 6-month therapy: (1) MCALP group: 0.5 g of methylprednisolone intravenously for three consecutive days at the beginning of the course and 3rd month respectively, oral prednisone at a dose of 15 mg every other day for 6 months. (2) FP group: 0.8-1.0 mg/kg/days of prednisone (maximum 70 mg/day) for 2 months, then tapered by 5 mg every 10 days for the next 4 months. All patients were followed up for another 12 months. The primary outcome was complete remission (CR) of proteinuria at 12 months. The percentage of CR at 12th and 18th month were similar in the MCALP and FP groups (51% vs 58%, P = 0.490, at 12th month; 60% vs 56%, P = 0.714, at 18th month). The cumulative dosages of glucocorticoid were less in the MCALP group than FP group (4.31 ± 0.26 g vs 7.34 ± 1.21 g, P < 0.001). The analysis of the correlation between kidney biopsy Oxford MEST-C scores with clinical outcomes indicated the percentages of total remission was similar between two groups with or without M1, E1, S1, T1/T2, and C1/C2. More patients in the FP group presented infections (8% in MCALP vs 21% in FP), weight gain (4% in MCALP vs 19% in FP) and Cushing syndrome (3% in MCALP vs 18% in FP). These data indicated that MCALP maybe one of the choices for IgAN patients with a high risk for progression into ESKD.Trial registration: The study approved by the Chinese Clinical Trial Registry (registration date 13/01/2018, approval number ChiCTR1800014442, https://www.chictr.org.cn/ ).
Assuntos
Glomerulonefrite por IGA/tratamento farmacológico , Glucocorticoides/administração & dosagem , Metilprednisolona/administração & dosagem , Prednisona/administração & dosagem , Proteinúria/tratamento farmacológico , Administração Intravenosa , Administração Oral , Adulto , Progressão da Doença , Redução da Medicação , Quimioterapia Combinada , Feminino , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/imunologia , Glucocorticoides/efeitos adversos , Humanos , Falência Renal Crônica/imunologia , Falência Renal Crônica/prevenção & controle , Masculino , Metilprednisolona/efeitos adversos , Prednisona/efeitos adversos , Estudos Prospectivos , Proteinúria/diagnóstico , Proteinúria/imunologia , Pulsoterapia , Indução de Remissão , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Anti-phospholipase A2 receptor autoantibody (PLA2R-Ab) plays a critical role in the pathogenesis of primary membranous nephropathy (PMN), an autoimmune kidney disease characterized by immune deposits in the glomerular subepithelial spaces and proteinuria. However, the mechanism of how PLA2R-Abs interact with the conformational epitope(s) of PLA2R has remained elusive. PLA2R is a single transmembrane helix receptor containing ten extracellular domains that begin with a CysR domain followed by a FnII and eight CTLD domains. Here, we examined the interactions of PLA2R-Ab with the full PLA2R protein, N-terminal domain truncations, and C-terminal domain deletions under either denaturing or physiological conditions. Our data demonstrate that the PLA2R-Abs against the dominant epitope (the N-terminal CysR-CTLD1 triple domain) possess weak cross-reactivities to the C-terminal domains beyond CTLD1. Moreover, both the CysR and CTLD1 domains are required to form a conformational epitope for PLA2R-Ab interaction, with FnII serving as a linker domain. Upon close examination, we also observed that patients with newly diagnosed PMN carry two populations of PLA2R-Abs in sera that react to the denatured CysR-CTLD3 (the PLA2R-Ab1) and denatured CysR-CTLD1 (the PLA2R-Ab2) domain complexes on Western blots, respectively. Furthermore, the PLA2R-Ab1 appeared at an earlier time point than PLA2R-Ab2 in patients, whereas the increased levels of PLA2R-Ab2 coincided with the worsening of proteinuria. In summary, our data support that an integrated folding of the three PLA2R N-terminal domains, CysR, FnII, and CTLD1, is a prerequisite to forming the PLA2R conformational epitope and that the dominant epitope-reactive PLA2R-Ab2 plays a critical role in PMN clinical progression.
