RESUMO
The Plasmodium secreted protein with an altered thrombospondin repeat (SPATR) has been known to play an important role in the malaria parasite's invasion into host erythrocytes. This protein is immunogenic and has been considered as one of the potential vaccine candidates against malaria parasite infection. Thus far, only a handful immunological studies have been carried out on P. knowlesi SPATR (PkSPATR), and none of these studies investigated the immunoprotective properties of the protein. In the present study, the ability of anti-PkSPATR antibodies to inhibit invasion of human erythrocytes was assessed in an in vitro merozoite invasion inhibition assay. The antibodies were harvested from the serum of a rabbit which was immunised with recombinat PkSPATR. Results from the merozoite invasion inhibition assay revealed significant antibody invasion inhibitory activity in a concentration dependent manner (concentration range: 0.375 - 3.00 mg/ml) with inhibition rate ranging from 20% to 32%. Future studies, such as anti-PkSPATR antibodies inhibitory effect on sporozoite invasion of human liver cells, need to be carried out to assess the potential of PkSPATR as a knowlesi malaria vaccine candidate.
Assuntos
Anticorpos Antiprotozoários , Eritrócitos , Merozoítos , Plasmodium knowlesi , Proteínas de Protozoários , Plasmodium knowlesi/imunologia , Humanos , Eritrócitos/parasitologia , Coelhos , Animais , Anticorpos Antiprotozoários/imunologia , Proteínas de Protozoários/imunologia , Merozoítos/imunologia , Trombospondinas/imunologia , Vacinas Antimaláricas/imunologiaRESUMO
Cell migration regulated by Thrombospondin 2 (THSB2) is important for the development of pulmonary artery remodeling, but the mechanism by which THBS2-mediated cell migration regulates the development of pulmonary artery remodeling in broiler ascites syndrome (AS) is unclear. In addition, the lack of chicken THBS2 antibodies makes it difficult to study the mechanism in depth. In our study, we used recombinant gene technology, protein purification, and other techniques to obtain mouse anti-chicken THBS2 antibody and analyze its expression in broilers, ascites broilers and other animals. The results showed that we immunized mouse with recombinant THBS2 protein and obtained an antibody titer of 1:204,800, and the addition of astragalus polysaccharide as an immunomodulator during immunization significantly increased the titer of the antibody. Western blotting (WB) and immunofluorescence results showed that the THBS2 was significantly down-regulated in the ascites broiler. The THBS2 antibody we prepared can also detect THBS2 protein in duck, mouse, goat, and rabbit tissues. These results provide a foundation for further investigation of the role of THBS2 in pulmonary artery remodeling in broiler ascites syndrome and a powerful tool for studying the role of THBS2 in AS.
Assuntos
Anticorpos , Galinhas , Hipertensão Pulmonar , Proteínas Recombinantes , Trombospondinas , Animais , Proteínas Recombinantes/imunologia , Trombospondinas/imunologia , Trombospondinas/genética , Camundongos , Hipertensão Pulmonar/imunologia , Anticorpos/imunologia , Ascite/imunologia , Artéria Pulmonar , Doenças das Aves Domésticas/imunologiaRESUMO
Following the discovery of podocyte phospholipase A2 receptor and thrombospondin type-1 domain-containing 7A, various potential target antigens for membranous nephropathy (MN) have been reported one after another. MN target antigens have now been identified in a significant proportion of patients, and a new classification framework classifies patients with MN based on the detected antigen and associated disease phenotype. A serology-based approach that does not require a histological diagnosis for patients suspected of having MN has also been proposed. However, there have been cases in which dual positivity for MN antigens and/or corresponding antibodies has been shown. Importantly, some of them showed a transition of the affected patient's immune responses to MN antigens, suggesting that serological diagnosis changes depending on the timing of the analysis. In this review, we provide detailed information on these cases and present an overview of our recent understanding of their putative mechanisms involved in these cases. Greater awareness is required to adequately recognize and develop appropriate therapeutic strategies for this condition.
Assuntos
Glomerulonefrite Membranosa , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/sangue , Humanos , Receptores da Fosfolipase A2/imunologia , Receptores da Fosfolipase A2/metabolismo , Autoantígenos/imunologia , Prevalência , Podócitos/metabolismo , Podócitos/imunologia , Podócitos/patologia , Autoanticorpos/imunologia , Autoanticorpos/sangue , Trombospondinas/imunologia , Trombospondinas/metabolismoRESUMO
BACKGROUND: This study aims to investigate the incidence and prognosis of malignancy in individuals with thrombospondin type-1 domain-containing 7A (THSD7A)-associated membranous nephropathy (MN). METHODS: First, we performed a systematic literature review of prevalence of malignancy in THSD7A-associated MN. Then, we conducted a retrospective analysis of 454 patients diagnosed with MN through renal biopsy at our hospital between January 2016 and December 2020. We assessed the presence of serum anti-THSD7A antibodies and performed immunohistochemical staining of renal tissue for THSD7A. Subsequently, we followed patients with THSD7A-associated MN for a minimum of 3-5 years, collecting their clinical, pathological characteristics, and prognosis. Additionally, we conducted a literature review on patients with THSD7A-associated MN in conjunction with malignancy. RESULTS: We identified a total of nine articles containing comprehensive data on THSD7A-associated MN and malignancy. Among 235 patients with THSD7A-positive MN, 36 individuals had concurrent malignancies, resulting in a malignancy prevalence of 13.3% (95% CI: 8.9-17.7%). In our center, we followed up with 15 patients diagnosed with THSD7A-associated MN and observed three cases of concomitant tumors: two cases of lung adenocarcinoma and one case of small cell lung cancer with multiple metastases. The prevalence of malignancy in our cohort was 20%. Notably, we detected positive THSD7A staining in both renal and lung cancer tissues in one patient with small cell lung cancer. CONCLUSIONS: Patients with THSD7A-associated MN should undergo vigilant follow-up assessments, with a particular focus on actively seeking potential tumorigenic lesions to prevent misdiagnosis or oversight.
Assuntos
Glomerulonefrite Membranosa , Trombospondinas , Humanos , Glomerulonefrite Membranosa/epidemiologia , Glomerulonefrite Membranosa/patologia , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/diagnóstico , Prognóstico , Trombospondinas/imunologia , Prevalência , Estudos Retrospectivos , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Neoplasias/epidemiologia , Idoso , Rim/patologiaRESUMO
Primary membranous nephropathy (pMN) is an autoimmune kidney disease and a common cause of nephrotic syndrome in adults. Rituximab is becoming a first line therapy for patients with persistent nephrotic syndrome with proven safety and efficacy, achieving remission in 60%-80% of cases. For the remaining 20%-40% of patients there is an urgent need to identify early biomarkers of resistance to rituximab to adapt therapeutic management. In nephrotic patients, rituximab is found in the blood more transiently than in other autoimmune diseases without proteinuria, due to rituximab wasting in the urine. However, rituximab immunomonitoring is not routinely performed. We evaluated the predictive value of serum rituximab levels in patients with pMN three months after rituximab injection (month-3) on clinical remission rates six months (month-6) and 12 months (month-12) after injection and investigated predictive factors for serum rituximab levels at month-3. Sixty-eight patients treated with rituximab between July 2015 and January 2020 from two French nephrology centers were included. We identified residual rituximab levels at month-3 as a novel early predictor of remission at month-6 (p <0.0001) and month-12 (p = 0.001). Reduced likelihood of remission in patients with undetectable rituximab at month-3 was associated with lower serum albumin and higher anti-PLA2R1 titers at baseline and with lower serum albumin, higher proteinuria, higher CD19+ counts and higher anti-PLA2R1 titers during follow-up. In multivariate analysis, high baseline proteinuria and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-6 and high baseline weight and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-12. We identified serum albumin at baseline as a predictive factor for serum rituximab levels at month-3. Patients with serum albumin below 22.5 g/L at baseline had an 8.66-fold higher risk of having undetectable rituximab levels at month-3. Therefore, rituximab immunomonitoring in pMN patients treated with rituximab would allow the detection of patients at risk of treatment failure as early as month-3. Studies are needed to assess whether patients with low residual rituximab levels at month-3 may benefit from an early additional course of rituximab.
