http://kidney.niddk.nih.gov/about/Research_Updates/KidneyDiseaseFall09/1.htmKidney Disease Research UpdatesFall 2009
PLA2R Target of Kidney Autoimmune AttackScientists funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) have identified a key protein involved in idiopathic membranous nephropathy, a kidney disease. The protein, called M-type phospholipase A2 receptor (PLA2R), was found in the kidneys' filtering units, called glomeruli. Additionally, anti-PLA2R antibodies were found in the blood and kidneys of people with idiopathic membranous nephropathy.
"Our findings show that PLA2R is a major target antigen in idiopathic membranous nephropathy," wrote Laurence Beck Jr., M.D., Ph.D., assistant professor of medicine, Boston University, and colleagues in their report on the study, which appeared July 2 in The New England Journal of Medicine.
The findings open new doors to diagnostic tests and treatments for this important and devastating disease.
Mysterious OriginsMembranous nephropathy is characterized by the accumulation of immune deposits in the glomerular capillaries, which filter waste from blood while retaining protein the body needs. The immune deposits initiate a chain of events that ultimately compromises the integrity of the capillary wall, leading to leakage of protein into the urine, also called proteinuria. Over time, damage to the capillary wall can become more prominent and lead to kidney failure. Systemic lupus erythematosus, hepatitis B, and some forms of cancer can cause so-called "secondary" membranous nephropathy, but the most common form is idiopathic, which means the cause is unknown.
For years, mystery surrounded the mechanism causing the formation of these immune deposits. Recently, scientists at the Boston University School of Medicine found unique antibodies present in the blood of people with idiopathic membranous nephropathy. These antibodies recognized a specific protein in glomerular tissue extracts that were taken from normal kidneys.
Upon purification, the scientists learned the protein was PLA2R. Although its functional role in the glomerulus is unclear, PLA2R is one of four mammalian members of the mannose-receptor family.
Analysis of sectioned normal kidney tissue stained with anti-PLA2R antibody showed PLA2R to be present on podocytes–cells that line the glomerular membrane and prevent protein from leaking into the urine.
"The expression of PLA2R on podocytes is a new finding and is very relevant to the paradigm of how antibodies to podocyte proteins can lead to proteinuria," said Beck. "The finding supports the hypothesis that autoantibodies against PLA2R could cause disease."
Additionally, in sectioned kidney tissue from individuals with idiopathic membranous nephropathy, PLA2R was found in the immune deposits located immediately adjacent to the podocytes. Combined with the observation that PLA2R antibodies were absent in blood from people with secondary membranous nephropathy and controls, the finding strongly suggests the immune deposits are actively formed in the glomerular capillaries and not elsewhere in the body, as some researchers had believed.
Major Breakthrough"The present observations of Beck, et al., represent a major breakthrough that will almost certainly initiate a new era of investigation into human membranous nephropathy," wrote Richard J. Glassock, M.D., professor emeritus at the David Geffen School of Medicine, University of California, Los Angeles, in a companion editorial. "Five decades after its initial recognition, membranous nephropathy is now entering an exciting, dynamic new era."
In addition to shedding light on the pathogenesis of this enigmatic disease and other autoimmune disorders, discovery of PLA2R as a central autoimmune target in membranous nephropathy will potentially enable the development of noninvasive assays for diagnosing and monitoring disease and response to treatment.
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