Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.302
Filtrar
1.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638835

RESUMO

Extracellular vesicles (EVs) are nanoparticles that transmit molecules from releasing cells to target cells. Recent studies link urinary EVs (uEV) to diverse processes such as infection and rejection after kidney transplantation. This, and the unmet need for biomarkers diagnosing kidney transplant dysfunction, has led to the current high level of interest in uEV. uEV provide non-intrusive access to local protein, DNA, and RNA analytics without invasive biopsy. To determine the added value of uEV measurements for detecting allograft dysfunction after kidney transplantation, we systematically included all related literature containing directly relevant information, with the addition of indirect evidence regarding urine or kidney injury without transplantation. According to their varying characteristics, uEV markers after transplantation could be categorized into kidney-specific, donor-specific, and immune response-related (IR-) markers. A few convincing studies have shown that kidney-specific markers (PODXL, ion cotransporters, SYT17, NGAL, and CD133) and IR-markers (CD3, multi-mRNA signatures, and viral miRNA) could diagnose rejection, BK virus-associated nephropathy, and calcineurin inhibitor nephrotoxicity after kidney transplantation. In addition, some indirect proof regarding donor-specific markers (donor-derived cell-free DNA) in urine has been demonstrated. Together, this literature review provides directions for exploring novel uEV markers' profiling complications after kidney transplantation.


Assuntos
Vesículas Extracelulares/metabolismo , Rejeição de Enxerto/urina , Transplante de Rim , Rim/metabolismo , Aloenxertos , Biomarcadores/urina , Vesículas Extracelulares/imunologia , Rejeição de Enxerto/imunologia , Humanos , Rim/imunologia , Rim/cirurgia
2.
Nutrients ; 13(10)2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34684578

RESUMO

In a previous study, we demonstrated that melatonin prevents kidney damage in a salt-induced hypertension model by decreasing oxidative stress. We hypothesized that this effect involves melatonin's immunomodulatory properties. In vivo Study-Dahl salt-sensitive (DSS) rats were fed normal chow, a high-salt diet (HSD), or a HSD and melatonin (30 mg/kg/day) in their water for eight weeks. Kidneys were harvested for immediate lymphocyte isolation and characterization by Flow cytometry (CD3+CD4+ and CD3+CD8+) and for lymphocyte chemoattractant (mainly CXCL chemokines) gene expression studies. In vitro study-rat mesangial cells (RMC) were cultured in a high-salt medium without and with melatonin. A HSD was associated with significant renal infiltration of CD4+ and CD8+ T lymphocytes compared to control. Melatonin significantly reduced renal lymphocyte infiltration. A HSD significantly increased mRNA expression of CXCL chemokines. Adding melatonin to the HSD abolished this effect. Treating RMC cells with salt increased the expression of CXCL10 and CXCL11 but not CXCL9. Adding melatonin to the culture media prevented this increase. Treating HSD-fed rats with melatonin decreased renal lymphocyte chemoattractant mRNA expression and is associated with significantly reducing renal T lymphocyte infiltration. Salt may have a direct effect on chemokine-producing renal cells, which is blunted by melatonin treatment.


Assuntos
Quimiocinas/metabolismo , Hipertensão/imunologia , Rim/imunologia , Melatonina/farmacologia , Receptores CXCR3/metabolismo , Linfócitos T/imunologia , Animais , Linhagem Celular , Hipertensão/prevenção & controle , Rim/efeitos dos fármacos , Ligantes , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Ratos , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta , Linfócitos T/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
3.
Nutrients ; 13(10)2021 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-34684638

RESUMO

Chronic kidney disease (CKD) is generally progressive and irreversible, structural or functional renal impairment for 3 or more months affecting multiple metabolic pathways. Recently, the composition, dynamics, and stability of a patient's microbiota has been noted to play a significant role during disease onset or progression. Increasing urea concentration during CKD can lead to an acceleration of the process of kidney injury leading to alterations in the intestinal microbiota that can increase the production of gut-derived toxins and alter the intestinal epithelial barrier. A detailed analysis of the relationship between the role of intestinal microbiota and the development of inflammation within the symbiotic and dysbiotic intestinal microbiota showed significant changes in kidney dysfunction. Several recent studies have determined that dietary factors can significantly influence the activation of immune cells and their mediators. Moreover, dietary changes can profoundly affect the balance of gut microbiota. The aim of this review is to present the importance and factors influencing the differentiation of the human microbiota in the progression of kidney diseases, such as CKD, IgA nephropathy, idiopatic nephropathy, and diabetic kidney disease, with particular emphasis on the role of the immune system. Moreover, the effects of nutrients, bioactive compounds on the immune system in development of chronic kidney disease were reviewed.


