Olive C, Allen A C, Harper S J, Wicks A C, Feehally J, Falk M C
Department of Renal Medicine, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Kidney Int. 1997 Oct;52(4):1047-53. doi: 10.1038/ki.1997.427.
IgA nephropathy (IgAN) is characterized by the deposition of IgA in the glomerular mesangium and often leads to progressive renal dysfunction and kidney failure. We have previously shown that the mesangial IgA is likely to derive from the bone marrow plasma cells, and suggested that a primary abnormality within the mucosal immune system may underly the pathogenesis of IgAN. This study has analyzed the T cell receptor (TCR) variable (V) region expression by gamma delta T cells in the intestinal mucosa of patients with IgAN. The V gamma and V delta usage of TCR transcripts was determined using a semiquantitative reverse transcriptase-PCR protocol. Primers specific for the four human V gamma and six V delta subfamilies were used each with a constant (C) gamma or C delta specific primer, and the PCR-amplified TCR transcripts were detected by Southern blotting and oligonucleotide hybridization. gamma delta TCR V region expression was determined in gut biopsies and peripheral blood of 11 patients with IgAN, and the TCR V gamma and V delta repertoires were compared to those in gut and peripheral blood of 11 control individuals. gamma delta T cells in normal blood predominantly expressed V gamma 2 (V gamma 9 gene) and V delta 2 gene segments whereas those in normal gut mainly expressed V gamma 3 and V delta 3. In IgAN patients, V delta 2 was also the predominant V delta gene utilized by peripheral blood gamma delta T cells, however, we observed a predominance of V gamma 3 and reduced V gamma 2 usage by these cells. gamma delta T cells in the gut of IgAN patients mainly used V gamma 3 and V delta 1. While the gamma and delta TCR V region repertoires did not differ significantly between the peripheral blood of patients and controls, there were significant differences in V gamma and V delta repertoire expression between IgAN and control gut biopsies. V gamma 3 gene expression was significantly decreased in IgAN gut compared to control gut (P = 0.023). In addition, there was a significant decrease in V delta 3 gene expression in IgAN gut compared to control gut (P = 0.043). These findings indicate that a subpopulation of gamma delta T cells, which represent the majority of gamma delta T cells in normal gut mucosa, are significantly diminished in the gut of patients with IgAN. This suggests that a "hole" in the mucosal gamma delta T cell repertoire may play a fundamental role in contributing to the pathogenesis of IgAN.
IgA肾病（IgAN）的特征是IgA在肾小球系膜沉积，常导致进行性肾功能障碍和肾衰竭。我们之前已经表明，系膜IgA可能来源于骨髓浆细胞，并提示黏膜免疫系统内的原发性异常可能是IgAN发病机制的基础。本研究分析了IgAN患者肠黏膜中γδT细胞的T细胞受体（TCR）可变（V）区表达。使用半定量逆转录聚合酶链反应方案确定TCR转录本的Vγ和Vδ使用情况。使用针对四个人类Vγ和六个Vδ亚家族的特异性引物，每个引物都与一个恒定（C）γ或Cδ特异性引物一起使用，通过Southern印迹和寡核苷酸杂交检测PCR扩增的TCR转录本。在11例IgAN患者的肠道活检组织和外周血中测定γδTCR V区表达，并将TCR Vγ和Vδ库与11例对照个体的肠道和外周血中的库进行比较。正常血液中的γδT细胞主要表达Vγ2（Vγ9基因）和Vδ2基因片段，而正常肠道中的γδT细胞主要表达Vγ3和Vδ3。在IgAN患者中，Vδ2也是外周血γδT细胞使用的主要Vδ基因，然而，我们观察到这些细胞中Vγ3占优势且Vγ2使用减少。IgAN患者肠道中的γδT细胞主要使用Vγ3和Vδ1。虽然患者外周血与对照之间的γ和δTCR V区库没有显著差异，但IgAN与对照肠道活检组织之间的Vγ和Vδ库表达存在显著差异。与对照肠道相比，IgAN肠道中Vγ3基因表达显著降低（P = 0.023）。此外，与对照肠道相比，IgAN肠道中Vδ3基因表达显著降低（P = 0.043）。这些发现表明，γδT细胞亚群（在正常肠道黏膜中占γδT细胞的大多数）在IgAN患者的肠道中显著减少。这表明黏膜γδT细胞库中的一个“空缺”可能在IgAN发病机制中起重要作用。
