Lessons from IgA Nephropathy Models

Abstract

IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide; however, the underlying mechanisms of this disease are not fully understood. This review explores several animal models that provide insights into IgAN pathogenesis, emphasizing the roles of aberrant IgA1 glycosylation and immune complex formation. It discusses spontaneous, immunization, and transgenic models illustrating unique aspects of IgAN development and progression. The animal models, represented by the grouped ddY (gddY) mouse, have provided guidance concerning the multi-hit pathogenesis of IgAN. In this paradigm, genetic and environmental factors, including the dysregulation of the mucosal immune system, lead to increased levels of aberrantly glycosylated IgA, nephritogenic immune complex formation, and subsequent glomerular deposition, followed by mesangial cell activation and injury. Additionally, this review considers the implications of clinical trials targeting molecular pathways influenced by IgAN (e.g., a proliferation-inducing ligand [APRIL]). Collectively, these animal models have expanded the understanding of IgAN pathogenesis while facilitating the development of therapeutic strategies that are currently under clinical investigation. Animal-model-based studies have the potential to facilitate the development of targeted therapies with reduced side effects for IgAN patients.

Keywords: APRIL (a proliferation-inducing ligand); IgA nephropathy; Toll-like receptors; animal models; endothelin; galactose deficient IgA1; immune complex.

Figure 1

Multi-hit model of IgA nephropathy development. Hit 1: Patients and mice with IgAN have genetically increased serum levels of aberrantly glycosylated IgA. Additionally, the disruption of the mucosal immune response to exogenous antigens in mucosa-associated lymphoid tissue leads to increased levels of aberrantly glycosylated IgA via Toll-like receptors. Hits 2 and 3: autoantibodies that recognize this aberrantly glycosylated IgA develop and form nephritogenic immune complexes (ICs). Hit 4: These nephritogenic IgA-containing ICs undergo glomerular deposition. They activate mesangial cells and the complement pathway, leading to extracellular matrix proliferation, cytokine and chemokine secretion, and glomerular injury. Created with BioRender.com (accessed on 25 August 2024).

Figure 2

Mechanism of galactose-deficient IgA1 (Gd-IgA1) and immunological complexes (ICs) formation in humans. The human α1 heavy chain contains several O-linked glycan chains at positions 3–6, attached to the Serine and Threonine residues in the hinge region. B lymphocytes produce IgA1 with a galactose deficiency in the hinge region of the heavy chain. IgG antibodies recognize GalNAc-containing epitopes on the galactose-deficient hinge region O-glycans of IgA1, resulting in the formation of ICs. Created with BioRender.com (accessed on 25 August 2024). Thr: Threonine, Ser: Serine, Pro: Proline.