Assuntos
Monitoramento de Medicamentos , Glomerulonefrite Membranosa/tratamento farmacológico , Imunossupressores/uso terapêutico , Monitorização Imunológica , Rituximab/uso terapêutico , Adulto , Idoso , Autoanticorpos/sangue , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , França , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/imunologia , Humanos , Imunossupressores/sangue , Imunossupressores/imunologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Receptores da Fosfolipase A2/imunologia , Indução de Remissão , Estudos Retrospectivos , Rituximab/sangue , Rituximab/imunologia , Albumina Sérica Humana/metabolismo , Trombospondinas/imunologia , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: Thrombospondin 2 (THBS2) acts as oncogenic or tumor suppressive gene in diverse cancers. Here we studied the prognostic and immunological role of THBS2 in colorectal cancer (CRC) using bioinformatic analysis. METHODS: The genetic and protein expression of THBS2 in CRC were explored across several databases, including ONCOMINE, GEPIA2, TIMER 2.0, UALCAN and HPA databases. Correlation between THBS2 expression and clinical features in CRC was assessed using UALCAN tool. Prognostic analysis was performed using GEPIA2 and PrognoScan. Immune infiltration correlation with THBS2 in CRC was investigated with TIMER 2.0 and TISIDB. THBS2 binding and correlated genes were analyzed using String, GEPIA2, and TIMER 2.0. RESULTS: THBS2 was significantly higher in CRC across multiple databases. Age and histological subtype were correlated with THBS2 level. High THBS2 expression correlated with short overall and disease-free survival. THBS2 expression was positively correlated with immune infiltrates in CRC. Moreover, extracellular matrix structural constituent and organization, PI3K-Akt pathway, were involved in the functional mechanisms of THBS2. CONCLUSIONS: THBS2 correlates with poor prognosis and immune infiltration in CRC. THBS2 may act as a prognostic and immunological biomarker for CRC.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Biologia Computacional/métodos , Linfócitos do Interstício Tumoral/imunologia , Trombospondinas/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Bases de Dados Genéticas , Humanos , Prognóstico , Taxa de Sobrevida , Trombospondinas/imunologiaRESUMO
Membranous nephropathy (MN) is an organ-restricted autoimmune disease mainly caused by circulating autoantibodies against podocyte antigens, including the M-type phospholipase A2 receptor (PLA2R) and thrombospondin domain-containing 7A (THSD7A). Antibodies against PLA2R are present in 70%-80% and against THSD7A in 2% of adult patients, which provides a paradigm shift in molecular diagnosis and management monitoring. Both antigens share some similar characteristics: they are expressed by podocytes and have wide tissue distributions; they are bound by autoantibodies only under nonreducing conditions, and the subtype of most autoantibodies is IgG4. However, the factors triggering autoantibody production as well as the association among air pollution, malignancy, and the pathogenesis of MN remain unclear. In this review, we discuss the similarity between the pathological mechanisms triggered by disparate antigens and their associated diseases. Furthermore, we demonstrated the possibility that PM2.5, malignancy, and gene expression specifically induce exposure of these antigens through conformational changes, molecular mimicry, or increased expression eliciting autoimmune responses. Thus, this review provides novel insights into the pathological mechanism of MN.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Glomerulonefrite Membranosa/imunologia , Receptores da Fosfolipase A2/imunologia , Trombospondinas/imunologia , Animais , Antígenos de Superfície/imunologia , Antígenos de Superfície/metabolismo , Autoanticorpos/sangue , Autoantígenos/metabolismo , Modelos Animais de Doenças , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/patologia , Humanos , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Podócitos/imunologia , Podócitos/metabolismo , Podócitos/patologia , Receptores da Fosfolipase A2/metabolismo , Trombospondinas/metabolismoRESUMO