Assuntos
Microbioma Gastrointestinal/imunologia , Sistema Imunitário/microbiologia , Fenômenos Fisiológicos da Nutrição/imunologia , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/microbiologia , Humanos , Rim/imunologia , Rim/microbiologia
4.
Front Immunol ; 12: 668974, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539623

RESUMO

Objectives: This aim of this study was to determine whether neutrophil extracellular traps (NETs) are involved in the pathogenesis of IgA vasculitis (IgAV) and investigate whether the circulating NETs levels are associated with disease activity in children. Methods: We performed a case-control study and collected blood samples from 193 children with different stages of IgAV (61 were at the onset stage, 64 at the remission stage, 43 at the active stage, and 25 were undergoing drug withdrawal). A total of 192 healthy children were recruited as controls. Circulating cell free DNA (cf-DNA) was obtained from the plasma and quantified by using the Quant-iT PicoGreen DNA quantification kit. NETs-associated myeloperoxidase-DNA (MPO-DNA), citrullinated-histone H3 (cit-H3), neutrophil elastase (NE), and the deoxyribonuclease I (DNase I) concentrations were measured using enzyme-linked immunosorbent assays. The presence of NETs in the kidney and gastrointestinal tissues of onset and active IgAV patients was determined by multiple immunofluorescence staining in 15 IgAV nephritis patients and 9 IgAV patients without IgAV nephritis, respectively. NETs degradation potency of collected sera samples from IgAV patients were checked in vitro. Relationships between circulating levels of cf-DNA with MPO-DNA, NE, and DNase I and the patients were analyzed. Results: Circulating levels of cf-DNA in onset and active IgAV patients were significantly higher than those in remission and drug withdrawal patients as well as healthy controls. The results were similar for MPO-DNA and NE. The levels of circulating cf-DNA correlated significantly with MPO-DNA, NE and DNase I. A significantly decreased degradation of NETs from the onset and active IgAV patients was observed, but was normal in healthy controls. Furthermore, presence of NETs was also confirmed in all renal and gastrointestinal tissues obtained from the onset and active IgAV patients but not control samples. Conclusions: Our data showed that NETs were released into the circulation of IgAV patients and are involved in the disease activity. The circulating levels of NETs maybe used to assess disease severity in children with IgAV.


Assuntos
Armadilhas Extracelulares/metabolismo , Imunoglobulina A/sangue , Neutrófilos/metabolismo , Púrpura de Schoenlein-Henoch/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Ácidos Nucleicos Livres/sangue , Criança , Pré-Escolar , DNA/sangue , Feminino , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/metabolismo , Humanos , Rim/imunologia , Rim/metabolismo , Masculino , Ativação de Neutrófilo , Neutrófilos/imunologia , Púrpura de Schoenlein-Henoch/sangue , Púrpura de Schoenlein-Henoch/diagnóstico , Púrpura de Schoenlein-Henoch/tratamento farmacológico , Índice de Gravidade de Doença
5.
Front Immunol ; 12: 688647, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34381446

RESUMO

Innate lymphoid cells (ILCs) are a recently discovered lymphocyte population with high cytokine productive capacity. Type-2 ILCs (ILC2s) are the most studied, and they exert a rapid type-2 immune response to eliminate helminth infections. Massive and sustainable ILC2 activation induces allergic tissue inflammation, so it is important to maintain correct ILC2 activity for immune homeostasis. The ILC2-activating cytokine IL-33 is released from epithelial cells upon tissue damage, and it is upregulated in various kidney disease mouse models and in kidney disease patients. Various kidney diseases eventually lead to renal fibrosis, which is a common pathway leading to end-stage renal disease and is a chronic kidney disease symptom. The progression of renal fibrosis is affected by the innate immune system, including renal-resident ILC2s; however, the roles of ILC2s in renal fibrosis are not well understood. In this review, we summarize renal ILC2 function and characterization in various kidney diseases and highlight the known and potential contributions of ILC2s to kidney fibrosis.


Assuntos
Imunidade Inata , Rim/imunologia , Linfócitos/imunologia , Nefrite/imunologia , Insuficiência Renal Crônica/imunologia , Animais , Citocinas/metabolismo , Progressão da Doença , Fibrose , Humanos , Rim/metabolismo , Rim/patologia , Linfócitos/metabolismo , Nefrite/metabolismo , Nefrite/patologia , Fenótipo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais
6.
Biomolecules ; 11(7)2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34356613

RESUMO

Renal fibrosis is a hallmark of chronic kidney disease (CKD) and a common manifestation of end-stage renal disease that is associated with multiple types of renal insults and functional loss of the kidney. Unresolved renal inflammation triggers fibrotic processes by promoting the activation and expansion of extracellular matrix-producing fibroblasts and myofibroblasts. Growing evidence now indicates that diverse T cells and macrophage subpopulations play central roles in the inflammatory microenvironment and fibrotic process. The present review aims to elucidate the role of CD8+ T cells in renal fibrosis, and identify its possible mechanisms in the inflammatory microenvironment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Rim/imunologia , Miofibroblastos/imunologia , Insuficiência Renal Crônica/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Fibrose , Humanos , Inflamação/imunologia , Inflamação/patologia , Rim/patologia , Miofibroblastos/patologia , Insuficiência Renal Crônica/patologia
7.
Pediatr Nephrol ; 36(11): 3789-3793, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34406477

