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Agnieszka Pozdzik, Isabelle Brochériou, Cristina David, Fahd Touzani, Jean Michel Goujon, Karl Martin Wissing
The discovery of circulating antibodies specific for native podocyte antigens has transformed the diagnostic workup and greatly improved management of idiopathic membranous nephropathy (iMN). In addition, their identification has clearly characterized iMN as a largely autoimmune disorder. Anti-PLA2R1 antibodies are detected in approximately 70% to 80% and anti-THSD7A antibodies in only 2% of adult patients with iMN. The presence of anti-THSD7A antibodies is associated with increased risk of malignancy. The assessment of PLA2R1 and THSD7A antigen expression in glomerular immune deposits has a better sensitivity than measurement of the corresponding autoantibodies...
2018: BioMed Research International
Yang Li, Dao Wen Wang, Yundai Chen, Can Chen, Jian Guo, Shu Zhang, Zhijun Sun, Hu Ding, Yan Yao, Lei Zhou, Ke Xu, Chun Song, Fan Yang, Bin Zhao, Han Yan, Wen-Jing Wang, Chong Wu, Xiangfeng Lu, Xueli Yang, Jie Dong, Guyan Zheng, Shuhan Tian, Yanjun Cui, Lijuan Jin, Gangqiong Liu, Hanbin Cui, Shenghuang Wang, Feng Jiang, Changhua Wang, Jeanette Erdmann, Linyao Zeng, Shian Huang, Jianfeng Zhong, Yuehua Ma, Wenjiang Chen, Jianli Sun, Wei Lei, Shenghan Chen, Shaoqi Rao, Dongfeng Gu, Heribert Schunkert, Xiao-Li Tian
OBJECTIVE: The genetic contribution to coronary artery disease (CAD) remains largely unclear. We combined genetic screening with functional characterizations to identify novel loci and candidate genes for CAD. APPROACH AND RESULTS: We performed genome-wide screening followed by multicenter validation in 8 cohorts consisting of 21 828 participants of Han ethnicity and identified 3 novel intragenic SNPs, rs9486729 ( SCML4 ; odds ratio, 1.25; 95% CI, 1.17-1.34; P =3...
February 22, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Shree G Sharma, Christopher P Larsen
Thrombospondin type-1 domain-containing 7A (THSD7A) is the most recently recognized target antigen in patients with membranous nephropathy. We stained membranous nephropathy biopsies processed in our laboratory for phospholipase A2 receptor and THSD7A over an 18-month period and selected all THSD7A-positive cases for study. Serum samples from most patients were tested by an indirect immunofluorescence assay for the presence of THSD7A antibodies (Euroimmun). A total of 31 patients were diagnosed with THSD7A-associated membranous nephropathy for a prevalence of 2...
December 15, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Fujun Lin, Dan Zhang, Juan Chang, Xuanli Tang, Wenbin Guan, Gengru Jiang, Chun Zhu, Fan Bian
Target antigens in idiopathic membranous nephropathy (MN) include the phospholipase A2 receptor (PLA2R), and in some cases, the thrombospondin type 1 domain-containing 7A (THSD7A). A notable phenomenon is the high rate of cancer (reported to be as high as 20%) in patients with THSD7A-associated MN. Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by NF1 gene mutation, and clinically characterized by multiple cutaneous neurofibromas and café-au-lait spots. In this article, we report a patient with NF1 who developed THSD7A-associated MN when the NF1 skin lesions deteriorated...
October 24, 2017: European Journal of Medical Genetics
Anne K Dettmar, Thorsten Wiech, Markus J Kemper, Armin Soave, Michael Rink, Jun Oh, Rolf A K Stahl, Elion Hoxha
BACKGROUND: Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults, but is less frequent in children. Antibodies against four antigens leading to MN have been described in children: phospholipase A2 receptor 1 (PLA2R1), thrombospondin type-1 domain-containing 7A (THSD7A), neutral endopeptidase (NEP), and cationic bovine serum albumin (BSA). METHODS: Twelve children with MN were included in this study. Sera of all patients were analyzed for antibodies against PLA2R1, THSD7A, NEP, and BSA...
October 15, 2017: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Norifumi Hayashi, Keiichirou Okada, Yuki Matsui, Keiji Fujimoto, Hiroki Adachi, Hideki Yamaya, Misao Matsushita, Hitoshi Yokoyama
Background: The M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) were identified as intrinsic antigens in primary membranous nephropathy (MN). Complement activation via the lectin pathway in intrinsic antigen-related MN is still unclear. Methods: We retrospectively enrolled 60 primary Japanese MN patients and detected activated complement pathways by staining complement proteins in glomerular deposition. According to the findings of PLA2R and THSD7A staining in glomeruli, they were classified into intrinsic antigen-related or -unrelated MN...