Membranous nephropathy (MN) is an autoimmune disease caused by autoantibodies against the podocyte antigens phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain containing protein 7A (THSD7A) in 80% and 2-3% of patients, respectively. THSD7A antibodies are considered to be pathogenic and highly specific for MN patients. Using an indirect immunofluorescence test (IIFT) we detected THSD7A-antibodies (titre 1:10) in the serum of a patient with high proteinuria who, however, in the kidney biopsy was diagnosed with diabetic nephropathy and MN was excluded as a possible cause of proteinuria. Different immunofluorescence assays and Western blot techniques using recombinant THSD7A (rTHSD7A) or THSD7A from different human tissues revealed that the circulating THSD7A-autoantibodies were only of the IgG3 subclass. The patient serum reacted exclusively with rTHSD7A and only when the antigen was present in reducing Western blot conditions, or on formaldehyde-fixed cells for the IIFT. Our findings show for the first time the existence of circulating THSD7A-antibodies recognizing denatured/reduced rTHSD7A, which do not react with glomerular THSD7A in vivo and are thus presumptively non-pathogenic. As a consequence, kidney biopsy or Western blot analyses of THSD7A under non-reducing conditions should be performed to confirm the diagnosis of THSD7A-associated MN, especially in cases with low THSD7A-antibody levels in the IIFT.
Assuntos
Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/fisiopatologia , Glomerulonefrite Membranosa/diagnóstico , Glomérulos Renais/patologia , Trombospondinas/imunologia , Idoso , Autoanticorpos/sangue , Diagnóstico Diferencial , Técnica Indireta de Fluorescência para Anticorpo , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/patologia , Humanos , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Masculino , Trombospondinas/sangueRESUMO
BACKGROUND: Phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain-containing 7A (THSD7A) are the two major pathogenic antigens for membranous nephropathy (MN). It has been reported that THSD7A-associated MN has a higher prevalence of comorbid malignancy than PLA2R1-associated MN. Here we present a case of MN whose etiology might change from idiopathic to malignancy-associated MN during the patient's clinical course. CASE PRESENTATION: A 68-year-old man with nephrotic syndrome was diagnosed with MN by renal biopsy. Immunohistochemistry showed that the kidney specimen was negative for THSD7A. The first course of corticosteroid therapy achieved partial remission; however, nephrotic syndrome recurred 1 year later. Two years later, his abdominal echography revealed a urinary bladder tumor, but he did not wish to undergo additional diagnostic examinations. Because his proteinuria increased consecutively, corticosteroid therapy was resumed, but it failed to achieve remission. Another kidney biopsy was performed and revealed MN with positive staining for THSD7A. PLA2R1 staining levels were negative for both first and second biopsies. Because his bladder tumor had gradually enlarged, he agreed to undergo bladder tumor resection. Pathological examination indicated that the tumor was THDS7A-positive bladder cancer. Subsequently, his proteinuria decreased and remained in remission. CONCLUSIONS: This case suggests that the etiology of MN might be altered during the therapeutic course. Intensive screening for malignancy may be preferable in patients with unexpected recurrence of proteinuria and/or change in therapy response.
Assuntos
Glomerulonefrite Membranosa/etiologia , Neoplasias da Bexiga Urinária/complicações , Corticosteroides/uso terapêutico , Idoso , Autoanticorpos/análise , Biópsia , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/imunologia , Humanos , Imuno-Histoquímica , Masculino , Receptores da Fosfolipase A2/imunologia , Receptores da Fosfolipase A2/metabolismo , Recidiva , Trombospondinas/imunologia , Trombospondinas/metabolismo , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
Immune checkpoint inhibitors (ICIs) became the standard treatment for many different kinds of cancers and can result in a variety of immune-related adverse events (irAEs). IrAEs of kidney are uncommon and consists of different pathology types. Among the different types, membranous nephropathy (MN) is rare and have not been well-described. Since MN can also be associated with malignancies, differential diagnosis in patients receiving ICIs who develop MN can be very difficult. We present the case of a 74-year-old man with metastatic non-small cell lung cancer who developed MN after ICIs therapy. The patient tested positive for thrombospondin type-1 domain-containing 7A antibodies (THSD7A) when diagnosed with MN. Supplementary examinations revealed the predisposing antigen in the primary tumor and present of the antibody after immunotherapy, which corresponded to the patient's clinical course of nephropathy. Treatment consisting of systemic glucocorticoids and rituximab resulted in a good clinical response, and the THSD7A antibodies were no longer detected. In this case, we first discuss the potential mechanism of immunotherapy related MN, in which the activation of humoral immunity may play an important role.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/etiologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/imunologia , Trombospondinas/imunologia , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Autoanticorpos/imunologia , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Suscetibilidade a Doenças , Imunofluorescência , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imuno-Histoquímica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Tomografia Computadorizada por Raios XRESUMO
Repair of the intestinal epithelium is tightly regulated to maintain homeostasis. The response after epithelial damage needs to be local and proportional to the insult. How different types of damage are coupled to repair remains incompletely understood. We report that after distinct types of intestinal epithelial damage, IL-1R1 signaling in GREM1+ mesenchymal cells increases production of R-spondin 3 (RSPO3), a Wnt agonist required for intestinal stem cell self-renewal. In parallel, IL-1R1 signaling regulates IL-22 production by innate lymphoid cells and promotes epithelial hyperplasia and regeneration. Although the regulation of both RSPO3 and IL-22 is critical for epithelial recovery from Citrobacter rodentium infection, IL-1R1-dependent RSPO3 production by GREM1+ mesenchymal cells alone is sufficient and required for recovery after dextran sulfate sodium-induced colitis. These data demonstrate how IL-1R1-dependent signaling orchestrates distinct repair programs tailored to the type of injury sustained that are required to restore intestinal epithelial barrier function.
Assuntos
Citrobacter rodentium , Infecções por Enterobacteriaceae/imunologia , Mucosa Intestinal/fisiologia , Receptores Tipo I de Interleucina-1/imunologia , Animais , Células Cultivadas , Técnicas de Cocultura , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Sulfato de Dextrana , Células Epiteliais , Fibroblastos , Interleucinas/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Camundongos Transgênicos , Organoides , Receptores Tipo I de Interleucina-1/genética , Regeneração , Transdução de Sinais , Trombospondinas/imunologia , Interleucina 22RESUMO
Membranous nephropathy (MN) is one of the most frequent causes of nephrotic syndrome. Renal biopsy is nowadays the gold standard for the diagnosis of MN. The presence of circulating PLA2R antibody is a very specific tool for the diagnosis of this disease, especially associated with primary or idiopathic MN (IMN), even though it can be also found in a small proportion of patients with secondary MN (SMN). This pilot study compares three different techniques for the detection of anti-PLA2R autoantibodies (immunofluorescence, ELISA immunoassay, and multiplex laser bead technology). Serum of 12 IMN and 9 SMN patients was obtained at diagnosis. Additionally, we employed serum samples of 15 healthy volunteers. From our patient cohort, we obtained a 7.75 RU/ml cut-off for the ELISA and 3104 MFI for the Luminex assays. The agreement between the three techniques improved considerably when applying the new cut-off points. As several authors have suggested, cut-offs may be calculated for each specific population instead of establishing global cut-off points. Patients with IMN showed significantly lower serum albumin levels and higher 24 h proteinuria compared to those with SMN. Analysis of ROC curves suggests that ELISA and LUMINEX assays are more useful than biochemical variables to differentiate patients with IMN and SMN. This pilot study contributes to confirming that the combination of ELISA and Luminex assays provide excellent sensitivity and specificity for the identification of IMN.
