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.
View: Text | PDF
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

×

Figure 6

Affinity-purified anti-THSD7A antibodies induce MN in mice.

Options: View larger image (or click on image) Download as PowerPoint
Affinity-purified anti-THSD7A antibodies induce MN in mice. (A) Serum fr...
(A) Serum from a patient with THSD7A-associated MN was run through chromatographic columns loaded with beaded agarose that was coupled to purified recombinant human THSD7A. The serum was passed 3 times over the columns (FL1–FL3) with 2 acid elutions per round (E1–E6). Immunoblots show the reactivity of purified anti-THSD7A antibodies and serum flow-through with HGEs and recombinant human THSD7A. (B–D) Immunofluorescence staining for huIgG and laminin (paraffin sections) (B), huIgG and THSD7A (frozen sections) (C), and mIgG and laminin (paraffin sections) (D) 28 days after injection of purified anti-THSD7A antibodies or of serum depleted of anti-THSD7A antibodies. Images are representative of analyses of 4 animals per group. Scale bars: 50 μm. Enlargements of boxed areas in B–D are shown in the far right upper and lower panels (original magnification, ×1,000; 4× zoom). (E) Albumin-to-creatinine ratios measured in urine samples from mice injected with either purified anti-THSD7A antibodies or depleted serum (n = 4 per group). Error bars indicate the mean ± SEM. *P < 0.05, by 2-tailed, nonparametric Mann-Whitney U test.