Discovery of Anti-Mesangial Autoantibodies Redefines the Pathogenesis of IgA Nephropathy
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. However, 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
In recent studies, scientists have utilized an authentic mouse model of IgA nephropathy (IgAN), known as gddy mice, to elucidate the underlying mechanisms restricting IgA deposits in the mesangium. GddY mice are genetically bred, spontaneous models of IgAN that exhibit disease processes resembling human IgAN, including proteinuria, deposition of IgA in the glomerular mesangium, and glomerular injury. It is discovered that, unlike control group mice without IgAN development, gddy mice's serum contains autoantibodies targeting their own cells. These autoantibodies specifically recognize βII-spectrin, CBX1, CBX3, and CBX5 proteins present in mesangial cells. The research findings provide evidence that IgA self-antibodies produced by the gddy mice directly recognize βII-spectrin, a surface protein of mesangial cells that is conventionally considered an intracellular protein. Additionally, anti-βII-spectrin IgA antibodies have also been detected in the sera of numerous patients with IgAN.
Fig.1 Detection of MC antigens targeted by IgA autoantibodies produced in gddY mice.1
Significant Increase in IgA Self-Antibodies Production in Gdyy Mice and IgAN Patients
Upon analyzing the serum, researchers have found that up to 70% of gddy mice produced IgA self-antibodies, compared to just 6% in the control group mice. Likewise, around 60% of tested IgAN patients produce βII-spectrin self-antibodies, but none is found in the control group. It is further revealed that cells producing IgA antibodies, specifically IgA+ plasma blast cells, accumulate in the kidneys of gddy mice and IgAN patients. The research exhibits 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 are 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
- Higashiyama, Mizuki, et al. "Oral bacteria induce IgA autoantibodies against a mesangial protein in IgA nephropathy model mice." Life Science Alliance 7.4 (2024). Distributed under Open Access license CC BY 4.0, without modification.
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