July 18, 2017: Nephrology, Dialysis, Transplantation
Zhichao Hou, Abulajiang Abudureheman, Lei Wang, Ayshamgul Hasim, Julaiti Ainiwaer, Haiping Zhang, Madiniyat Niyaz, Halmurat Upur, Ilyar Sheyhidin
Thsd7a (Thrombospondin type 1 domain containing 7a) is a critical transmembrane protein. Studies have indicated that Thsd7a was associated with cytoskeletal organization, cell migration and filopodia formation. However, the involvement of Thsd7a remains elusive in human Esophageal Squamous Cell Carcinoma (ESCC). Consequently, immunohistochemistry and reverse transcription-polymerase chain reaction were utilized to study the correlation between the expression of Thsd7a and clinical-pathological characteristics...
September 1, 2017: Oncotarget
Andreas Kronbichler, Jun Oh, Björn Meijers, Gert Mayer, Jae Il Shin
Primary membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. Discovery of several antibodies has contributed to an increased understanding of MN. Antibodies against the M-type phospholipase A2 receptor (PLA2R) are present in 50-100% with primary MN and are associated with a lower frequency of spontaneous remission. High levels are linked with a higher probability of treatment resistance, higher proteinuria, and impaired renal function, as well as a more rapid decline of kidney function during follow-up...
2017: BioMed Research International
Nicola M Tomas, Catherine Meyer-Schwesinger, Hanning von Spiegel, Ahmed M Kotb, Gunther Zahner, Elion Hoxha, Udo Helmchen, Nicole Endlich, Friedrich Koch-Nolte, Rolf A K Stahl
Thrombospondin type 1 domain-containing 7A (THSD7A) is a target for autoimmunity in patients with membranous nephropathy (MN). Circulating autoantibodies from patients with THSD7A-associated MN have been demonstrated to cause MN in mice. However, THSD7A-associated MN is a rare disease, preventing the use of patient antibodies for larger experimental procedures. Therefore, we generated antibodies against the human and mouse orthologs of THSD7A in rabbits by coimmunization with the respective cDNAs. Injection of these anti-THSD7A antibodies into mice induced a severe nephrotic syndrome with proteinuria, weight gain, and hyperlipidemia...
November 2017: Journal of the American Society of Nephrology: JASN
Jia Wang, Zhao Cui, Jie Lu, Christian Probst, Yi-Miao Zhang, Xin Wang, Zhen Qu, Fang Wang, Li-Qiang Meng, Xu-Yang Cheng, Gang Liu, Hanna Debiec, Pierre Ronco, Ming-Hui Zhao
BACKGROUND AND OBJECTIVES: Thrombospondin type-I domain-containing 7A (THSD7A) was recently identified as the target antigen in about 10% of patients with M-type phospholipase A2 receptor (PLA2R)-negative membranous nephropathy in European and North American populations. The prevalence of THSD7A in other populations and their clinical associations deserve further clarification. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Immunofluorescence assay was performed to investigate anti-THSD7A antibodies in 578 consecutive patients with biopsy-proven idiopathic membranous nephropathy, 114 patients with secondary membranous nephropathy, 64 disease controls, and 20 healthy controls...
October 6, 2017: Clinical Journal of the American Society of Nephrology: CJASN
Laurence H Beck
The phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) are the two major autoantigens in primary membranous nephropathy (MN), and define two molecular subclasses of this disease. Both proteins are large transmembrane glycoproteins expressed by the podocyte, and both induce IgG4-predominant humoral immune responses that produce circulating autoantibodies that can be used clinically for diagnostic and monitoring purposes. The biologic roles of these proteins remain speculative, although several features of THSD7A suggest a role in adhesion...
September 2017: Journal of the American Society of Nephrology: JASN
Piero Ruggenenti, Fernando C Fervenza, Giuseppe Remuzzi
In patients with membranous nephropathy, alkylating agents (cyclophosphamide or chlorambucil) alone or in combination with steroids achieve remission of nephrotic syndrome more effectively than conservative treatment or steroids alone, but can cause myelotoxicity, infections, and cancer. Calcineurin inhibitors can improve proteinuria, but are nephrotoxic. Most patients relapse after treatment withdrawal and can become treatment dependent, which increases the risk of nephrotoxicity. The discovery of nephritogenic autoantibodies against podocyte M-type phospholipase A2 receptor (PLA2 R) and thrombospondin type-1 domain- containing protein 7A (THSD7A) antigens provides a clear pathophysiological rationale for interventions that specifically target B-cell lineages to prevent antibody production and subepithelial deposition...
September 2017: Nature Reviews. Nephrology
Barbara Seitz-Polski, Gérard Lambeau, Vincent Esnault
Membranous nephropathy is a major cause of nephrotic syndrome in adults, with various etiologies and outcomes. One third of patients enter spontaneous remission with blockade of the renin-angiotensin system, one third develop a persistent nephrotic syndrome, while another third of patients develop end-stage kidney disease and 40% of them relapse after kidney transplantation. Treatment of membranous nephropathy remains controversial. Immunosuppressive therapy is only recommended in case of renal function deterioration or persistent nephrotic syndrome after 6months of renin-angiotensin system blockade...