RESUMO

BACKGROUND: Histological findings of kidney involvement have been rarely reported in pediatric patients with SARS-CoV-2 infection. Here, we describe clinical, laboratory, and histological findings of two pediatric cases with almost exclusive kidney involvement by SARS-CoV-2. RESULTS: A 10-year-old girl with IgA vasculitis nephritis underwent kidney biopsy, showing diffuse and segmental mesangial-proliferative glomerulonephritis, and steroid therapy was initiated. After the worsening of the clinical picture, including an atypical skin rash, she was diagnosed with SARS-CoV-2. The re-evaluation of initial biopsy showed cytoplasmatic blebs and virus-like particles in tubular cells at electron microscopy. Despite SARS-CoV-2 clearance and the intensification of immunosuppression, no improvement was observed. A second kidney biopsy showed a crescentic glomerulonephritis with sclerosis, while virus-like particles were no longer evident. The second patient was a 12-year-old girl with a 3-week history of weakness and weight loss. Rhinitis was reported the month before. No medications were being taken. Blood and urine analysis revealed elevated serum creatinine, hypouricemia, low molecular weight proteinuria, and glycosuria. A high SARS-CoV-2-IgG titre was detected. Kidney biopsy showed acute tubular-interstitial nephritis. Steroid therapy was started with a complete resolution of kidney involvement. CONCLUSION: We can speculate that in both cases SARS-CoV-2 played a major role as inflammatory trigger of the kidney damage. Therefore, we suggest investigating the potential kidney damage by SARS-CoV-2 in children. Moreover, SARS-CoV-2 can be included among infectious agents responsible for pediatric acute tubular interstitial nephritis.


Assuntos
COVID-19/complicações , Glomerulonefrite por IGA/imunologia , Rim/patologia , Nefrite Intersticial/imunologia , SARS-CoV-2/imunologia , Biópsia , COVID-19/imunologia , COVID-19/virologia , Criança , Feminino , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/patologia , Glomerulonefrite por IGA/virologia , Humanos , Rim/imunologia , Rim/ultraestrutura , Rim/virologia , Microscopia Eletrônica , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/patologia , Nefrite Intersticial/virologia , SARS-CoV-2/isolamento & purificação
8.
Front Immunol ; 12: 692216, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34381449

RESUMO

Primary Sjögren's syndrome is an autoimmune disease that is predominantly seen in women. The disease is characterized by exocrine gland dysfunction in combination with serious systemic manifestations. At present, the causes of pSS are poorly understood. Pulmonary and renal inflammation are observed in pSS mice, reminiscent of a subset of pSS patients. A growing body of evidence indicates that inflammation mediated by Damage-Associated Molecular Patterns (DAMPs) contributes to autoimmunity, although this is not well-studied in pSS. Degraded extracellular matrix (ECM) constituents can serve as DAMPs by binding pattern-recognition receptors and activating Myd88-dependent signaling cascades, thereby exacerbating and perpetuating inflammatory cascades. The ECM components biglycan (Bgn) and decorin (Dcn) mediate sterile inflammation and both are implicated in autoimmunity. The objective of this study was to determine whether these ECM components and anti-ECM antibodies are altered in a pSS mouse model, and whether this is dependent on Myd88 activation in immune cells. Circulating levels of Bgn and Dcn were similar among pSS mice and controls and tissue expression studies revealed pSS mice had robust expression of both Bgn and Dcn in the salivary tissue, saliva, lung and kidney. Sera from pSS mice displayed increased levels of autoantibodies directed against ECM components when compared to healthy controls. Further studies using sera derived from conditional knockout pSS mice demonstrated that generation of these autoantibodies relies, at least in part, on Myd88 expression in the hematopoietic compartment. Thus, this study demonstrates that ECM degradation may represent a novel source of chronic B cell activation in the context of pSS.