Assuntos
Glomerulonefrite Membranosa , Receptores da Fosfolipase A2 , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Epitopos , Feminino , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/urina , Humanos , Masculino , Proteinúria/genética , Proteinúria/imunologia , Receptores da Fosfolipase A2/química , Receptores da Fosfolipase A2/imunologiaRESUMO
Acute kidney injury (AKI) is a major cause of patient mortality and a major risk multiplier for the progression to chronic kidney disease (CKD). The mechanism of the AKI to CKD transition is complex but is likely mediated by the extent and length of the inflammatory response following the initial injury. Lymphatic vessels help to maintain tissue homeostasis through fluid, macromolecule, and immune modulation. Increased lymphatic growth, or lymphangiogenesis, often occurs during inflammation and plays a role in acute and chronic disease processes. What roles renal lymphatics and lymphangiogenesis play in AKI recovery and CKD progression remains largely unknown. To determine if the increased lymphatic density is protective in the response to kidney injury, we utilized a transgenic mouse model with inducible, kidney-specific overexpression of the lymphangiogenic protein vascular endothelial growth factor-D to expand renal lymphatics. "KidVD" mouse kidneys were injured using inducible podocyte apoptosis and proteinuria (POD-ATTAC) or bilateral ischemia reperfusion. In the acute injury phase of both models, KidVD mice demonstrated a similar loss of function measured by serum creatinine and glomerular filtration rate compared to their littermates. While the initial inflammatory response was similar, KidVD mice demonstrated a shift toward more CD4+ and fewer CD8+ T cells in the kidney. Reduced collagen deposition and improved functional recovery over time was also identified in KidVD mice. In KidVD-POD-ATTAC mice, an increased number of podocytes were counted at 28 days post-injury. These data demonstrate that increased lymphatic density prior to injury alters the injury recovery response and affords protection from CKD progression.
Assuntos
Injúria Renal Aguda/metabolismo , Rim/metabolismo , Vasos Linfáticos/metabolismo , Recuperação de Função Fisiológica , Traumatismo por Reperfusão/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/imunologia , Animais , Apoptose , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Colágeno/metabolismo , Modelos Animais de Doenças , Rim/imunologia , Linfangiogênese/genética , Camundongos , Camundongos Transgênicos , Podócitos , Proteinúria/imunologia , Proteinúria/metabolismo , Traumatismo por Reperfusão/imunologia , Tacrolimo/análogos & derivados , Tacrolimo/toxicidade , Fator D de Crescimento do Endotélio Vascular/genéticaRESUMO
Children with idiopathic nephrotic syndrome (INS) usually have podocyte injury, and recent studies suggest a B cell dysfunction in INS. Therefore, this study attempts to screen and identify the podocyte autoantibodies in patients. Two-dimensional electrophoresis and mass spectrometry were used to screen and identify the pathogenic podocyte autoantibodies in children with INS. The positive rate, expression pattern, and clinical correlation of these podocyte autoantibodies in children with INS were determined by clinical study. At least 66% of INS children have podocyte autoantibodies. Seven podocyte autoantibodies closely related to INS were screened and identified for the first time in this study. These podocyte autoantibodies are positively correlated with proteinuria, and its titer will decrease rapidly after effective treatment. In this study, a group of new disease subgroup-"autoimmune podocytes" were identified by podocyte autoantibodies.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Síndrome Nefrótica/imunologia , Podócitos/imunologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Proteinúria/imunologiaRESUMO
ABSTRACT: To investigate the clinicopathological features and outcomes of primary IgA nephropathy with nephrotic-range proteinuria in Chinese children. Patients with biopsy-proven IgA nephropathy and nephrotic-range proteinuria between January 2011 and December 2017 were included, and their proteinuria and renal function were followed up. A total of 90 patients were enrolled, and 21.1% (19/90) of them had decreased renal function at diagnosis. Complete remission, partial remission, and no response of proteinuria occurred in 88.6% (70/79), 10.1% (8/79), and 1.3% (1/79), respectively, of the 79 patients who were followed up for 6 to 104 months. 73.7% (14/19) of the patients with decreased renal function at diagnosis recovered to normal level while 26.3% (5/19) of them did not recover or progressed to end-stage renal disease. Two patients with normal renal function at diagnosis progressed to renal insufficiency during follow-up period. By multivariate analysis, the risk for renal function deterioration was significantly higher in the partial remission and no response groups than in the complete remission group. Remission of proteinuria was important for improving renal prognosis in children with IgA nephropathy and nephrotic-range proteinuria. The outcomes for pediatric patients appeared to be better than that reported in adults.