Assuntos
Autoanticorpos/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Técnica Indireta de Fluorescência para Anticorpo/métodos , Glomerulonefrite Membranosa/diagnóstico , Receptores da Fosfolipase A2/imunologia , Idoso , Estudos de Casos e Controles , Feminino , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/metabolismo , Humanos , Imunoensaio/métodos , Masculino , Projetos Piloto , Proteinúria/urina , Sensibilidade e Especificidade , Albumina Sérica/metabolismo , Trombospondinas/imunologia , População BrancaRESUMO
Membranous nephropathy (MN) is an autoimmune disease of the kidney glomerulus and one of the leading causes of nephrotic syndrome. The disease exhibits heterogenous outcomes with approximately 30% of cases progressing to end-stage renal disease. The clinical management of MN has steadily advanced owing to the identification of autoantibodies to the phospholipase A2 receptor (PLA2R) in 2009 and thrombospondin domain-containing 7A (THSD7A) in 2014 on the podocyte surface. Approximately 50-80% and 3-5% of primary MN (PMN) cases are associated with either anti-PLA2R or anti-THSD7A antibodies, respectively. The presence of these autoantibodies is used for MN diagnosis; antibody levels correlate with disease severity and possess significant biomarker values in monitoring disease progression and treatment response. Importantly, both autoantibodies are causative to MN. Additionally, evidence is emerging that NELL-1 is associated with 5-10% of PMN cases that are PLA2R- and THSD7A-negative, which moves us one step closer to mapping out the full spectrum of PMN antigens. Recent developments suggest exostosin 1 (EXT1), EXT2, NELL-1, and contactin 1 (CNTN1) are associated with MN. Genetic factors and other mechanisms are in place to regulate these factors and may contribute to MN pathogenesis. This review will discuss recent developments over the past 5 years.
Assuntos
Glomerulonefrite Membranosa/imunologia , Receptores da Fosfolipase A2/imunologia , Trombospondinas/imunologia , Animais , Ativação do Complemento , Epitopos , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/fisiopatologia , Humanos , Camundongos , N-Acetilglucosaminiltransferases/imunologia , Receptores da Fosfolipase A2/genéticaAssuntos
Glomerulonefrite Membranosa/patologia , Glomerulosclerose Segmentar e Focal/patologia , Glomérulos Renais/patologia , Adulto , Autoanticorpos/sangue , Feminino , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/terapia , Glomerulosclerose Segmentar e Focal/sangue , Glomerulosclerose Segmentar e Focal/etiologia , Glomerulosclerose Segmentar e Focal/terapia , Humanos , Glomérulos Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteinúria/etiologia , Receptores da Fosfolipase A2/imunologia , Receptores da Fosfolipase A2/metabolismo , Indução de Remissão , Estudos Retrospectivos , Trombospondinas/imunologia , Trombospondinas/metabolismoRESUMO
The understanding and management of membranous nephropathy, a common cause of nephrotic syndrome that is more frequently encountered in adults than in children, has rapidly evolved over the past decade. Identification of target antigens has allowed for more precise molecular diagnoses, and the ability to monitor circulating autoantibodies has added a new vantage point in terms of disease monitoring and decisions about immunosuppression. Although immunosuppression with alkylating agents combined with corticosteroids, or with calcineurin inhibitor-based regimens, has been the historical mainstay of treatment, observational and now randomized controlled trials with the B-cell-depleting agent rituximab have moved this agent to the forefront of therapy for primary membranous nephropathy. In this Core Curriculum, we discuss the typical features of primary and secondary disease; highlight the target antigens such as the phospholipase A2 receptor, thrombospondin type 1 domain-containing 7A, neural epidermal growth factor-like 1, and semaphorin-3B; describe the relationship between the immunologic and clinical courses of disease; and review modern management with supportive care or immunosuppressive treatment based on these composite parameters.
