The role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapies

Abstract

Immunoglobulin A nephropathy (IgAN), characterized by mesangial deposition of galactose-deficient-IgA1 (Gd-IgA1), is the most common biopsy-proven primary glomerulonephritis worldwide. Recently, an improved understanding of its underlying pathogenesis and the substantial risk of progression to kidney failure has emerged. The "four-hit hypothesis" of IgAN pathogenesis outlines a process that begins with elevated circulating levels of Gd-IgA1 that trigger autoantibody production. This results in the formation and deposition of immune complexes in the mesangium, leading to inflammation and kidney injury. Key mediators of the production of Gd-IgA1 and its corresponding autoantibodies are B-cell activating factor (BAFF), and A proliferation-inducing ligand (APRIL), each playing essential roles in the survival and maintenance of B cells and humoral immunity. Elevated serum levels of both BAFF and APRIL are observed in patients with IgAN and correlate with disease severity. This review explores the complex pathogenesis of IgAN, highlighting the pivotal roles of BAFF and APRIL in the interplay between mucosal hyper-responsiveness, B-cell activation, and the consequent overproduction of Gd-IgA1 and its autoantibodies that are key features in this disease. Finally, the potential therapeutic benefits of inhibiting BAFF and APRIL in IgAN, and a summary of recent clinical trial data, will be discussed.

Keywords: B-cell activating factor BAFF; IgA nephropathy; a proliferation-inducing ligand APRIL; atacicept; dual inhibition.

Figure 1

Within the mucosal-associated lymphoid tissue, antigens are taken up by antigen-presenting cells, such as dendritic cells, resulting in naïve B-cell activation and class switch recombination (CSR) to form committed IgA⁺ B cells, which require a T-cell dependent (TD) or T-cell independent (TID) co-stimulatory signal. B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), members of the tumor necrosis factor superfamily, play a key role in driving both TD and TID CSR and, thus, production of IgA⁺ B cells. The pathogenesis of IgAN is tied to aberrations in B-cell activation and CSR that lead to the increased production of galactose-deficient IgA1 (Gd-IgA1) (Hit 1) and the subsequent synthesis of autoantibodies directed against Gd-IgA1 (Hit 2). The formation of pathogenic IgA1-containing immune complexes (Hit 3) provokes inflammation leading to glomerular injury (Hit 4).

Figure 2

B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), members of the tumor necrosis factor superfamily, both bind to two receptors, B-cell maturation antigen (BCMA) and transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI). BCMA is primarily expressed on plasma cells, whereas TACI is expressed on mature B cells and plasma cells. A third receptor, BAFF receptor (BAFF-R), that is specific for BAFF, is expressed mainly on immature and mature naive B cells. BAFF and APRIL have pivotal roles in the interplay between gut mucosal hyper-responsiveness, B cell activation, and the consequent overproduction of Gd-IgA1 and its autoantibodies resulting in immune complex formation.

Figure 3

B cells undergo a sequential process of maturation and selection and play a crucial role in the adaptive immune system by generating antibodies as a response to foreign antigens. B cells have the ability to differentiate into short-lived plasma cells/plasmablasts, and long-lived plasma cells, which are responsible for producing immunoglobulins, including IgA. HSC: hematopoietic stem cells.