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In IgA nephropathy (IgAN), the mechanism by which IgA antibodies (Abs) are selectively deposited in the glomerular mesangial region has not been fully elucidated. 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 sequenced variable region of IgA heavy and light chains of IgA+ PB isolated from the kidney of gddY mice and found that most of them 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 unclear. In the present study, we analyzed CD4+ T cells infiltrated in the kidney of gddY.
Spontaneous IgAN model mice were used in this study. 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 stimulated by monensin, ionomysin and PMA (Phorbol 12-myristate 13-acetate) and surface stained for CD4 then intracellular stained for IFN-γ, IL-17 or FoxP3. analyzed by flow cytometry. Samples were analyzed using a FACS Canto II (BD Biosciences).
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+), regulatory T (Treg, CD4+ Foxp3+), and follicular helper T (Tfh, CD4+ CXCR5+ PD-1+) cells were significantly accumulated in the kidney of gddY compared to BALB/c. On the other hand, no significant differences were seen in the number of Th2 (CD4+ IL-4+) cells accumulated in the kidney of gddY and BALB/c mice.
We found that a significant number of CD4+ T cells, Th1, Th17, Treg and Tfh but not Th2 cells, were accumulated in kidney of gddY. At present, the direct link of these infiltrated CD4+ T cells to the production of IgA type auto-Abs were not clarified. We will clarify the role of these cells in the induction of IgA auto-Abs in IgAN.