Assuntos
Autoanticorpos/imunologia , Glomerulonefrite Membranosa/imunologia , Proteínas de Ligação ao Cálcio/imunologia , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/etiologia , Glomerulonefrite Membranosa/patologia , Glucocorticoides/uso terapêutico , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/imunologia , Hepatite B/complicações , Hepatite C/complicações , Humanos , Fatores Imunológicos/uso terapêutico , Imunossupressores , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Malária/complicações , Glicoproteínas de Membrana/imunologia , Doença Mista do Tecido Conjuntivo/complicações , Doença Mista do Tecido Conjuntivo/imunologia , Neoplasias/complicações , Receptores da Fosfolipase A2/imunologia , Rituximab/uso terapêutico , Semaforinas/imunologia , Síndrome de Sjogren/complicações , Síndrome de Sjogren/imunologia , Trombospondinas/imunologiaRESUMO
BACKGROUND: Serum and tissue-based tests using phospholipase A2 receptor 1 (PLA2R) and thrombospondin type-1 domain containing 7A (THSD7A) are established immune biomarkers for the diagnosis of primary membranous nephropathy (PMN). This study assessed the diagnostic performance of these biomarkers in the diagnosis of PMN in South Africans. METHODS: This was a cross-sectional analysis from a single centre in Cape Town, South Africa. Relevant biodata was collected from all patients. Histology, including slides for PLA2R and THSD7A were processed and assessed by typical microscopic and immunohistochemical features. Biopsy tissues of patients with membranous lupus nephritis (LN-V) and diabetic nephropathy (DN) were used as controls. The diagnostic accuracy for diagnosis of PMN using positive PLA2R and THSD7A were evaluated. RESULTS: Of the 88 patients included, 41 had PMN with a mean age of 44.5 ± 17.5 years and 61.0% were female. Histologically, PLA2R and THSD7A were only positive in the PMN group (51.2% and 4.9%, respectively) but negative in both control groups. The sensitivity of PLA2R and THSD7A for identifying PMN was 51.2% and 4.9%, respectively. The sensitivity of both tests together was 53.7% while the specificity and positive predictive values (PPV) for any of the tests (alone or in combination) was 100%. There was no difference in the sensitivity and specificity when using PLA2R alone compared to combining the two tests (p=0.32). CONCLUSION: Glomerular staining of PLA2R and THSD7A could have potential diagnostic values in South Africans. This has implications on how immunotherapies can be initiated and used in these settings.
Assuntos
Autoanticorpos/sangue , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/diagnóstico , Glomérulos Renais/química , Receptores da Fosfolipase A2/análise , Trombospondinas/imunologia , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , África do SulRESUMO
BACKGROUND AND OBJECTIVES: Patients with membranous nephropathy can have circulating autoantibodies against membrane-bound (phospholipase A2 receptor 1 [PLA2R1] and thrombospondin type-1 domain containing 7A [THSD7A]) and intracellular (aldose reductase, SOD2, and α-enolase) podocyte autoantigens. We studied their combined association with clinical outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Serum levels of anti-PLA2R1, anti-THSD7A, anti-aldose reductase, anti-SOD2, and anti-α-enolase autoantibodies were determined in 285 patients at diagnosis and during follow-up using standardized and homemade assays. An eGFR>60 ml/min per 1.73 m2 and remission of proteinuria (<0.3/<3.5 g per d) after 12 months were the outcomes of interest. RESULTS: At diagnosis, 182 (64%), eight (3%), and 95 (33%) patients were anti-PLA2R1+, anti-THSD7A+, and double negative, respectively. The prevalence of a detectable antibody to at least one intracellular antigen was similarly distributed in patients who were anti-PLA2R1+ (n=118, 65%) and double negative (n=64, 67%). Positivity for anti-PLA2R1, anti-SOD2, and anti-α-enolase antibodies and higher titers at diagnosis were associated with poor clinical outcome independently to each other. Combined positivity for anti-PLA2R1, anti-SOD2, and anti-α-enolase was associated with highest risk of poor outcome (odds ratio, 5.5; 95% confidence interval, 1.2 to 24; P=0.01). In Kaplan-Meier analysis, patients who were anti-PLA2R1+/anti-SOD2+ or anti-PLA2R1+/anti-α-enolase+ had lower eGFR at 12 months compared with patients who were anti-PLA2R1+/anti-SOD2- or anti-α-enolase-. Predictive tests (net reclassification index and area under the curve-receiver-operating characteristic analysis) showed that combined assessment of antibodies improved classification of outcome in 22%-34% of cases for partial remission of proteinuria and maintenance of normal eGFR. For patients with nephrotic syndrome at diagnosis, anti-SOD2 positivity and high anti-PLA2R1 titer were associated with a lack of complete remission. Patients who were anti-PLA2R1-/anti-intracellular antigens- had the lowest proteinuria and the highest eGFR at diagnosis and the lowest risk of lower eGFR at 12 months. Epitope spreading was present in 81% of patients who were anti-PLA2R1+ and was associated with increased positivity for intracellular antigens and poor eGFR at diagnosis and 12 months. CONCLUSIONS: Combined serological analysis of autoantibodies targeting membrane-bound and intracellular autoantigens identifies patients with poor clinical outcomes.