Assuntos
Autoanticorpos/imunologia , Matriz Extracelular/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Síndrome de Sjogren/imunologia , Animais , Biglicano/imunologia , Decorina/imunologia , Elastina/imunologia , Feminino , Rim/imunologia , Pulmão/imunologia , Camundongos Transgênicos , Fator 88 de Diferenciação Mieloide/genética , Saliva/imunologia , Glândulas Salivares/imunologia
9.
Front Immunol ; 12: 669162, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248948

RESUMO

Renal ischemia is the most common cause of acute kidney injury (AKI) that might be exacerbate lupus activity through neutrophil extracellular traps (NETs) and apoptosis. Here, the renal ischemia reperfusion injury (I/R) was performed in Fc gamma receptor 2b deficient (Fcgr2b-/-) lupus mice and the in vitro experiments. At 24 h post-renal I/R injury, NETs in peripheral blood neutrophils and in kidneys were detected using myeloperoxidase (MPO), neutrophil elastase (NE) and citrullinated histone H3 (CitH3), as well as kidney apoptosis (activating caspase-3), which were prominent in Fcgr2b-/- mice more compared to wild-type (WT). After 120 h renal-I/R injury, renal NETs (using MPO and NE) were non-detectable, whereas glomerular immunoglobulin (Ig) deposition and serum anti-dsDNA were increased in Fcgr2b-/- mice. These results imply that renal NETs at 24 h post-renal I/R exacerbated the lupus nephritis at 120 h post-renal I/R injury in Fcgr2b-/- lupus mice. Furthermore, a Syk inhibitor attenuated NETs, that activated by phorbol myristate acetate (PMA; a NETs activator) or lipopolysaccharide (LPS; a potent inflammatory stimulator), more prominently in Fcgr2b-/- neutrophils than the WT cells as determined by dsDNA, PAD4 and MPO. In addition, the inhibitors against Syk and PAD4 attenuated lupus characteristics (serum creatinine, proteinuria, and anti-dsDNA) in Fcgr2b-/- mice at 120 h post-renal I/R injury. In conclusion, renal I/R in Fcgr2b-/- mice induced lupus exacerbation at 120 h post-I/R injury partly because Syk-enhanced renal NETs led to apoptosis-induced anti-dsDNA, which was attenuated by a Syk inhibitor.


Assuntos
Injúria Renal Aguda/metabolismo , Apoptose , Armadilhas Extracelulares/metabolismo , Rim/metabolismo , Nefrite Lúpica/metabolismo , Neutrófilos/metabolismo , Receptores de IgG/deficiência , Traumatismo por Reperfusão/metabolismo , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/patologia , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores de IgG/genética , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Quinase Syk/antagonistas & inibidores , Quinase Syk/metabolismo , Fatores de Tempo
10.
Front Immunol ; 12: 646650, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194427

RESUMO

Objective: To analyze the expression of macrophages, AIM, TGF-ß1 in the kidney of IgAN patients, and to explore the role of macrophages, AIM, TGF-ß1 in the progression of renal fibrosis in IgAN patients. Methods: The paraffin specimens of renal tissue from 40 IgAN patients were selected as the observation group. At the same time, paraffin specimens of normal renal tissue from 11 patients treated by nephrectomy were selected as the normal control group. We observed the distribution of macrophages, the expression of AIM and TGF-ß1 by immunohistochemical staining and/or immunofluorescence. Result: The number of M0, M1, M2 macrophages could be found increased in IgAN patients. M0 macrophages are mainly polarized towards M2 macrophages. The expression of AIM and TGF-ß1 were significantly higher in IgAN patients than in NC. M2 macrophage, AIM and TGF-ß1 were positively correlated with serum creatinine and 24-hour proteinuria, but negatively correlated with eGFR. M2 macrophages, AIM, TGF-ß1 were positively correlated with fibrotic area. Conclusion: M2 macrophages, AIM and TGF-ß1 play important roles in the process of IgAN fibrosis, and the three influence each other.


Assuntos
Proteínas Reguladoras de Apoptose/imunologia , Glomerulonefrite por IGA/imunologia , Rim/imunologia , Macrófagos/imunologia , Receptores Depuradores/imunologia , Fator de Crescimento Transformador beta1/imunologia , Análise de Variância , Proteínas Reguladoras de Apoptose/metabolismo , Feminino , Fibrose , Imunofluorescência/métodos , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/patologia , Humanos , Imuno-Histoquímica/métodos , Rim/metabolismo , Rim/patologia , Macrófagos/classificação , Masculino , Receptores Depuradores/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
11.
Front Immunol ; 12: 650856, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211460

RESUMO

Accumulating evidence suggests that cholesterol accumulation in leukocytes is causally associated with the development of autoimmune diseases. However, the mechanism by which fatty acid composition influences autoimmune responses remains unclear. To determine whether the fatty acid composition of diet modulates leukocyte function and the development of systemic lupus erythematosus, we examined the effect of eicosapentaenoic acid (EPA) on the pathology of lupus in drug-induced and spontaneous mouse models. We found that dietary EPA supplementation ameliorated representative lupus manifestations, including autoantibody production and immunocomplex deposition in the kidneys. A combination of lipidomic and membrane dynamics analyses revealed that EPA remodels the lipid composition and fluidity of B cell membranes, thereby preventing B cell differentiation into autoantibody-producing plasma cells. These results highlight a previously unrecognized mechanism by which fatty acid composition affects B cell differentiation into autoantibody-producing plasma cells during autoimmunity, and imply that EPA supplementation may be beneficial for therapy of lupus.