Assuntos
Glomerulonefrite por IGA/tratamento farmacológico , Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Falência Renal Crônica/epidemiologia , Proteinúria/epidemiologia , Adolescente , Biópsia , Criança , Pré-Escolar , China/epidemiologia , Quimioterapia Combinada/métodos , Feminino , Seguimentos , Mesângio Glomerular/patologia , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/patologia , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/imunologia , Falência Renal Crônica/urina , Masculino , Proteinúria/diagnóstico , Proteinúria/imunologia , Proteinúria/urina , Indução de Remissão/métodos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Ambiguities remain regarding the role of clinicopathological characteristics in the early prediction of the prognosis of lupus nephritis (LN). Systemic lupus erythematosus (SLE) patients who completed routine follow-up were identified and retrospectively reviewed for eligible cases. Poor prognosis was defined as all-cause mortality or a persistent decrease of eGFR greater than half the baseline level or progression to end-stage renal disease (ESRD). An optimal Cox regression model was constructed for the early prediction of a poor prognosis for LN. Among the 2163 SLE patients, 376 eligible LN cases were enrolled in the study, with a median follow-up time of 55 [27.0, 87.0] months. The male-to-female ratio was 1:7.2, and 37 patients (9.8%) progressed to the composite endpoint. The ISN/RPS class was significantly associated with proteinuria levels (P-value < 0.001), and class IV/IV + V patients, but not class V patients, had the most severe proteinuria. Our optimal multivariate Cox regression model indicated that sex, ISN/RPS class, tubular atrophy/interstitial fibrosis, serum albumin, tertiles of proteinuria, and their interaction were independently associated with a poor prognosis. ROC analysis and external validation demonstrated that our model was efficient and robust for distinguishing LN patients with a poor prognosis. Our study constructed a robust and early predictive model for convenience in clinical practice to identify poor prognosis in LN patients. We found a significant interaction effect between proteinuria and serum albumin for the prediction of poor prognosis. LN patients with low-level proteinuria and hypoalbuminemia exhibit an increased hazard of progression to poor outcomes.
Assuntos
Falência Renal Crônica/epidemiologia , Túbulos Renais/patologia , Nefrite Lúpica/mortalidade , Proteinúria/epidemiologia , Adulto , Biópsia , Progressão da Doença , Feminino , Fibrose , Seguimentos , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/imunologia , Falência Renal Crônica/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Masculino , Prognóstico , Proteinúria/diagnóstico , Proteinúria/imunologia , Proteinúria/patologia , Estudos Retrospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Albumina Sérica Humana/análise , Índice de Gravidade de DoençaRESUMO
BACKGROUND: The Oxford classification of IgA nephropathy (IgAN) was revised in 2016 which lacked sufficient evidence for prognostic value of subclassification of focal segmental glomerular sclerosis (S lesion), and the proper proportion of S lesion for subclassification remains undetermined. AIM: This study aimed to explore the predictive value of the new subclassification of S score on renal outcomes of IgAN patients. METHODS: 348 patients with IgAN-associated S lesion were enrolled. According to the optimal cut-off of 25% established by receiver operating characteristic (ROC) curves, we divided S1 patients into two groups: S1a group (S lesion < 25%) and S1b group (S lesion ≥ 25%). IgAN patients with mild lesion (M0E0S0T0C0) were set as the control group. The clinical features at renal biopsy, pathological findings, and follow-up parameters (follow-up time ranged from 1 to 5 years) were collected. We used univariate and multivariate analyses to assess whether the subclassification of S score could refine risk prediction and clinical utility. RESULTS: We demonstrated that S lesion ≥ 25% was associated with a more rapid GFR loss and a lower rate of complete remission of proteinuria even adjusted for multiple clinic pathological variables, compared to S1a group (All p values <.05). And the ratio of glomeruli with T lesion and crescents were higher in patients with S lesion ≥ 25%. Data showed that IgAN patients with S lesion ≥ 25% were at an increased risk of poor renal outcomes even with immunosuppression. CONCLUSION: This study might recommend new subclassification of S scores (S0 (no S lesion), S1 (S lesion <25% of glomeruli), and S2 (S lesion ≥ 25% of glomeruli)) for the Oxford classification. This model may also help to evaluate pros and cons of immunosuppressive therapy in IgAN patients with different level of S lesion.KEY MESSAGESS lesion ≥ 25% is an independent risk factor for poor renal outcome in IgAN patients.This new subclassification of S scores may help to evaluate pros and cons of immunotherapy in IgAN patients with different level of S lesion.
