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Science Advances: Identification of a Potential Immune System Target Antigen in Autoimmune Kidney Disease

Researchers have identified a protein that may play a key role in the development of an autoimmune form of kidney disease known as “idiopathic membranous nephropathy.” This type of kidney disease is a common cause of nephrotic syndrome in adults. It is an autoimmune disease, meaning that the body's immune system incorrectly mounts an attack against a normally-occurring protein in the body. The disease is characterized by protein in the urine, lowered protein levels in the blood, elevated cholesterol, and swelling of the face, hands, and feet. The identification of the protein that induces this immune response (termed an “antigen”) will open new avenues of exploration in idiopathic membranous nephropathy. 

To identify potential target antigens, scientists collected blood samples from patients with idiopathic membranous nephropathy, and mixed them with proteins that were obtained from kidney tissue. In 70 percent of the tested blood samples, self-reactive antibodies (autoantibodies) identified a single kidney protein that was ultimately determined to be the M-type phospholipase A2 receptor or PLA2R. This protein is expressed by cells in glomeruli, tiny filtering units in the kidney that are injured in this syndrome. The subtype of antibody that reacted with PLA2R in the assay is the same kind that is found in immune deposits within the glomeruli in patients with this disease. Antibodies isolated from glomeruli of patients with idiopathic membranous nephropathy react with PLA2R, whereas antibodies isolated from the glomeruli of patients with nephropathy arising from other causes do not. Furthermore, there is evidence to suggest that, in patients with clinically significant disease activity, autoantibodies against PLA2R can be readily detected in the blood. In contrast, in patients in whom the disease is in remission, levels of these antibodies decline or disappear.

Fifty years ago, researchers studying a rat model of idiopathic membranous nephropathy identified a kidney protein that appeared to be an immunological target for autoantibodies; however, progress stalled when this protein was found to be absent in human kidneys. These new findings will also have important implications for patient care. For example, they may permit the noninvasive diagnosis of membranous nephropathy, as well as provide an easier way to follow the disease in response to treatment. Better understanding of the potential triggers of autoantibody production in patients with a susceptibility to idiopathic membranous nephropathy may also uncover possible new targets for preventing or treating this disease. 

Beck LH, Bonegio RGB, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, and Salant DJ. M-Type Phospholipase A2 Receptor as Target Antigen in Idiopathic Membranous Nephropathy. New Engl J Med 361: 11-21, 2009.

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