Assuntos
Autoimunidade/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Suplementos Nutricionais , Ácido Eicosapentaenoico/farmacologia , Lúpus Eritematoso Sistêmico/prevenção & controle , Plasmócitos/efeitos dos fármacos , Animais , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Autoimunidade/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Células Cultivadas , Modelos Animais de Doenças , Ácido Eicosapentaenoico/administração & dosagem , Feminino , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Lúpus Eritematoso Sistêmico/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmócitos/imunologia , Plasmócitos/metabolismo
12.
Biomolecules ; 11(6)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205864

RESUMO

Animals acquire nutrients and energy through feeding to achieve a balance between growth and organismal health. When there is a change in nutrient acquisition, the state of growth changes and may also cause changes in the intrinsic immune system. Compensatory growth (CG), a specific growth phenomenon, involves the question of whether changes in growth can be accompanied by changes in innate immunity. The zebrafish (Danio rerio), a well-known fish model organism, can serve as a suitable model. In this study, the zebrafish underwent 3 weeks of fasting and refeeding for 3 to 7 day periods. It was found that CG could be achieved in zebrafish. Zebrafish susceptibility to Streptococcus agalactiae increased after starvation. In addition, the amount of melano-macrophage centers increased after fasting and the proportion of injured tubules increased after refeeding for 3 and 5 days, respectively. Furthermore, the kidneys of zebrafish suffering from starvation were under oxidative stress, and the activity of several antioxidant enzymes increased after starvation, including catalase, glutathione peroxidases and superoxide dismutase. Innate immune parameters were influenced by starvation. Additionally, the activity of alkaline phosphatase and lysozyme increased after starvation. The mRNA expression of immune-related genes like il-1ß was elevated to a different extent after fasting with or without lipopolysaccharides (LPS) challenge. This study showed that the function of the innate immune system in zebrafish could be influenced by nutrition status.


Assuntos
Ingestão de Alimentos/imunologia , Jejum , Imunidade Inata , Rim/imunologia , Peixe-Zebra/imunologia , Animais , Antioxidantes , Interleucina-1beta/imunologia , Lipopolissacarídeos/toxicidade , Oxirredutases/imunologia , Proteínas de Peixe-Zebra/imunologia
13.
Front Immunol ; 12: 595150, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262555

RESUMO

As one of the current global health conundrums, COVID-19 pandemic caused a dramatic increase of cases exceeding 79 million and 1.7 million deaths worldwide. Severe presentation of COVID-19 is characterized by cytokine storm and chronic inflammation resulting in multi-organ dysfunction. Currently, it is unclear whether extrapulmonary tissues contribute to the cytokine storm mediated-disease exacerbation. In this study, we applied systems immunology analysis to investigate the immunomodulatory effects of SARS-CoV-2 infection in lung, liver, kidney, and heart tissues and the potential contribution of these tissues to cytokines production. Notably, genes associated with neutrophil-mediated immune response (e.g. CXCL1) were particularly upregulated in lung, whereas genes associated with eosinophil-mediated immune response (e.g. CCL11) were particularly upregulated in heart tissue. In contrast, immune responses mediated by monocytes, dendritic cells, T-cells and B-cells were almost similarly dysregulated in all tissue types. Focused analysis of 14 cytokines classically upregulated in COVID-19 patients revealed that only some of these cytokines are dysregulated in lung tissue, whereas the other cytokines are upregulated in extrapulmonary tissues (e.g. IL6 and IL2RA). Investigations of potential mechanisms by which SARS-CoV-2 modulates the immune response and cytokine production revealed a marked dysregulation of NF-κB signaling particularly CBM complex and the NF-κB inhibitor BCL3. Moreover, overexpression of mucin family genes (e.g. MUC3A, MUC4, MUC5B, MUC16, and MUC17) and HSP90AB1 suggest that the exacerbated inflammation activated pulmonary and extrapulmonary tissues remodeling. In addition, we identified multiple sets of immune response associated genes upregulated in a tissue-specific manner (DCLRE1C, CHI3L1, and PARP14 in lung; APOA4, NFASC, WIPF3, and CD34 in liver; LILRA5, ISG20, S100A12, and HLX in kidney; and ASS1 and PTPN1 in heart). Altogether, these findings suggest that the cytokines storm triggered by SARS-CoV-2 infection is potentially the result of dysregulated cytokine production by inflamed pulmonary and extrapulmonary (e.g. liver, kidney, and heart) tissues.