Assuntos
Tomada de Decisão Clínica , Glomerulonefrite por IGA/classificação , Glomerulonefrite por IGA/diagnóstico , Glomerulosclerose Segmentar e Focal/classificação , Glomerulosclerose Segmentar e Focal/diagnóstico , Adulto , Biópsia , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/imunologia , Glomerulosclerose Segmentar e Focal/imunologia , Humanos , Imunossupressores/uso terapêutico , Rim/imunologia , Masculino , Valor Preditivo dos Testes , Proteinúria/imunologia , Curva ROC , Valores de Referência , Indução de Remissão , Estudos Retrospectivos , Adulto JovemRESUMO
Pathogens such as the Epstein Barr virus (EBV) have long been implicated in the etiology of systemic lupus erythematosus (SLE). The Epstein Barr virus nuclear antigen I (EBNA-1) has been shown to play a role in the development of anti-nuclear antibodies characteristic of SLE. One mechanism by which EBV may play a role in SLE is molecular mimicry. We previously generated two monoclonal antibodies (mAbs) to EBNA-1 and demonstrated that they cross-react with double-stranded DNA (dsDNA). In the present study, we demonstrate that these mAbs have pathogenic potential. We show that they can bind to isolated rat glomeruli and that binding can be greatly diminished by pretreatment of glomeruli with DNase I, suggesting that these mAbs bind dsDNA in the kidney. We also demonstrate that these antibodies can deposit in the kidney when injected into mice and can induce proteinuria and elicit histopathological alterations consistent with glomerulonephritis. Finally, we show that these antibodies can cross-react with laminin and collagen IV in the extracellular matrix suggesting that direct binding to the glomerular basement membrane or mesangial matrix may also contribute to the antibody deposition in the kidney. In summary, our results indicate that EBNA-1 can elicit antibodies that cross-react with dsDNA, that can deposit in the kidney, and induce kidney damage. These results are significant because they support the role of a viral protein in SLE and lupus nephritis.
Assuntos
Anticorpos Antinucleares/toxicidade , Anticorpos Monoclonais/toxicidade , Anticorpos Antivirais/imunologia , DNA/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Glomérulos Renais/imunologia , Animais , Anticorpos Antinucleares/imunologia , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/isolamento & purificação , Colágeno/imunologia , Reações Cruzadas/imunologia , Desoxirribonuclease I , Infecções por Vírus Epstein-Barr/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/imunologia , Feminino , Membrana Basal Glomerular/imunologia , Membrana Basal Glomerular/metabolismo , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Glomerulonefrite/virologia , Células HEK293 , Humanos , Imunoglobulina G/imunologia , Glomérulos Renais/patologia , Laminina/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Mimetismo Molecular , Proteinúria/imunologia , Ratos , Ratos Sprague-DawleyRESUMO
Collapsing glomerulopathy represents a special variant of the proteinuric kidney disease focal segmental glomerulosclerosis (FSGS). Histologically, the collapsing form of FSGS (cFSGS) is characterized by segmental or global condensation and obliteration of glomerular capillaries, the appearance of hyperplastic and hypertrophic podocytes and severe tubulointerstitial damage. Clinically, cFSGS patients present with acute kidney injury, nephrotic-range proteinuria and are at a high risk of rapid progression to irreversible kidney failure. cFSGS can be attributed to numerous etiologies, namely, viral infections like HIV, cytomegalovirus, Epstein-Barr-Virus, and parvovirus B19 and also drugs and severe ischemia. Risk variants of the APOL1 gene, predominantly found in people of African descent, increase the risk of developing cFSGS. Patients infected with the new Corona-Virus SARS-CoV-2 display an increased rate of acute kidney injury (AKI) in severe cases of COVID-19. Besides hemodynamic instability, cytokine mediated injury and direct viral entry and infection of renal epithelial cells contributing to AKI, there are emerging reports of cFSGS associated with SARS-CoV-2 infection in patients of mainly African ethnicity. The pathogenesis of cFSGS is proposed to be linked with direct viral infection of podocytes, as described for HIV-associated glomerulopathy. Nevertheless, there is growing evidence that the systemic inflammatory cascade, activated in acute viral infections like COVID-19, is a major contributor to the impairment of basic cellular functions in podocytes. This mini review will summarize the current knowledge on cFSGS associated with viral infections with a special focus on the influence of systemic immune responses and potential mechanisms propagating the development of cFSGS.
