An Indirect Immunofluorescence Method Facilitates Detection of Thrombospondin Type 1 Domain–Containing 7A–Specific Antibodies in Membranous Nephropathy

Abstract

Thrombospondin type 1 domain-containing 7A (THSD7A) is a target antigen identified in adult membranous nephropathy (MN) along with the major antigen phospholipase A receptor 1 (PLAR1). The prevalence of THSD7A-Ab-positive patients is unknown, and it is unclear whether the clinical presentation differs between patients positive for PLAR1-Ab or THSD7A-Ab. We screened serum samples of 1276 patients with MN from three different cohorts for the presence of THSD7A-Ab by Western blot analysis and a newly developed indirect immunofluorescence test (IFT). Compared with Western blot analysis, the IFT had a 92% sensitivity and a 100% specificity. The prevalence of THSD7A-associated MN in a prospective cohort of 345 patients with MN was 2.6%, and most were women. In this cohort, the percentage of patients with THSD7A-associated MN and malignant disease significantly exceeded that of patients with PLAR1-associated MN and malignant disease. In all cohorts, we identified 40 patients with THSD7A-associated MN, eight of whom developed a malignancy within a median time of 3 months from diagnosis of MN. In one patient with THSD7A-associated MN and metastases of an endometrial carcinoma, immunohistochemistry showed THSD7A expression on the metastatic cells and within follicular dendritic cells of the metastasis-infiltrated lymph node. We conclude that the IFT allows sensitive and specific measurement of circulating THSD7A-Ab in patients with MN. Patients with THSD7A-associated MN differ in their clinical characteristics from patients with PLAR1-associated MN, and more intensive screening for the presence of malignancies may be warranted in those with THSD7A-associated MN.

Primary Membranous Glomerulonephritis: The Role of Serum and Urine Biomarkers in Patient Management

“…Forty of them tested positive for anti-THSD7A and 8 out of the 40 developed malignancy within an average follow-up period of 3 months. Thus, this finding denoted that THSD7A is associated with malignancy [52]. In another study involving 81 patients with breast cancer and 20 with colorectal cancer, THS7A expression was detected by immunohistochemical stains in 100% and 97.5% of breast cancer and colorectal cancer, respectively [53].…”

The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy

“…Before study inclusion, all patients tested positive for anti-THSD7A antibodies in the serum by a recently developed indirect immunofluorescence test. 11 Nineteen (61%) patients were men, and the median age was 67 years old (IQR, 53.5-74.5 years old). The median time between renal biopsy and first serum collection was 1 month (IQR, 0.0-1.0 months), median proteinuria at the time of first serum collection was 7.1 g/d (IQR, 4.8-9.9 g/d), and median serum creatinine was 1.3 mg/dl (IQR, 0.8-1.6 mg/dl).…”

“…[7][8][9][10] The prevalence of THSD7A-associated MN is significantly lower compared with that of PLA2R1-associated MN, and the clinical usefulness of anti-THSD7A autoantibody measurement is currently under investigation. 11 Noteworthy, 20% of white patients with THSD7A-associated MN have concurrent malignancies, suggesting that intensive screening for malignancies is advised in these patients. 12,13 The identification of antigen epitopes in renal autoimmune diseases, such as anti-glomerular basement membrane disease and ANCA vasculitis, has contributed to the understanding of the disease mechanisms in these entities.…”

THSD7A expression in human cancer

“…There is only limited knowledge of the role of THSD7A in human disease. Besides the involvement in the pathogenesis of MN there is evidence for participation in angiogenesis as well as an association with obesity …”

“…1 There is only limited knowledge of the role of THSD7A in human disease. Besides the involvement in the pathogenesis of MN [1][2][3][4] there is evidence for participation in angiogenesis [5][6][7] as well as an association with obesity. 8 THSD7A is hypothesized to be a membrane-associated N-glycoprotein with a soluble form produced by cells of endothelial and neuronal origin.…”