Assuntos
COVID-19/epidemiologia , COVID-19/imunologia , Rim/imunologia , Fígado/imunologia , Pulmão/imunologia , Miocárdio/imunologia , Pandemias , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Biomarcadores/sangue , COVID-19/sangue , COVID-19/complicações , Estudos de Casos e Controles , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/biossíntese , Humanos , Imunidade/genética , Monócitos/imunologia , Neutrófilos/imunologia , Transcriptoma , Regulação para Cima/genética
14.
PLoS Pathog ; 17(7): e1009705, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34265022

RESUMO

COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is a disease affecting several organ systems. A model that captures all clinical symptoms of COVID-19 as well as long-haulers disease is needed. We investigated the host responses associated with infection in several major organ systems including the respiratory tract, the heart, and the kidneys after SARS-CoV-2 infection in Syrian hamsters. We found significant increases in inflammatory cytokines (IL-6, IL-1beta, and TNF) and type II interferons whereas type I interferons were inhibited. Examination of extrapulmonary tissue indicated inflammation in the kidney, liver, and heart which also lacked type I interferon upregulation. Histologically, the heart had evidence of myocarditis and microthrombi while the kidney had tubular inflammation. These results give insight into the multiorgan disease experienced by people with COVID-19 and possibly the prolonged disease in people with post-acute sequelae of SARS-CoV-2 (PASC).


Assuntos
COVID-19/imunologia , Regulação para Baixo/imunologia , Interferon Tipo I/imunologia , Rim/imunologia , Miocárdio/imunologia , Sistema Respiratório/imunologia , SARS-CoV-2/imunologia , Animais , COVID-19/patologia , Cricetinae , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Inflamação/patologia , Rim/patologia , Rim/virologia , Masculino , Mesocricetus , Miocárdio/patologia , Sistema Respiratório/patologia , Sistema Respiratório/virologia
15.
Nat Commun ; 12(1): 4372, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272370

RESUMO

Intrarenal B cells in human renal allografts indicate transplant recipients with a poor prognosis, but how these cells contribute to rejection is unclear. Here we show using single-cell RNA sequencing that intrarenal class-switched B cells have an innate cell transcriptional state resembling mouse peritoneal B1 or B-innate (Bin) cells. Antibodies generated by Bin cells do not bind donor-specific antigens nor are they enriched for reactivity to ubiquitously expressed self-antigens. Rather, Bin cells frequently express antibodies reactive with either renal-specific or inflammation-associated antigens. Furthermore, local antigens can drive Bin cell proliferation and differentiation into plasma cells expressing self-reactive antibodies. These data show a mechanism of human inflammation in which a breach in organ-restricted tolerance by infiltrating innate-like B cells drives local tissue destruction.


Assuntos
Aloenxertos/imunologia , Linfócitos B/metabolismo , Rejeição de Enxerto/imunologia , Inflamação/metabolismo , Transplante de Rim/efeitos adversos , Animais , Autoanticorpos/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Ontologia Genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Imunoglobulina G/imunologia , Rim/imunologia , Rim/metabolismo , Camundongos , Tonsila Palatina/imunologia , Tonsila Palatina/metabolismo , RNA-Seq , Análise de Célula Única , Transplante Homólogo
16.
Front Immunol ; 12: 661643, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093552

RESUMO

Despite advances in post-transplant management, the long-term survival rate of kidney grafts and patients has not improved as approximately forty percent of transplants fails within ten years after transplantation. Both immunologic and non-immunologic factors contribute to late allograft loss. Chronic kidney transplant rejection (CKTR) is often clinically silent yet progressive allogeneic immune process that leads to cumulative graft injury, deterioration of graft function. Chronic active T cell mediated rejection (TCMR) and chronic active antibody-mediated rejection (ABMR) are classified as two principal subtypes of CKTR. While significant improvements have been made towards a better understanding of cellular and molecular mechanisms and diagnostic classifications of CKTR, lack of early detection, differential diagnosis and effective therapies continue to pose major challenges for long-term management. Recent development of high throughput cellular and molecular biotechnologies has allowed rapid development of new biomarkers associated with chronic renal injury, which not only provide insight into pathogenesis of chronic rejection but also allow for early detection. In parallel, several novel therapeutic strategies have emerged which may hold great promise for improvement of long-term graft and patient survival. With a brief overview of current understanding of pathogenesis, standard diagnosis and challenges in the context of CKTR, this mini-review aims to provide updates and insights into the latest development of promising novel biomarkers for diagnosis and novel therapeutic interventions to prevent and treat CKTR.


