title: Deposition of IgA in primary IgA nephropathy: it takes at least four to tango.
abstract: Berthelot et al. investigated the role of different players in the induction of IgA-mediated inflammation combining mice with a knock-in of the human IgA1 heavy chain (α1KI), with mice expressing the human IgA receptor CD89 (CD89Tg). These experiments suggest that IgA1 interacts with CD89 on mononuclear cells and induces the release of sCD89 and the formation of IgA1-CD89 complexes. These complexes then interact with the transferrin receptor (CD71/TfR1) on mesangial cells and further enhance the expression of TfR1 via transglutaminase-2 (TGase2). TGase2 is a calcium-dependent enzyme that is involved in cross-linking proteins through the formation of ε(γ-glutamyl)-lysine bonds. TfR1 and TGase2 were both shown to bind sCD89, but also to directly interact with each other, providing an amplification step for IgA1 accumulation and inflammation in the kidney. Importantly, when α1KI/CD89 Tg mice were crossed with TGase2-deficient mice, both IgA deposition and renal disease were strongly attenuated. Immunohistochemical studies demonstrated the enhanced mesangial deposition of IgA1-sCD89 complexes not only in Tg mice, but also in biopsies of a limited number of patients with IgAN and not in controls. Taken together, these exciting and detailed studies reveal a number of results that are of importance for our understanding of the intricate mechanisms that may lead to the deposition of IgA1 in the mesangium and the minimum requirements for the induction of an inflammatory cascade leading to glomerular damage and decline of renal function.
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
mesh_terms: D000818:Animals; D005922:Glomerulonephritis, IGA / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D051379:Mice
chemical_list: D007070:Immunoglobulin A