Antigen-Specific IgG Subclasses in Primary and Malignancy-Associated Membranous Nephropathy

Abstract

Membranous nephropathy (MN) is an autoimmune disease caused by binding of circulating antibodies to podocyte antigens in the kidney. For decades and still today primary MN has been considered to have an unspecified IgG4-driven autoimmune genesis, while secondary MN has been associated with other diseases, most notably cancer, and not linked to IgG4. Immunologic mechanisms of primary and malignancy-associated MN are assumed to be different, however, this has never been systematically evaluated. The identification of Phospholipase A2 Receptor 1 (PLA2R1) and Thrombospondin Type-1 Domain-Containing 7A (THSD7A) as target antigens in MN allows a pathogenesis-driven differential diagnosis. Recent data showing a molecular link between increased THSD7A-expression in tumors and THSD7A-antibody positive MN suggest a similar pathogenesis of malignancy-associated and primary MN. In order to better define the underlying immunologic processes, we systematically analyzed circulating antigen-specific IgG subclasses in the serum of 76 patients with PLA2R1-associated MN and 41 patients with THSD7A-associated MN in relationship to concurrent malignancy and disease outcome. Twenty-three patients in the study had malignancy-associated MN. We analyzed antigen-specific IgG subclasses in the serum of all patients at baseline and in 55 patients during follow-up by Western blot applying antigens derived from human kidney and lung. At baseline all 117 patients were positive for IgG4-antibodies against either PLA2R1 or THSD7A, while IgG3, IgG1, and IgG2-antibodies were found in 87, 72, and 26% of patients, respectively. There were no differences in the IgG subclass distribution between patients with primary vs. cancer-associated MN and no association with disease outcome. Moreover, levels of antigen-specific IgG4-antibodies were not different between primary and malignancy-associated MN and levels of all IgG subclasses did not differ between these groups. Both podocytes and lung bronchioles showed expression of both PLA2R1 and THSD7A when analyzed by immunofluorescence and Western blot. Every antigen-specific IgG subclass showed identical binding in both organs and autoantibodies bound the respective antigen only under non-reducing conditions. We conclude that antigen-specific IgG subclasses do not differentiate primary from malignancy-associated MN or predict disease prognosis. These data support the view that one common pathway may lead to primary and cancer-associated MN induced by PLA2R1- or THSD7A-antibodies.

Complete remission of membranous nephropathy in a patient with lung adenocarcinoma treated with erlotinib

“…In addition, erlotinib demonstrated its renoprotective effects against renal fibrosis in 5/6 nephrectomized rats via inhibition of the Akt and ERK 1/2 signalling pathways associated with renal fibrosis . Despite these results, we think that the response of tumour to erlotinib is the major cause of MN remission, because of reports in the literature that the complete remission of MN occurred only in patients with tumour remission, whereas complete remission of MN did not occur in any of the patients whose tumours were not in remission …”

“…Recent studies have not found differences between the distributions of the IgG subclasses (PLA2R1 or THSD7A) in patients with primary vs. cancer‐associated MN, and no association with disease outcome . Both podocytes and lung bronchioles showed expression of PLA2R1 and thrombospondin type‐1 domain‐containing 7A (THSD7A) by immunofluoroscopy and Western blotting . Altogether, these findings indicate that antigen‐specific IgG subclasses do not allow differentiation between primary MN and malignancy‐associated MN nor prediction of disease outcomes.…”

“…The remission could be the complete remission (26.09%) and partial remission (13.04%) companied by the tumour remission; meanwhile, some tumour remission (21.43%) was companied by the persistent cancer‐related MN . In another case‐pool study, complete remission of MN occurred in patients with remission of tumour, but none of the patients whose tumour was not in remission developed complete remission of MN …”

“…In animal models of cancer, oncogenic viruses induce immune complex formation and deposits in the glomeruli . Recent studies have not found differences between the distributions of the IgG subclasses (PLA2R1 or THSD7A) in patients with primary vs. cancer‐associated MN, and no association with disease outcome . Both podocytes and lung bronchioles showed expression of PLA2R1 and thrombospondin type‐1 domain‐containing 7A (THSD7A) by immunofluoroscopy and Western blotting .…”

“…6 In another case-pool study, complete remission of MN occurred in patients with remission of tumour, but none of the patients whose tumour was not in remission developed complete remission of MN. 10 The treatment of paraneoplastic syndromes is usually associated with the treatment of primary malignancy. 2,6 The To the best of our knowledge, there have not been any case reports on the complete remission of paraneoplastic nephrotic syndrome associated with the response of lung cancer to an EGFR tyrosine kinase inhibitor until now.…”