Autoantibodies against thrombospondin type 1 domain–containing 7A induce membranous nephropathy
Nicola M. Tomas, … , Catherine Meyer-Schwesinger, Rolf A.K. Stahl
Nicola M. Tomas, … , Catherine Meyer-Schwesinger, Rolf A.K. Stahl
Published May 23, 2016
Citation Information: J Clin Invest. 2016;126(7):2519-2532. https://doi.org/10.1172/JCI85265.
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Research Article Nephrology

Autoantibodies against thrombospondin type 1 domain–containing 7A induce membranous nephropathy

Abstract

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, and one-third of patients develop end-stage renal disease (ESRD). Circulating autoantibodies against the podocyte surface antigens phospholipase A2 receptor 1 (PLA2R1) and the recently identified thrombospondin type 1 domain–containing 7A (THSD7A) are assumed to cause the disease in the majority of patients. The pathogenicity of these antibodies, however, has not been directly proven. Here, we have reported the analysis and characterization of a male patient with THSD7A-associated MN who progressed to ESRD and subsequently underwent renal transplantation. MN rapidly recurred after transplantation. Enhanced staining for THSD7A was observed in the kidney allograft, and detectable anti-THSD7A antibodies were present in the serum before and after transplantation, suggesting that these antibodies induced a recurrence of MN in the renal transplant. In contrast to PLA2R1, THSD7A was expressed on both human and murine podocytes, enabling the evaluation of whether anti-THSD7A antibodies cause MN in mice. We demonstrated that human anti-THSD7A antibodies specifically bind to murine THSD7A on podocyte foot processes, induce proteinuria, and initiate a histopathological pattern that is typical of MN. Furthermore, anti-THSD7A antibodies induced marked cytoskeletal rearrangement in primary murine glomerular epithelial cells as well as in human embryonic kidney 293 cells. Our findings support a causative role of anti-THSD7A antibodies in the development of MN.

Authors

Nicola M. Tomas, Elion Hoxha, Anna T. Reinicke, Lars Fester, Udo Helmchen, Jens Gerth, Friederike Bachmann, Klemens Budde, Friedrich Koch-Nolte, Gunther Zahner, Gabriele Rune, Gerard Lambeau, Catherine Meyer-Schwesinger, Rolf A.K. Stahl

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Figure 7

Anti-THSD7A antibodies cause cytoskeletal rearrangement in THSD7A- expressing primary cultured GECs.

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Anti-THSD7A antibodies cause cytoskeletal rearrangement in THSD7A- expre...
(A) Western blot analysis shows expression of THSD7A in GECs. Rec. THSD7A, recombinant human THSD7A. (B) Immunofluorescence staining for huIgG and α-actinin-4 in GECs following a 40-minute exposure to affinity-purified anti-THSD7A antibodies or to serum that was depleted of anti-THSD7A antibodies. Arrows indicate cells that did not express α-actinin-4 and that showed no huIgG binding. Asterisks indicate the glomerulus from which the cells grew. Scale bars: 50 μm. Enlargements of boxed areas are shown in the far right upper and lower panels (original magnification, ×1,000, 4× zoom). (C) Immunofluorescence staining for huIgG, F-actin (phalloidin), and p-paxillin in GECs following a 40-minute exposure to affinity-purified anti-THSD7A antibodies or to serum that was depleted of anti-THSD7A antibodies. Arrows indicate a cell that had no huIgG bound to the membrane and that did not exhibit enhanced F-actin staining. Asterisks indicate the glomerulus from which the cells grew. Scale bars: 50 μm. (D) Quantification of stress fiber formation after treatment of GECs with purified anti-THSD7A antibodies or serum depleted of anti-THSD7A antibodies. A total of 30 images from 3 independent experiments were analyzed. Data indicate F-actin OD of individually circled cells normalized to the control condition (depleted serum). Error bars represent the mean ± SEM.***P < 0.001, by 2-tailed, nonparametric Mann-Whitney U test.