Journal
ANNUAL REVIEW OF PATHOLOGY: MECHANISMS OF DISEASE, VOL 15, 2020
Volume 15, Issue -, Pages 287-313Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-pathol-020117-043811
Keywords
neutral endopeptidase; phospholipase A2 receptor; PLA2R; thrombospondin domain-containing 7A; THSD7A; genome-wide association studies; GWAS; HLA-D risk variants; membrane attack complex of complement
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Funding
- European Research Council Advanced Investigators Grant [ERC-2012-ADG 20120314, 322947]
- Seventh Framework Program of the European Community (European Consortium for High-Throughput Research in Rare Kidney Diseases) [2012-305608]
- French National Research Agency [ANR-17-CE17-0012-01]
- Agence Nationale de la Recherche (ANR) [ANR-17-CE17-0012] Funding Source: Agence Nationale de la Recherche (ANR)
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Membranous nephropathy is a noninflammatory autoimmune disease of the kidney glomerulus, characterized by the formation of immune deposits, complement-mediated proteinuria, and risk of renal failure. Considerable advances in understanding the molecular pathogenesis have occurred with the identification of several antigens [neutral endopeptidase, phospholipase A2 receptor (PLA2R), thrombospondin domain-containing 7A (THSD7A)] in cases arising from the neonatal period to adulthood and the characterization of antibody-binding domains (that is, epitopes). Immunization against PLA2R occurs in 70% to 80% of adult cases. The development of highly specific and sensitive assays of circulating antibodies has induced a paradigm shift in diagnosis and treatment monitoring. In addition, several interacting loci in HLA-DQ, HLA-DR, and PLA2R1, as well as classical human leukocyte antigen (HLA)-D alleles have been identified as being risk factors, depending on a patient's ethnicity. Additionally, mechanisms of antibody pathogenicity and pathways of complement activation are now better understood. Further research is mandatory for designing new therapeutic strategies, including the identifying triggering events, the molecular bases of remission and progression, and the T cell epitopes involved.
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