Editors' ChoiceAutoimmunity

Connecting the Dots to Describe a Mechanism for IgA Nephropathy

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Science Translational Medicine  18 Apr 2012:
Vol. 4, Issue 130, pp. 130ec65
DOI: 10.1126/scitranslmed.3004149

In some autoimmune diseases, the immune system puts on its gloves and delivers a shot to the kidney. Immunoglobulin A (IgA) nephropathy (IgAN) is the most common primary autoimmune kidney disease. In IgAN, IgA1 in immune complexes gets stuck in the filtering units of the kidney—the glomeruli—and disrupts kidney function. However, it remains unclear what exactly contributes to IgA1 deposition in the glomeruli. Using genetically humanized mice, Berthelot et al. have uncovered a mechanism for IgAN pathogenesis that connects receptors for IgA1 with transglutaminase 2 (TGase2)—a molecule that has been previously linked to another autoimmune disease, celiac disease.

Berthelot et al. showed that mice that express human IgA1 and a receptor for IgA1—CD89—developed the hallmarks of human IgAN. Furthermore, they showed that soluble CD89 induced kidney cell expression of another receptor for IgA1, transferrin receptor (TfR1, CD71). The IgA1-CD89-CD71 chain induced inflammation and surface expression of the usually cytosolic TGase2. Indeed, TGase2 was necessary for kidney injury in this setting, although the role of TGase2 in IgAN is likely distinct from its role in celiac disease.

In addition to providing a mechanism for how IgA1-immune complex deposition in the kidney causes IgAN, the authors’ successful candidate approach to studying immunopathogenesis provides a description of how inflammation can provoke previously unidentified receptor-ligand interactions. These interactions, which are not seen under homeostatic conditions but uncovered after chronic inflammation, can be central to autoimmune states. However, therapeutics that capitalize on these data will depend on the actual physiologic roles of these inflammation-induced receptor-ligand interactions. This work connects the dots between recent and ongoing studies that identify disease-associated genetic variation for IgAN, helping us better view the complex picture of IgAN pathogenesis.

L. Berthelot et al., Transglutaminase is essential for IgA nephropathy development acting through IgA receptors. J. Exp. Med. 209, 793–806 (2012). [Abstract]

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