Assuntos
COVID-19/complicações , Glomerulosclerose Segmentar e Focal/etiologia , Glomérulos Renais/virologia , Animais , COVID-19/imunologia , COVID-19/virologia , Células Epiteliais/imunologia , Células Epiteliais/virologia , Glomerulosclerose Segmentar e Focal/imunologia , Glomerulosclerose Segmentar e Focal/virologia , Humanos , Imunidade/imunologia , Glomérulos Renais/imunologia , Podócitos/imunologia , Podócitos/virologia , Proteinúria/etiologia , Proteinúria/imunologia , Proteinúria/virologia , SARS-CoV-2/imunologiaRESUMO
The novel coronavirus (SARS-CoV-2) has turned into a life-threatening pandemic disease (Covid-19). About 5% of patients with Covid-19 have severe symptoms including septic shock, acute respiratory distress syndrome, and the failure of several organs, while most of them have mild symptoms. Frequently, the kidneys are involved through direct or indirect mechanisms. Kidney involvement mainly manifests itself as proteinuria and acute kidney injury (AKI). The SARS-CoV-2-induced kidney damage is expected to be multifactorial; directly it can infect the kidney podocytes and proximal tubular cells and based on an angiotensin-converting enzyme 2 (ACE2) pathway it can lead to acute tubular necrosis, protein leakage in Bowman's capsule, collapsing glomerulopathy and mitochondrial impairment. The SARS-CoV-2-driven dysregulation of the immune responses including cytokine storm, macrophage activation syndrome, and lymphopenia can be other causes of the AKI. Organ interactions, endothelial dysfunction, hypercoagulability, rhabdomyolysis, and sepsis are other potential mechanisms of AKI. Moreover, lower oxygen delivery to kidney may cause an ischaemic injury. Understanding the fundamental molecular pathways and pathophysiology of kidney injury and AKI in Covid-19 is necessary to develop management strategies and design effective therapies.
Assuntos
Injúria Renal Aguda/patologia , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/patologia , Coagulação Intravascular Disseminada/patologia , Linfopenia/patologia , Necrose/patologia , Proteinúria/patologia , Sepse/patologia , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/virologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/imunologia , COVID-19/imunologia , COVID-19/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Citocinas/genética , Citocinas/imunologia , Coagulação Intravascular Disseminada/imunologia , Coagulação Intravascular Disseminada/virologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Túbulos Renais Proximais/imunologia , Túbulos Renais Proximais/fisiopatologia , Linfopenia/imunologia , Linfopenia/virologia , Necrose/imunologia , Necrose/virologia , Podócitos/imunologia , Podócitos/patologia , Proteinúria/imunologia , Proteinúria/virologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Sepse/imunologia , Sepse/virologia , Serina Endopeptidases/genética , Serina Endopeptidases/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologiaRESUMO
Systemic lupus erythematosus (SLE) is a multifactorial and heterogeneous autoimmune disease involving multiple organ systems and tissues. Lupus nephritis occurs in approximately 60% of patients with SLE and is the leading cause of morbidity. Diffuse alveolar hemorrhage (DAH) is a rare but very serious complication of SLE with a greater than 50% associated mortality. The etiology of SLE is unclear but has proposed genetic, hormonal, and environmental aspects. Pristane is a saturated terpenoid alkane and has become the most popular laboratory model for inducing lupus in mice. The pristane model of SLE has the capacity to reproduce many components of the human presentation of the disease. Previous studies have demonstrated that virus-derived immune-modulating proteins have the potential to control inflammatory and autoimmune disorders. Serp-1, a 55 kDa secreted and highly glycosylated immune modulator derived from myxoma virus (MYXV), has potent immunomodulatory activity in models of vasculitis, viral sepsis, collagen-induced arthritis, and transplant rejection. This chapter describes the mouse preclinical pristane lupus model as a method to examine virus-derived protein efficacy for treating autoimmune diseases and specifically lupus nephritis and DAH.