Fondazione Ricerca Molinette, Regina Margherita Hospital, Turin, Italy.
Department of Nephrology, Dialysis and Transplantation, Regina Margherita Hospital, Turin, Italy.
Nephrol Dial Transplant. 2021 Jul 23;36(8):1389-1398. doi: 10.1093/ndt/gfaa092.
The proteasome to immunoproteasome (iPS) switch consists of β1, β2 and β5 subunit replacement by low molecular weight protein 2 (LMP2), LMP7 and multicatalytic endopeptidase-like complex-1 (MECL1) subunits, resulting in a more efficient peptide preparation for major histocompatibility complex 1 (MHC-I) presentation. It is activated by toll-like receptor (TLR) agonists and interferons and may also be influenced by genetic variation. In a previous study we found an iPS upregulation in peripheral cells of patients with immunoglobulin A nephropathy (IgAN). We aimed to investigate in 157 IgAN patients enrolled through the multinational Validation Study of the Oxford Classification of IgAN (VALIGA) study the relationships between iPS switch and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous long follow-up (6.4 years in median) that allowed an accurate calculation of their slope of renal function decline. We also evaluated the effects of the PSMB8/PSMB9 locus (rs9357155) associated with IgAN in genome-wide association studies and the expression of messenger RNAs (mRNAs) encoding for TLRs and CD46, a C3 convertase inhibitor, acting also on T-regulatory cell promotion, found to have reduced expression in progressive IgAN. We detected an upregulation of LMP7/β5 and LMP2/β1 switches. We observed no genetic effect of rs9357155. TLR4 and TLR2 mRNAs were found to be significantly associated with iPS switches, particularly TLR4 and LMP7/β5 (P < 0.0001). The LMP7/β5 switch was significantly associated with the rate of eGFR loss (P = 0.026), but not with eGFR at biopsy. Fast progressors (defined as the loss of eGFR >75th centile, i.e. -1.91 mL/min/1.73 m2/year) were characterized by significantly elevated LMP7/β5 mRNA (P = 0.04) and low CD46 mRNA expression (P < 0.01). A multivariate logistic regression model, categorizing patients by different levels of kidney disease progression, showed a high prediction value for the combination of high LMP7/β5 and low CD46 expression.
蛋白酶体向免疫蛋白酶体（iPS）的转换包括β1、β2 和β5 亚基被低分子量蛋白 2（LMP2）、LMP7 和多催化内肽酶样复合物-1（MECL1）亚基取代，从而更有效地制备主要组织相容性复合体 1（MHC-I）呈递的肽。它被 Toll 样受体（TLR）激动剂和干扰素激活，也可能受到遗传变异的影响。在之前的研究中，我们发现免疫球蛋白 A 肾病（IgAN）患者外周细胞中的 iPS 上调。我们旨在通过多中心牛津 IgAN 分类验证研究（VALIGA）研究中纳入的 157 例 IgAN 患者，研究 iPS 转换与肾活检至采样期间估计肾小球滤过率（eGFR）变化之间的关系。患者有之前的长期随访（中位数 6.4 年），这使得能够准确计算他们肾功能下降的斜率。我们还评估了与全基因组关联研究中 IgAN 相关的 PSMB8/PSMB9 基因座（rs9357155）的影响，以及编码 TLR 和 CD46 的信使 RNA（mRNA）的表达，CD46 是一种 C3 转化酶抑制剂，也可促进 T 调节细胞的增殖，发现其在进展性 IgAN 中表达降低。我们检测到 LMP7/β5 和 LMP2/β1 转换的上调。我们没有观察到 rs9357155 的遗传效应。TLR4 和 TLR2 mRNA 与 iPS 转换显著相关，特别是 TLR4 和 LMP7/β5（P<0.0001）。LMP7/β5 转换与 eGFR 损失率显著相关（P=0.026），但与肾活检时的 eGFR 无关。快速进展者（定义为 eGFR 损失>第 75 百分位数，即-1.91mL/min/1.73m2/年）的 LMP7/β5 mRNA 显著升高（P=0.04），CD46 mRNA 表达水平较低（P<0.01）。根据不同水平的肾脏疾病进展对患者进行分类的多变量逻辑回归模型显示，高 LMP7/β5 和低 CD46 表达的组合具有较高的预测价值。
