Some of the resultant immune complexes in the circulation escape normal clearance mechanisms, deposit in the renal mesangium, and induce glomerular injury. recently identified candidate receptors that may mediate binding of IgA1 and IgA1 complexes are CD71 (transferrin receptor) (88, 91-93) and the Fc/ receptor (94). CD71 Gap 26 appears to be the major IgA1 receptor on human mesangial cells (reviewed Gap 26 by Moura in this issue) (88, 92). Notably, the expression of CD71 is enhanced in Anxa5 the mesangium of IgAN patients and it co-localizes with IgA1 deposits (95). Engagement of CD71 by IgA1 induces cellular proliferation and cytokine production. This accentuated cellular proliferation and cytokine production by IgA1 is inhibited completely by anti-CD71 blocking antibody, indicating that CD71 plays a major role in IgA1 binding (93). Hypothetical model of the pathogenesis of IgAN Based on published data, a hypothetical model of the pathogenesis of IgAN is emerging. Some IgA1 molecules produced by immunoglobulin-secreting cells in patients with IgAN are galactose-deficient and consequently recognized by anti-glycan IgG (or IgA1) antibodies. The resultant immune complexes are too bulky to enter the space of Disse in the liver. IgA1-containing immune complexes that escape normal clearance mechanisms reach the renal circulation and pass through the larger fenestrae in the glomerular capillaries overlying the mesangium. These complexes bind to mesangial cells and induce glomerular injury (Figure 3). Together, these characteristics classify IgAN as an autoimmune disease, with the aberrantly glycosylated IgA1 being the autoantigen. Acknowledgments Supported in part by grants from National Institutes of Health DK78244, DK61525, DK71802, and DK64400, and by a grant from Czech Republic VZ MSM0021620812. Footnotes Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been Gap 26 accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain..