Iwatani Hirotsugu, Nagasawa Yasuyuki, Yamamoto Ryohei, Iio Kenichiro, Mizui Masayuki, Horii Arata, Kitahara Tadashi, Inohara Hidenori, Kumanogoh Atsushi, Imai Enyu, Rakugi Hiromi, Isaka Yoshitaka
Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Clin Exp Nephrol. 2015 Apr;19(2):216-24. doi: 10.1007/s10157-014-0968-z. Epub 2014 May 6.
Hematuria is the first manifestation of urinary abnormality in immunoglobulin A nephropathy (IgAN). Hematuria has recently been reported as a risk factor for deterioration of renal function; however, its cause remains unknown.
We analyzed the surface marker of peripheral blood mononuclear cells before and immediately after tonsillectomy in IgAN patients and controls (chronic tonsillitis or tonsillar hypertrophy) by flow cytometry and investigated the association with hematuria. To prove our hypothesis that NK cells induce hematuria, we administered IL-12, activator of NK cells, to HIGA mice. In addition, we transferred cultured NK cells to nude rats and transferred the CD16(+)CD56(+) cells, including NK cells, that are derived from the peripheral blood of IgAN patients immediately after tonsillectomy to nude rats to assess the hematuria level and renal histology of the recipients. We also performed cytotoxicity assays against glomerular endothelial cells by NK cells.
We found that IgAN patients who showed rapid deterioration of hematuria after tonsillectomy also displayed a significant increase in CD16(+)CD56(+) cells in the peripheral blood immediately after tonsillectomy. Exogenous administration of IL-12 to HIGA mice induced hematuria. Adoptive transfer of either cells of an NK cell line, or of CD16(+)CD56(+) cells derived from IgAN patients, into nude rats induced hematuria in the recipients. In vitro analysis showed that NK cells exert cytotoxic activity toward human glomerular endothelial cells in a dose-dependent manner.
CD16(+)CD56(+) cells seem to be responsible for hematuria in IgAN.
血尿是免疫球蛋白A肾病（IgAN）中泌尿系统异常的首发表现。最近有报道称血尿是肾功能恶化的危险因素；然而，其病因仍不清楚。
我们通过流式细胞术分析了IgAN患者和对照组（慢性扁桃体炎或扁桃体肥大）扁桃体切除术前及术后即刻外周血单个核细胞的表面标志物，并研究了其与血尿的相关性。为了证实我们关于自然杀伤（NK）细胞诱导血尿的假设，我们给HIGA小鼠注射了NK细胞激活剂白细胞介素-12（IL-12）。此外，我们将培养的NK细胞转移到裸鼠体内，并将扁桃体切除术后即刻取自IgAN患者外周血的包括NK细胞在内的CD16(+)CD56(+)细胞转移到裸鼠体内，以评估受体的血尿水平和肾脏组织学。我们还进行了NK细胞对肾小球内皮细胞的细胞毒性测定。
我们发现，扁桃体切除术后血尿迅速恶化的IgAN患者在术后即刻外周血中CD16(+)CD56(+)细胞也显著增加。给HIGA小鼠外源性注射IL-12可诱导血尿。将NK细胞系细胞或源自IgAN患者的CD16(+)CD56(+)细胞过继转移到裸鼠体内可诱导受体出现血尿。体外分析表明，NK细胞对人肾小球内皮细胞具有剂量依赖性的细胞毒性活性。
CD16(+)CD56(+)细胞似乎是IgAN患者血尿的病因。
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