ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO2330

Novel Nephrin Protein/HLA Class II Complexes: A New Mechanism of Steroid-Sensitive Nephrotic Syndrome

Session Information

Category: Pediatric Nephrology

  • 1700 Pediatric Nephrology

Authors

  • Horinouchi, Tomoko, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
  • Aoto, Yuya, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
  • Ishiko, Shinya, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
  • Sakakibara, Nana, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
  • Nagano, China, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
  • Yamamura, Tomohiko, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
  • Ninchoji, Takeshi, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
  • Nozu, Kandai, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
  • Iijima, Kazumoto, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
Background

We have recently identified the risk allele (HLA-DRB1*08:02) and the protective allele (HLA-DRB1*13:02) in the development of childhood steroid-sensitive nephrotic syndrome (SSNS) in a Japanese population (JASN 2018). HLA-DRB1*07:01-DQA1*02:01-DQB1*02:01 was also identified as a risk haplotype in other populations. In addition, we found that NPHS1, coding nephrin, which is a key component of podocytes, was associated with susceptibility to childhood SSNS (Kidney Int 2020). HLA class II genes are associated with susceptibility to many kinds of autoimmune diseases, with one of the mechanisms being misfolded protein/HLA class II complexes that are aberrantly transported to the cell surface inducing immune responses (Jin, Arase et al. PNAS 2014). Therefore, we investigated the relationship between each HLA allele and nephrin, based on the hypothesis that nephrin protein/HLA class II complexes might be involved in the development of SSNS.

Methods

Nephrin lacking the transmembrane domain (Nephmis) was used as a model of misfolded protein that is not expressed on the cell surface. We co-transfected Nephmis and HLA-DR to HEK293T cells and assessed the expression patterns by flow cytometry and immunoprecipitation.

Results

Nephmis was detected on the cell surface in the presence of HLA-DR, which was more intense in the risk alleles than in the protective allele (DRB1*07:01>DRB1*08:02>DRB1*13:02). While Nephmis coimmunoprecipitated with HLA-DR, Nephmis was not detected in the absence of HLA-DR.
[Discussion]
Podocytes are sometimes considered as non-hematopoietic professional antigen presenting cells because they present antigens on the cell surface via HLA class II and stimulate immune signaling. We showed that the risk HLA DR allele tended to present Nephmis stronger than the protective allele, suggesting that an immune response could be more easily induced in the risk alleles than in the protective allele. Although there are a variety of possible mechanisms by which HLA polymorphisms could be associated with SSNS, the binding of specific molecules, such as nephrin or Nephmis, and their presentation may provide new insights into the pathogenesis of SSNS.

Conclusion

Our results suggest that nephrin protein/HLA classII complexes can be involved in the pathogenesis of childhood SSNS.

Funding

  • Government Support - Non-U.S.