Assuntos
Aldeído Redutase/imunologia , Autoanticorpos/sangue , Biomarcadores Tumorais/imunologia , Proteínas de Ligação a DNA/imunologia , Glomerulonefrite Membranosa/imunologia , Fosfopiruvato Hidratase/imunologia , Receptores da Fosfolipase A2/imunologia , Superóxido Dismutase/imunologia , Trombospondinas/imunologia , Proteínas Supressoras de Tumor/imunologia , Adulto , Idoso , Biomarcadores/sangue , Estudos Transversais , Feminino , França , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/terapia , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Testes Sorológicos , Fatores de TempoRESUMO
Membranous nephropathy (MN) is an immune complex mediated disease. Although limited to the kidney, in up to 20% of patients MN is associated with other autoimmune, infectious or malignant diseases. The initial pathogenetic event in what is still considered "primary" MN is the binding of circulating autoantibodies to proteins (autoantigens) expressed in glomerular podocytes. This antibody binding leads to the formation of immune complexes in the glomerular basement membrane. There is clinical and experimental evidence that these immune deposits lead to the activation of the complement system. Experimental studies in the MN model of Heymann's nephritis show that the terminal membrane attack complex (MAC) of the complement system induces a disturbance of the glomerular filtration barrier and leads to proteinuria, the clinical hallmark of MN. After the discovery of the phospholipase A2 receptor 1 and thrombospondin type 1 domain containing protein 7A as endogenous antigens, it is assumed that IgG4 antibodies directed against these proteins induce MN in over 85% of patients with primary MN. As a result, the role of complement in the pathogenesis of MN needs to be defined in light of these developments. In this review we describe the current knowledge on the function of the complement system in primary MN and discuss the open questions, which have to be solved for a better understanding of the potential role of complement in the pathophysiology of primary MN.
Assuntos
Proteínas do Sistema Complemento/imunologia , Glomerulonefrite Membranosa/imunologia , Animais , Complexo Antígeno-Anticorpo/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Membrana Basal/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Humanos , Imunoglobulina G/imunologia , Rim/imunologia , Glomérulos Renais/imunologia , Podócitos/imunologia , Receptores da Fosfolipase A2/imunologia , Trombospondinas/imunologiaRESUMO
Membranous nephropathy is an autoimmune disease caused in most cases by binding of circulating antibodies to antigens on podocytes. PLA2R1 and THSD7A have been identified as target antigens in 70-80â% and 2-3â% of patients, respectively. The detection of PLA2R1- and THSD7A-antibodies in the blood and staining of renal biopsies for the respective antigens allow the correct diagnosis of PLA2R1- and THSD7A-associated membranous nephropathy, respectively, in practically 100â% of cases. Measurement of PLA2R1- and THSD7A-antibodies is helpful in order to further individualize the decision whether to perform a renal biopsy in patients with suspected membranous nephropathy. PLA2R1-antibody level is a strong predictor for remission of proteinuria, loss of renal function and relapse of disease. Moreover, treatment decisions in patients with PLA2R1-associated MN are increasingly based on the PLA2R1-antibody levels. Rituximab was shown to be non-inferior to ciclosporine A to induce remission of proteinuria after 12 months. After 24 months rituximab was superior to ciclosporine A for the same endpoint. Development of novel treatment strategies, focusing on disease pathogenesis, remains highly relevant for these patients.