Discovery of Anti-Mesangial Autoantibodies Redefines the Pathogenesis of IgA Nephropathy
Researchers have found that IgA autoantibodies that bind to a specific antigen on the mesangial cells are the trigger for IgA nephropathy
IgA nephropathy is a common form of chronic glomeluronephritis. It is thought to be caused by the buildup of IgA immune complexes in the glomeruli; however, this does not explain their site-specific deposition in the mesangium. A new study has revealed for the first time that the glomerular IgA deposition takes place owing to their affinity for self-antigens expressed on mesangial cells. This discovery potentially redefines the pathogenesis of IgA nephropathy.
IgA nephropathy (IgAN) is a kidney disorder characterized by the buildup of immunoglobin A (IgA) in the glomeruli, which are bundles of capillaries that filter blood in the kidney. In advanced stages of the disease, the buildup of IgA in the glomeruli disrupts kidney functioning and, in approximately 30% to 40% of cases, leads to kidney failure. IgA is thought to form complexes with IgG, IgM, and C3 proteins in the blood and then accumulate in the glomeruli during filtration. However, the accepted explanation does not explain a unique hallmark of the disease: during the initial stages of IgAN, IgA deposition is seen in the mesangium, an area composed of mesangial cells and matrix within the glomerulus.
In a study that was recently published in Science Advances, a group of researchers from Japan has uncovered the reason for IgA deposition being restricted to the mesangium. The researchers, including Professor Daisuke Kitamura from Tokyo University of Science and Dr. Yoshihito Nihei and Professor Yusuke Suzuki from Juntendo University, investigated the development of IgAN using specially bred mice, called gddY mice, which exhibit a disease similar to human IgAN.
The researchers found that unlike the serum of control mice that did not develop IgAN, the serum of gddY mice contained autoantibodies (antibodies that attack the cells of one's own body) that recognize a protein called βII-spectrin found in the mesangial cells. "We have demonstrated that βII-spectrin, previously thought to be an intracellular protein, is in fact exposed on the surface of mesangial cells and directly recognized by the IgA autoantibodies produced by gddY mice. Similarly, anti-βII-spectrin IgA antibodies were found in the sera of many patients with IgAN," explains lead researcher Prof. Kitamura.
The researchers conducted serum analyses, which revealed that a whopping 70% of the gddY mice produced IgA autoantibodies, whereas only 6% of the control mice were found to have them. Similarly, while about 60% of patients with IgAN tested in the study produced autoantibodies to βII-spectrin, none of the individuals in the control group had them. The researchers further discovered that cells producing IgA antibody called IgA+ plasmablasts accumulated in the kidneys of gddY mice and patients with IgAN.
To determine whether IgA autoantibodies specifically recognize and bind to βII-spectrin, the researchers introduced βII-spectrin in embryonic kidney-derived cell line and analyzed by flow cytometry, a laser-mediated analysis of immunofluorescence-stained cells. The result confirmed that the IgA autoantibodies did indeed bind specifically to βII-spectrin on the cell surface. The researchers further confirmed their findings by injecting mice with IgA autoantibodies and visualizing the structures of the glomeruli in kidney using immunofluorescence staining. "IgA antibodies isolated from gddY mice bound to βII-spectrin on the surface of mesangial cells, and when administered intravenously, bound to the renal mesangial cells. Thus, this study showed for the first time that IgA-type autoantibody production against mesangial cells may be the cause of IgAN," Prof. Kitamura notes.
Understanding the mechanism of initial disease development in IgAN can help design better treatments for the disease in the future. Moreover, the findings of this study can make testing for IgAN easier than ever before. "Until now, IgAN could only be diagnosed by risky kidney biopsy. Now that we know that 36% to 60% of IgAN patients have IgA-type autoantibodies to beta 2-spectrin in their blood, we will be able to diagnose IgAN using the patient's blood," Prof. Kitamura concludes.
|Title of original paper||:||Identification of IgA autoantibodies targeting mesangial cells redefines the pathogenesis of IgA nephropathy|
|Authors||:||Yoshihito Nihei1,2, Kei Haniuda2†, Mizuki Higashiyama2, Shohei Asami2, Hiroyuki Iwasaki1,2, Yusuke Fukao1, Maiko Nakayama1, Hitoshi Suzuki1, Mika Kikkawa3, Saiko Kazuno3, Yoshiki Miura3, Yusuke Suzuki1, Daisuke Kitamura2|
1Department of Nephrology, Juntendo University Faculty of Medicine
2Division of Cancer Cell Biology, Research Institute for Biomedical Sciences, Tokyo University of Science
3Laboratory of Proteomics and Biomolecular Science, Biomedical Research Core Facilities, Juntendo University Graduate School of Medicine
Prof. Daisuke Kitamura
Division of Cancer Cell Biology, Research Institute for Biomedical Sciences
Tokyo University of Science
Prof. Yusuke Suzuki
Department of Nephrology
Juntendo University Faculty of Medicine
Public Relations Division
Tokyo University of Science
Public Relations Division
Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.
With a mission of "Creating science and technology for the harmonious development of nature, human beings, and society," TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.
About Professor Daisuke Kitamura
from Tokyo University of Science
This work was supported by the Japan Society for the Promotion of Science KAKENHI, 720 Grant-in-Aid for Scientific Research (A) 20H00510 (D.K.).