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Hemorragia/prevenção & controle , Fatores Imunológicos/farmacologia , Nefrite Lúpica/tratamento farmacológico , Myxoma virus/química , Proteinúria/tratamento farmacológico , Proteínas Virais/farmacologia , Animais , Autoanticorpos/biossíntese , Citocinas/biossíntese , Modelos Animais de Doenças , Feminino , Hemorragia/imunologia , Hemorragia/patologia , Humanos , Fatores Imunológicos/imunologia , Injeções Intraperitoneais , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteinúria/induzido quimicamente , Proteinúria/imunologia , Proteinúria/patologia , Terpenos/administração & dosagem , Resultado do Tratamento , Proteínas Virais/imunologiaRESUMO
BACKGROUND: Systemic-lupus-nephritis is a chronic autoimmune disease characterized by immune complex deposition and a flare of autoantibodies and leading to renal injury. OBJECTIVES: To expose anti-Dense-Fine-Speckled-70 (DFS70)-antibodies to genetically-prone-lupus-mice. METHODS: NZBXW/F1 female mice were monitored for the onset of glomerulonephritis by proteinuria upon infusion of anti-DFS70 (40 µg/mouse), commercial-human-IgG (cIgG) or phosphate-buffered-saline (PBS) as controls. The survival time was detected by mice death. Circulating anti-dsDNA were tested by ELISA. Proteinuria, was defined by a standard semi-quantitative-Bayer-Multistix-dipstick. Kidney histology was analyzed by periodic-acid-Schiff-PAS staining. RESULTS: A significantly higher percentage of anti-DFS70-infused mice exhibited prolonged survival time as compared with cIgG and PBS-subjected mice (p < 0.022). One mouse out of 10 mice injected with anti-DFS70-antibodies died at week 36, whereas, 6 out of 10 mice subjected with PBS found dead at this time. Eighty percent of anti-DFS70 injected mice did not show severe glomerulonephritis by histology. CONCLUSIONS: anti-DFS70 attenuated the progression of glomerulonephritis and prolonged the survival time. Circulating anti-DFS70-autoantibodies may confer a protective role against renal injury in murine-lupus-nephritis. Our data may propose a novel therapy approach for lupus patients.
Assuntos
Anticorpos Antinucleares/imunologia , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Anticorpos Antinucleares/farmacologia , Modelos Animais de Doenças , Feminino , Rim/patologia , Camundongos , Camundongos Endogâmicos NZB , Proteinúria/imunologia , Proteinúria/patologia , Taxa de Sobrevida , Fatores de Transcrição/imunologiaRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disease in which the main contributors to organ damage are antibodies against autoantigens, such as double-stranded DNA (dsDNA). Calorie restriction and intermittent fasting (IF) have been shown to improve autoimmune disease symptoms in patients and animal models. Here, we tested the hypothesis that IF might improve symptoms in MRL/lpr mice, which spontaneously develop an SLE-like disease. Groups of mice were fed every other day (IF) or provided food ad libitum (controls), and various lupus-associated clinicopathological parameters were analyzed for up to 28 weeks. Contrary to expectations, anti-dsDNA antibody levels, immune complex deposition in the kidney, and glomerular injury were higher in the IF group than the control group, although there were no differences in spleen and lymph node weights between groups. Proteinuria was also worsened in the IF group. IF also increased the abundance of B cells, plasmablasts, and plasma cells and elevated autophagy in plasma cells in the spleen and lymph nodes. Secretion of anti-dsDNA antibody by splenocytes in vitro was reduced by chloroquine-induced inhibition of autophagy. These results suggest that IF exacerbates lupus nephritis in MRL/lpr mice by increasing autoantibody immune complex formation.
