Prediagnostic Appearance of THSD7A Autoantibodies in Membranous Nephropathy

Description

Background: Pathogenic autoantibodies against thrombospondin type-1 domain 7A (THSD7A) are present in approximately 3% of patients with membranous nephropathy (MN). Compared to PLA2R antibodies, less is known about THSD7A autoantibodies (AB) due to the relative rarity and lack of a commercially, available quantitative immunoassay. Methods: Here we describe the development and validation of a highly quantitative, luciferase immunoprecipitation systems (LIPS) assay for detecting THSD7A AB and used it to study dominant THSD7A epitopes, disease associations and monitoring disease activity. The Department of Defense Serum Repository (DODSR) was then used to analyze THSD7A AB in 371 longitudinal serum samples collected before clinical diagnosis of MN from 110 PLA2R-negative MN subjects. Results: LIPS analysis demonstrated that a near full-length THSD7A (amino acids 1-1656) detected robust autoantibody levels in all known seropositive MN patients with 100% sensitivity and specificity compared to ELISA and/or Western blotting. The majority of THSD7A seropositive subjects in our pilot cohort had evidence of coexisting autoimmunity or cancer. Moreover, three THSD7A seropositive cases undergoing immunosuppressive therapy showed longitudinal autoantibody levels that tracked clinical status. Additional epitope analysis of two smaller protein THSD7A fragments spanning amino acids 1-416 and 1-671 demonstrated lower sensitivity of 32% and 44%, respectively. In the DODSR cohort, THSD7A seropositivity was detected in 4.5% of PLA2R negative MN cases. In one "primary" and in one secondary MN-associated with cancer, THSD7A AB were detectable less than one month prior to biopsy-proven diagnosis. In addition, 3 cases of lupus membranous nephropathy had detectable THSD7A AB years before hypoalbuminemia and biopsy-proven diagnosis. Conclusions: While further studies are needed to explore the significance of THSD7A AB in lupus membranous nephropathy, this study describes a novel, highly sensitive LIPS immunoassay for detecting THSD7A AB and adds to the existing literature on THSD7A-associated MN.

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