IgA Nephropathy (IgAN) is the most common primary glomerulonephritis, characterized by the accumulation of Immunoglobulin A (IgA) in the glomeruli - the tufts of capillaries filtering blood in the kidneys. In the advanced stages of the disease, IgA deposition within the glomeruli compromises kidney function, leading to kidney failure in 30% to 40% of cases. It's widely accepted that IgA forms complexes with IgG, IgM, and C3 proteins in the blood, which accumulate in the glomeruli during filtration. But this conventional explanation fails to account for a unique feature of the disease. In the initial stages of IgAN, IgA deposits in the mesangium - an area composed of mesangial cells and renal matrix.
Unraveling the Mechanism of IgA Deposition in the Mesangium
Japanese researchers recently published a study in the journal Science Advances that sheds light on why IgA deposits are confined to the mesangium. They studied the development of IgAN using genetically bred, spontaneous IgAN mice, called gddy mice which exhibit a disease similar to human IgAN. These researchers made a fascinating discovery. Unlike control group mice that did not produce IgAN, the serum of gddy mice contained self-antibodies (antibodies attacking their cells). These self-antibodies can identify a protein discovered in mesangial cells called βII-spectrin. The study provided evidence that βII-spectrin, previously considered an intracellular protein, was exposed on the surface of mesangial cells and recognized directly by IgA self-antibodies produced by the gddy mice. Anti βII-spectrin IgA antibodies were also identified in the serum of many IgAN patients.
Fig 1. Serum IgA auto-Abs in gddY mice recognizing βII-spectrin in MCs.1
Significant Increase in IgA Self-Antibodies Production in gdyy Mice and IgAN Patients
Upon analyzing the serum, researchers found that up to 70% of gdyy mice produced IgA self-antibodies, compared to just 6% in the control group mice. Likewise, around 60% of tested IgAN patients produced βII-spectrin self-antibodies, but none were found in the control group. It was further revealed that cells producing IgA antibodies, specifically IgA+ plasma blast cells, accumulated in the kidneys of gddy mice and IgAN patients. The research exhibited that IgA self-antibodies recognize and bind to βII-spectrin, the surface of mesangial cells, and the glomerular mesangial regions in situ.
New Diagnostic Opportunities for IgAN
The implication of this groundbreaking research is the suggestion that the production of IgA anti-mesangial cell self-antibodies could be the cause of IgAN. This understanding of the initial development of IgAN could help in designing improved disease treatments in the future. Moreover, these discoveries make testing for IgAN easier than ever before. Up until now, potentially dangerous kidney biopsies were the only means of diagnosing IgAN. With the knowledge that 36% to 60% of IgAN patients carry βII-spectrin IgA self-antibodies in their blood, a simple blood test could now be utilized for a more accurate diagnosis.This groundbreaking research provides hope that the strides in understanding IgAN will translate to more efficient diagnosis methods and effective treatments for this potentially life-altering disease.
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Reference
- Nihei, Yoshihito, et al. "Identification of IgA autoantibodies targeting mesangial cells redefines the pathogenesis of IgA nephropathy." Science Advances 9.12 (2023): eadd6734.
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