Assuntos
Células Produtoras de Anticorpos/imunologia , Autofagia/imunologia , Jejum/fisiologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Animais , Anticorpos Antinucleares/imunologia , Células Produtoras de Anticorpos/patologia , Autoanticorpos/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Modelos Animais de Doenças , Feminino , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , Proteinúria/imunologia , Proteinúria/patologia , Baço/imunologia , Baço/patologiaRESUMO
Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-ß (TGF-ß) cytokine family and an inflammation-associated protein. Here, we investigated the role of GDF15 in murine anti-glomerular basement membrane (GBM) glomerulonephritis. Glomerulonephritis induction in mice induced systemic expression of GDF15. Moreover, we demonstrate the protective effects for GDF15, as GDF15-deficient mice exhibited increased proteinuria with an aggravated crescent formation and mesangial expansion in anti-GBM nephritis. Herein, GDF15 was required for the regulation of T-cell chemotactic chemokines in the kidney. In addition, we found the upregulation of the CXCR3 receptor in activated T-cells in GDF15-deficient mice. These data indicate that CXCL10/CXCR3-dependent-signaling promotes the infiltration of T cells into the organ during acute inflammation controlled by GDF15. Together, these results reveal a novel mechanism limiting the migration of lymphocytes to the site of inflammation during glomerulonephritis.
Assuntos
Movimento Celular/imunologia , Membrana Basal Glomerular/imunologia , Glomerulonefrite Membranosa/imunologia , Fator 15 de Diferenciação de Crescimento/imunologia , Proteinúria/imunologia , Linfócitos T/imunologia , Animais , Movimento Celular/genética , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Membrana Basal Glomerular/patologia , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/patologia , Fator 15 de Diferenciação de Crescimento/genética , Camundongos , Camundongos Knockout , Proteinúria/genética , Proteinúria/patologia , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Linfócitos T/patologiaRESUMO
BACKGROUND: Angiotensin II type 1 receptors (AT1Rs) are expressed on podocytes, endothelial and other cells, and play an essential role in the maintenance of podocyte function and vascular homeostasis. The presence of AT1R antibodies (AT1R-Abs) leads to activation of these receptors resulting in podocyte injury and endothelial cell dysfunction. We assessed the correlation between AT1R-Abs and the risk of post-transplant FSGS. METHODS: This is a retrospective study, which included all kidney transplant recipients with positive AT1R-Abs (≥ 9 units/ml), who were transplanted and followed at our center between 2006 and 2016. We assessed the development of biopsy proven FSGS and proteinuria by urine protein to creatinine ratio of ≥1 g/g and reviewed short and long term outcomes. RESULTS: We identified 100 patients with positive AT1R-Abs at the time of kidney transplant biopsy or proteinuria. 49% recipients (FSGS group) had biopsy-proven FSGS and/or proteinuria and 51% did not (non-FSGS group). Pre-transplant hypertension was present in 89% of the FSGS group compared to 72% in the non-FSGS group, p = 0.027. Of the FSGS group, 43% were on angiotensin converting enzyme inhibitors or angiotensin receptor blockers prior to transplantation, compared to 25.5% in the non-FSGS group, p = 0.06. Primary idiopathic FSGS was the cause of ESRD in 20% of the FSGS group, compared to 6% in the non-FSGS group, p = 0.03. The allograft loss was significantly higher in the FSGS group 63% compared to 39% in non-FSGS. Odds ratio and 95% confidence interval were 2.66 (1.18-5.99), p = 0.017. CONCLUSIONS: Our data suggest a potential association between AT1R-Abs and post-transplant FSGS leading to worse allograft outcome. Therefore, AT1R-Abs may be considered biomarkers for post-transplant FSGS.
Assuntos
Anticorpos/imunologia , Glomerulosclerose Segmentar e Focal/epidemiologia , Rejeição de Enxerto/epidemiologia , Falência Renal Crônica/cirurgia , Transplante de Rim , Complicações Pós-Operatórias/epidemiologia , Proteinúria/epidemiologia , Receptor Tipo 1 de Angiotensina/imunologia , Adulto , Feminino , Glomerulosclerose Segmentar e Focal/complicações , Glomerulosclerose Segmentar e Focal/imunologia , Glomerulosclerose Segmentar e Focal/terapia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/terapia , Humanos , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/terapia , Proteinúria/imunologia , Proteinúria/terapia , Recidiva , Estudos RetrospectivosRESUMO
BACKGROUND: Previous reports suggest initial presentation of IgA nephropathy (IgAN) in children is different from adults. No systematic comparison of clinical, biological, and histological childhood- and adult-onset IgAN is currently available. METHODS: We compared pediatric and adult clinical and histological characteristics at IgAN diagnosis. Data on 211 consecutive patients from two different centers in Paris (82 children, 129 adults) were reviewed. Kidney biopsies were scored for Oxford classification and podocytopathic (P1) features. RESULTS: We report higher eGFR at diagnosis in children compared to adults (89.5 vs. 64 ml/min/1.73 m2; p = 0.0001) but no difference in proteinuria. Histological analysis of kidney biopsy found higher proportions of mesangial (M1) and endocapillary (E1) hypercellularity in children compared with adults (M1 [80.7% vs. 27.9%, p = 0.0001]; E1 [71.3% vs. 30%, p = 0.0001]). Focal glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis ≥ 25% (T1), and P1 were more frequent in adults (S1 [81.5% vs. 61.3%, p = 0.0012], T1 [49.5% vs. 1.35%, p = 0.0001], P1 [33.8% vs. 16.4%, p = 0.008). Proteinuria associated with M1, E1, and C1 in children (M1, p = 0.0001; E1, p = 0.0005; C1, p = 0.0014) but S1, P1, and T1 in adults (S1, p = 0.0001; P1, p = 0.0001; T1, p = 0.001). After steroid treatment (41 children and 28 adults), proteinuria decreased in children (p < 0.001, follow-up 38 months) and adults (p < 0.001, follow-up 76.9 months), whereas eGFR remained stable in adults but increased significantly in children (90.6 to 110 ml/min/1.73m2). CONCLUSION: Proteinuria in children with IgAN is a marker of glomerular proliferative lesions whereas its presence in adults often reflects the presence of chronic lesions. This suggests the need for histological assessment.
Assuntos
Glomerulonefrite por IGA/diagnóstico , Glomerulosclerose Segmentar e Focal/epidemiologia , Glucocorticoides/administração & dosagem , Glomérulos Renais/patologia , Proteinúria/diagnóstico , Adulto , Fatores Etários , Biópsia , Criança , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/imunologia , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/imunologia , Humanos , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/imunologia , Masculino , Proteinúria/tratamento farmacológico , Proteinúria/imunologia , Proteinúria/urina , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disorder. Renal involvement usually develops in the first few years of illness and should be detected early by periodic urine analysis and quantitation of proteinuria. The aim of our work was to evaluate the biological marker [anti-complement 1q antibodies (anti-C1q Ab)] in lupus nephritis (LN) patients and its correlation to SLE disease activity. Sixty-five subjects were divided into four groups; Group I: SLE patients with LN (proteinuria >0.5 g/day), Group II: SLE patients without LN (all of them had a lupus flares rather than nephritis; active nonrenal), Group III: SLE patients without any activity (inactive disease), and Group IV: Control group. All subjects underwent urine analysis, complete blood picture, liver function tests, kidney function tests, albumin/ creatinine ratio, antinuclear antibody, anti-double stranded DNA (anti-dsDNA) antibody, C3, C4, and anti-C1q Ab. All patients in the first group underwent renal biopsy and pathological diagnosis showed: Class II in two patients, Class III and IV in nine patients, and Class V in four patients. Anti-C1q Ab were found in the serum of SLE patients and not in the control group and showed an association with active lupus with much higher concentration in active renal group, specifically those with severe renal histological lesions (proliferative form). There was significant statistical positive correlation between anti-C1q Ab with anti-dsDNA and SLE disease activity index in both active groups. There was statistically significant negative correlation between anti-C1q Ab with C3 and C4 in both active groups. Anti-C1q Ab could be used as useful marker for active lupus, especially with nephritis.