Upregulation of PD-1 and its ligands and expansion of T peripheral helper cells in the nephritic kidneys of lupus-prone BXSB-Yaa mice.

OBJECTIVE: This study aimed to investigate the role of the programmed cell death protein 1 (PD-1) pathway and T peripheral helper (Tph) cells in the pathogenesis of lupus nephritis using lupus-prone BXSB-Yaa mice. METHODS: Male BXSB-Yaa mice and age-matched male C57BL/6 mice were used. The expression of PD-1 and its ligands (programmed cell death 1 ligand-1, PD-L1 and programmed cell death 1 ligand-2, PD-L2) and the phenotypes of kidney-derived cells and splenocytes expressing these molecules were analyzed by immunofluorescence and flow cytometry. RESULTS: Nephritis spontaneously developed in 16-week-old but not in 8-week-old BXSB-Yaa or C57BL/6 mice. PD-1 was expressed on CD4+ mononuclear cells (MNCs) that infiltrated the glomeruli of 16-week-old BXSB-Yaa mice. The frequency of CD4+PD-1+CXCR5-ICOS+ kidney-derived Tph cells was higher in 16-week-old than in 8-week-old BXSB-Yaa and C57BL/6 mice, whereas the frequency of CD4+PD-1+CXCR5+ICOS+ kidney-derived T follicular helper (Tfh) cells was not significantly different between the mice. PD-L1 was constitutively expressed in the renal tubules. PD-L2 was expressed in the glomeruli of 16-week-old BXSB-Yaa mice. The frequency of PD-L1highCD11c+CD3-CD19- and PD-L2+CD11c+CD3-CD19- kidney-derived MNCs in 16-week-old BXSB-Yaa mice was significantly higher than that of the control mice. The percentage of kidney-derived Tph cells but not Tfh cells was correlated with the urinary protein levels in the nephritic mice. CONCLUSION: The results of this study suggest that kidney-infiltrating PD-1+ Tph cells expanded concomitantly with the upregulation of PD-L1 and PD-L2 in the kidneys and the progression of lupus nephritis.

Clinical usefulness of anti-M-type phospholipase-A-receptor antibodies in patients with membranous nephropathy and the comparison of three quantification methods.

Associations between anti-M-type phospholipase A2 receptor (PLA2R) antibodies and disease activity and prognosis have been suggested in primary membranous nephropathy (MN); however, more evidence is needed. We aimed to establish a clinically useful method to measure anti-PLA2R antibodies. We developed a western blot assay and a cell-based enzyme-linked immunosorbent assay (ELISA). Anti-PLA2R antibodies were evaluated retrospectively using these assays and the commercial solid-phase ELISA. Anti-PLA2R antibodies were detected in 12, 6, and 12 out of 23 Japanese patients with biopsy-proven primary MN using the western blot, the cell-based ELISA, and the solid-phase ELISA, respectively. The samples of the lupus MN patients tested negative. The levels of proteinuria correlated moderately with the titres of anti-PLA2R antibodies measured by the three methods (r = 0.39-0.47). Anti-PLA2R antibodies were significantly associated with physicians' decisions on immunosuppressive treatment without prior knowledge of anti-PLA2R antibody positivity (p < .01). In the longitudinal analysis, the titres of anti-PLA2R antibodies measured by the solid-phase ELISA declined significantly following treatment (p = .03). In conclusion, these results suggest the usefulness of anti-PLA2R antibody as a diagnostic, prognostic, and surrogate biomarker in primary MN. The three methods proved to be reliable for measuring anti-PLA2R antibody titres, but their performances differ.