Assuntos
Anticorpos/imunologia , Rejeição de Enxerto/imunologia , Transplante de Rim/métodos , Rim/imunologia , Linfócitos T/imunologia , Biomarcadores/análise , Doença Crônica , Diagnóstico Precoce , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/prevenção & controle , Humanos , Rim/patologia , Transplante de Rim/efeitos adversos , Transplante Homólogo
17.
J Am Soc Nephrol ; 32(9): 2242-2254, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34112705

RESUMO

BACKGROUND: Although coronavirus disease 2019 (COVID-19) causes significan t morbidity, mainly from pulmonary involvement, extrapulmonary symptoms are also major componen ts of the disease. Kidney disease, usually presenting as AKI, is particularly severe among patients with COVID-19. It is unknown, however, whether such injury results from direct kidney infection with COVID-19's causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or from indirect mechanisms. METHODS: Using ex vivo cell models, we sought to analyze SARS-CoV-2 interactions with kidney tubular cells and assess direct tubular injury. These models comprised primary human kidney epithelial cells (derived from nephrectomies) and grown as either proliferating monolayers or quiescent three-dimensional kidney spheroids. RESULTS: We demonstrated that viral entry molecules and high baseline levels of type 1 IFN-related molecules were present in monolayers and kidney spheroids. Although both models support viral infection and replication, they did not exhibit a cytopathic effect and cell death, outcomes that were strongly present in SARS-CoV-2-infected controls (African green monkey kidney clone E6 [Vero E6] cultures). A comparison of monolayer and spheroid cultures demonstrated higher infectivity and replication of SARS-CoV-2 in actively proliferating monolayers, although the spheroid cultures exhibited high er levels of ACE2. Monolayers exhibited elevation of some tubular injury molecules-including molecules related to fibrosis (COL1A1 and STAT6) and dedifferentiation (SNAI2)-and a loss of cell identity, evident by reduction in megalin (LRP2). The three-dimensional spheroids were less prone to such injury. CONCLUSIONS: SARS-CoV-2 can infect kidney cells without a cytopathic effect. AKI-induced cellular proliferation may potentially intensify infectivity and tubular damage by SARS-CoV-2, suggesting that early intervention in AKI is warranted to help minimize kidney infection.


Assuntos
Injúria Renal Aguda/etiologia , Injúria Renal Aguda/virologia , COVID-19/complicações , SARS-CoV-2/patogenicidade , Esferoides Celulares/virologia , Animais , Células Cultivadas , Chlorocebus aethiops , Estudos de Coortes , Efeito Citopatogênico Viral , Células Epiteliais/patologia , Células Epiteliais/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Interferon Tipo I/metabolismo , Rim/imunologia , Rim/patologia , Rim/virologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Biológicos , Pandemias , Receptores Virais/metabolismo , Estudos Retrospectivos , SARS-CoV-2/fisiologia , Esferoides Celulares/patologia , Células Vero , Replicação Viral
18.
Exp Cell Res ; 405(2): 112705, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34166678

RESUMO

The interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) pathway modulates immune response and inflammation, associated with allograft dysfunction and rejection. We hypothesized that IL-33/ST2 is a marker of renal allograft rejection and IL-33/ST2 expression may differ according to rejection type. IL-33/ST2 expression was measured in sera and kidney tissues from recipients with acute antibody-mediated rejection (AAMR), acute cell-mediated rejection (ACMR), chronic antibody-mediated rejection (CAMR), and healthy controls. The soluble ST2 and IL-33/ST2 expression levels were higher in participants with all three rejection types than in controls. Although the expression levels in recipients with AAMR and ACMR were significantly higher than those with CAMR, there was no significant difference between the expression levels in AAMR and ACMR. Although IL-33, IL-8, and fibronectin expression were significantly increased after the addition of the recipients' serum in primary cultured human renal proximal tubular epithelial cells, the levels decreased after treatment with an anti-ST2 antibody. Furthermore, the anti-ST2 antibody specifically suppressed the upregulation of the mixed lymphocyte reaction. Boyden chamber assays demonstrated that anti-ST2 antibody abrogated chemotaxis induced by recombinant IL-33. Thus, IL-33 and ST2 are potent mediators of rejection. Treatment with an anti-ST2 antibody ameliorates rejection and could be a potential therapeutic strategy for renal allograft rejection.


Assuntos
Aloenxertos/imunologia , Rejeição de Enxerto/imunologia , Interleucina-33/metabolismo , Transplante de Rim , Adulto , Anticorpos/farmacologia , Biomarcadores/análise , Feminino , Humanos , Rim/imunologia , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo/métodos
19.
Exp Cell Res ; 405(2): 112704, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34126056

