Investigation of T Cells Contributing to the Production of IgA-Type Autoantibodies Against Mesangial Cells in IgA Nephropathy
- Glomerular Diseases: From Inflammation to Fibrosis - III
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: From Inflammation to Fibrosis
- Iwasaki, Hiroyuki, Juntendo University, Tokyo, Japan
- Aoki, Ryousuke, Juntendo University, Tokyo, Japan
- Nihei, Yoshihito, Juntendo University, Tokyo, Japan
- Suzuki, Hitoshi, Juntendo University, Tokyo, Japan
- Suzuki, Yusuke, Juntendo University, Tokyo, Japan
In IgA nephropathy (IgAN), the mechanism by which IgA antibodies (Abs) are selectively deposited in the glomerular mesangial region has not been elucidated. However, we have recently uncovered its mechanism by identifying IgA type auto-Ab against mesangial antigens, βII-spectrin, in gddY mice, a spontaneous IgAN animal model and IgAN patients (Y. Nihei, H. Iwasaki and Y. Suzuki et al, Sci. Adv 2023). We also found that a significant number of IgA+ plasmablasts (PBs) accumulated in the kidneys of gddY mice and these PBs produced IgA auto-Abs that bind to βII-spectrin and the surface of mesangial cells. We cloned cDNAs encoding IgA heavy and light chains from single IgA+ PB isolated from the kidney of gddY mice and found that most of the heavy- and light-chain V region genes of these PBs contained significant numbers of somatic mutations, indicating that they were generated in a T-cell-dependent manner through the germinal center. However, the detailed mechanisms of IgA auto-Abs production, such as which types of T cells are responsible for the induction of auto-Abs, are not clear. In the present study, we analyzed CD4+T cells in the kidney of gddY.
GddY mice were generated through selectively mating individuals within an early-disease onset group of ddY mice for more than 20 generations. All individual gddY mice exhibit proteinuria and glomerular IgA deposition by 8 weeks of age, followed by obvious renal failure and the pathology being similar to human IgAN. Isolated leukocytes from kidney of gddY or BALB/c mice at age of 8 weeks were analyzed by flow cytometry.
We found that a significant number of CD4+ T cells accumulated in the kidneys of gddY mice compared to BALB/c. In details, Th1(CD4+ IFN-γ+), Th17(CD4+ IL-17+) and Treg(CD4+ Foxp3+) cells were significantly accumulated in the kidney of gddY compared to BALB/c. No significant differences were seen in the number of Th2(CD4+ IL-4+) accumulated in the kidney of gddY and BALB/c.
Present findings revealed that a significant number of CD4+ T cells, especially Th1, Th17 and Treg, but not Th2 cells accumulated in kidney of gddY. We will clarify the role of these CD4+ T cells in the induction of IgA auto-Abs in IgAN.