April 2017: Néphrologie & Thérapeutique
Elion Hoxha, Franziska von Haxthausen, Thorsten Wiech, Rolf A K Stahl
Since the discovery of the phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain-containing 7A (THSD7A) as endogenous antigens involved in the development of membranous nephropathy (MN) in over 80% of adult patients, substantial progress in the diagnosis, prognosis, and therapy of MN has been made. In most cases of patients with MN, it is now possible to specifically define the responsible pathogenic mechanisms of disease and make a diagnosis even without a renal biopsy. Moreover, the presence of antibodies in the blood and the detection of the antigens in renal biopsies allow the definite diagnosis without the morphologic uncertainties, which now still apply for only about 20% of all renal biopsies showing MN...
August 2017: Pflügers Archiv: European Journal of Physiology
William G Couser
Membranous nephropathy (MN) is a unique glomerular lesion that is the most common cause of idiopathic nephrotic syndrome in nondiabetic white adults. About 80% of cases are renal limited (primary MN, PMN) and 20% are associated with other systemic diseases or exposures (secondary MN). This review focuses only on PMN. Most cases of PMN have circulating IgG4 autoantibody to the podocyte membrane antigen PLA2R (70%), biopsy evidence PLA2R staining indicating recent immunologic disease activity despite negative serum antibody levels (15%), or serum anti-THSD7A (3%-5%)...
June 7, 2017: Clinical Journal of the American Society of Nephrology: CJASN
Zhichao Hou, Abulajiang Abudureheman, Lei Wang, Ayshamgul Hasim, Julaiti Ainiwaer, Haiping Zhang, Madiniyat Niyaz, Halmurat Upur, Ilyar Sheyhidin
Thsd7a (Thrombospondin type 1 domain containing 7a) is a critical transmembrane protein. Studies have indicated that Thsd7a was associated with cytoskeletal organization, cell migration and filopodia formation. However, the involvement of Thsd7a remains elusive in human Esophageal Squamous Cell Carcinoma (ESCC). Consequently, immunohistochemistry and reverse transcription-polymerase chain reaction were utilized to study the correlation between the expression of Thsd7a and clinical-pathological characteristics...
April 8, 2017: Oncotarget
Franck Pourcine, Karine Dahan, Fabrice Mihout, Marine Cachanado, Isabelle Brocheriou, Hanna Debiec, Pierre Ronco
INTRODUCTION: Clinical course of membranous nephropathy (MN) is difficult to predict. Measurement of circulating anti-PLA2R autoantibodies (PLA2R-Ab) and detection in immune deposits of PLA2R antigen (PLA2R-Ag) are major advances in disease understanding. We evaluated the clinical significance of these biomarkers. METHODS: In this 14-year retrospective study, we collected data from 108 MN patients and assessed the relationship between clinical course, PLA2R-Ab and PLA2R-Ag...
2017: PloS One
Daniel C Cattran, Paul E Brenchley
Idiopathic membranous nephropathy (INM) remains a common cause of the nephrotic syndrome in adults. The autoimmune nature of IMN was clearly delineated in 2009 with the identification of the glomerular-deposited IgG to be a podocyte receptor, phospholipase A2 receptor (PLA2R) in 70% to 75% of cases. This anti-PLA2R autoantibody, predominantly the IgG4 subclass, has been quantitated in serum using an enzyme-linked immunosorbent assay and has been used to aid diagnosis and monitor response to immunosuppressive therapy...
March 2017: Kidney International
Phillip R Stahl, Elion Hoxha, Thorsten Wiech, Cornelia Schröder, Ronald Simon, Rolf A K Stahl
We recently described a case of a Thrombospondin Type-1 Domain containing 7A (THSD7A) associated membranous nephropathy in a female patient who was synchronously suffering from a THSD7A-positive malignancy. We here investigated the role of THSD7A as a new potential tumor antigen by evaluating over 20 000 tissue spots in more than 70 different tumor entities by immunohistochemistry using tissue microarrays. THSD7A expression was highly variable in different neoplasias with differing staining patterns. Both gain and loss of THSD7A expression compared to expression status in non-tumor tissue were linked to tumor-specific markers in the different tumor entities and were of prognostic value...
April 2017: Genes, Chromosomes & Cancer
Andrew Smith, Vincenzo L'Imperio, Elena Ajello, Franco Ferrario, Niccolò Mosele, Martina Stella, Manuel Galli, Clizia Chinello, Federico Pieruzzi, Goce Spasovski, Fabio Pagni, Fulvio Magni
Membranous Nephropathy (MN) is an immunocomplex mediated renal disease that represents one of the most frequent glomerulopathies worldwide. This glomerular disease can manifest as primary (idiopathic) or secondary and this distinction is crucial when choosing the most appropriate course of treatment. In secondary cases, the best strategy involves treating the underlying disease, whereas in primary forms, the identification of confirmatory markers of the idiopathic etiology underlining the process is requested by clinicians...
July 2017: Biochimica et Biophysica Acta
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