Abstract
Although IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, its etiology remains only partly understood. It is clear that the pathogenesis of IgAN involves the formation of macromolecular IgA1 complexes and increased levels of serum IgA1 and IgA1-immune complexes(IC), due to defective IgA1 clearance. Previous studies suggest that the blood and tissue myeloid cell-expressed IgA Fc receptor (FcαR/CD89) mediates IgA-IC clearance and its dysfunction, via decreased activity or excessive levels of soluble FcαR/sCD89 induces IgAN. Such a mechanism requires robust stimulation of IgAN levels via forced expression of CD89. In the absence of unequivocal evidence supporting such a mechanism to date, we attempted to test the extent of CD89-evoked IgAN by generating a transgenic mouse strain expressing human CD89 under the control of murine CD14 promotor. No deposition of IgA-CD89 complexes or glomerulonephritis was detected, however. Further studies showed that elimination of murine IgA was mediated by Kupffer cells. In patients, however, CD89/IgA complexes were detected, and injection of patient IgA induced IgAN-like features in CD89 Tg mice. In transgenic mice, IgAN pathogenesis involves impaired clearance of abnormal IgA via CD89, primarily by the Kupffer cells. Conditional IgAN progression in CD89 transgenic mice thus reveals important aspects of IgAN pathogenesis.
Highlights
IgA nephropathy (IgAN) is a major cause of renal failure[1,2]
Our results indicate that CD89 plays an important role in IgA and IgA immune complexes (IgA-ICs) clearance, defective endocytosis of underglycosylated IgA is necessary for the development of experimental IgAN
To generate transgenic mice with CD89 expressed on the cell surface of monocyte/macrophages, a knock-in targeting vector was designed that contained a cDNA encoding the human CD89 cDNA, the 2A self-processing peptide, and a total of 5.2 kb of homology to the murine CD14 gene. 2A-CD89 was targeted to the CD14 locus using homologous recombination, resulting in the expression of human CD89 under the control of the mouse endogenous CD14 promoter (Fig 1)
Summary
IgA nephropathy (IgAN) is a major cause of renal failure[1,2]. A defining feature of the disease is the presence of mesangial IgA deposits, usually containing IgA1[3]. Central to the pathogenesis of IgAN is the formation of circulating IgA immune complexes (IgA-ICs) that are deposited in the renal mesangial areas, triggering glomerular injury. Various components of IgA-ICs include C3, IgG, IgM and fibronectin[4,5,6]. Increased serum levels of IgA1 and IgA1-IC were observed in patients with IgAN[7,8] and appear at least partly derived from overproduction of IgA1 by B cells[9]. Impaired clearance of IgA1 and IgA1-IC by dysfunctional IgA
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