RESUMO

Fractalkine (FKN) is a chemokine with several roles, including chemotaxis; adhesion; and immune damage, which also participates in cell inflammation and apoptosis and responds to the pathogenesis of autoimmune diseases. Given the involvement of regulatory T cells (Treg) cells in autoimmune diseases, this study investigated the regulatory mechanism of FKN in renal injury and Treg apoptosis via the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway in lupus-prone mice. Lupus was induced in BALB/c female mice by injection of pristane, followed by isolation of CD4+CD25+ Treg cells from the spleen of lupus model mice. To deplete FKN, mice received injection of an anti-FKN antibody, and Treg cells were transfected with FKN small-interfering RNA. Lupus mice and Treg cells were treated with the p38MAPK inhibitor SB203580 and activator U-46619, respectively, and urine protein and serum urea nitrogen, creatinine, and autoantibodies were measured and renal histopathological changes analyzed. We determined levels of FKN, phosphorylated p38 (p-p38), and forkhead box P3 (FOXP3) in renal tissue and Treg cells, and analyzed apoptosis rates and levels of key apoptotic factors in Treg cells. The renal FKN and p-p38 levels increased, whereas renal FOXP3 level decreased in lupus-prone mice. Treatment with the anti-FKN antibody and the p38MAPK inhibitor ameliorated proteinuria and renal function, significantly reducing serum autoantibody, renal FKN, and p-p38 levels while increasing renal FOXP3 level in lupus-prone mice. Moreover, FKN knockdown and administration of the p38MAPK inhibitor reduced apoptosis and levels of pro-apoptotic factors, increased levels of anti-apoptotic factors, and suppressed activation of p38MAPK signaling in Treg cells derived from lupus model mice. Furthermore, treatment with the p38MAPK activator U-46619 had the opposite effect on these cells. These data indicated that depletion of FKN ameliorated renal injury and Treg cell apoptosis via inhibition of p38MAPK signaling in lupus nephritis, suggesting that targeting FKN represents a potential therapeutic strategy for treating Lupus nephritis.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Apoptose/efeitos dos fármacos , Quimiocina CX3CL1/farmacologia , Nefrite Lúpica/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/metabolismo , Animais , Apoptose/fisiologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/metabolismo , Rim/imunologia , Rim/metabolismo , Nefrite Lúpica/metabolismo , Camundongos Endogâmicos BALB C , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Medicine (Baltimore) ; 100(23): e26273, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115025

RESUMO

ABSTRACT: The association of nephropathy with autoimmune thyroid disease (AITD) has been reported previously. However, there is limited information on the relationship between thyroid autoantibodies and nephropathy. A retrospective study was conducted using the medical records of 246 patients with nephropathy, 82 of whom had concurrent AITD. General characteristics, thyroid function, autoantibodies, and the pathological types of nephropathy were analyzed. Immunohistochemistry was used to detect the thyroglobulin antibody (TG-Ab) and thyroid peroxidase antibody (TPO-Ab) in the kidneys. We found nephropathy patients with AITD exhibited higher serum levels of TPO-Ab, TG-Ab, thyroid-stimulating hormone receptor antibody (TR-Ab), and immunoglobulin G (IgG) (P < .05). Compared with the nephropathy without AITD group, the nephropathy with AITD group exhibited higher proportions of membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS), and relatively lower proportions of mesangial proliferative glomerulonephritis (MsPGN) and minimal change nephropathy (MCN) (P = .005). TPO-Ab and TG-Ab levels in the kidney were more prevalent in nephropathy patients with AITD than those without AITD (P = .015 and P = .026, respectively). Subgroup analysis demonstrated that serum levels of thyroid stimulating hormone (TSH), TG-Ab, TPO-Ab, immunoglobulin M (IgM), and IgG in the MN group were significantly higher, whereas the levels of free thyroxine (FT4) and estimated glomerular filtration rate (eGFR) were lower, as compared with MN with Hashimoto thyroiditis (HT) group (P < .05). TPO-Ab and TG-Ab expression levels in the kidneys were more prevalent in the MN group than in the MN with HT group (P = .034). The expression levels of FT4, TG-Ab, TPO-Ab, and thyroid-stimulating hormone receptor antibody (TSHR-Ab) in the serum were significantly higher in the MN group than in the MN with Graves disease (GD) group (P < .05). The expression of TPO-Ab in the kidneys was more prevalent in the MN group than in the MN with GD group (P = .011). In sum, the expressions of TPO-Ab and TG-Ab were more prevalent in the kidneys of patients with nephropathy and AITD. Our findings indicate that TPO-Ab and TG-Ab may play a role in the development of AITD-related nephropathy.


Assuntos
Autoanticorpos/análise , Glomerulonefrite Membranosa , Glomerulosclerose Segmentar e Focal , Doença de Hashimoto , Iodeto Peroxidase/imunologia , Receptores da Tireotropina/imunologia , Tireoglobulina/imunologia , Tireoidite Autoimune , Correlação de Dados , Feminino , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/patologia , Glomerulosclerose Segmentar e Focal/imunologia , Glomerulosclerose Segmentar e Focal/patologia , Doença de Hashimoto/sangue , Doença de Hashimoto/diagnóstico , Humanos , Imuno-Histoquímica , Rim/imunologia , Rim/patologia , Masculino , Pessoa de Meia-Idade , Testes de Função Tireóidea , Tireoidite Autoimune/sangue , Tireoidite Autoimune/diagnóstico , Tireoidite Autoimune/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...