原发性干燥综合征、相关干燥综合征和非干燥综合征性口干综合征患者唾液腺中的内质网应激：一项比较分析及氯喹的影响
Endoplasmic reticulum stress in the salivary glands of patients with primary Sjögren's syndrome, associated Sjögren's syndrome, and non-Sjögren's sicca syndrome: a comparative analysis and the influence of chloroquine.
作者信息
Cavalcanti Graziela Vieira, de Oliveira Fabiola Reis, Bannitz Rafael Ferraz, de Paula Natalia Aparecida, Motta Ana Carolina Fragoso, Rocha Eduardo Melani, Chiorini John, Ricz Hilton Marcos Alves, Garcia Denny Marcos, Foss-Freitas Maria Cristina, de Freitas Luiz Carlos Conti
机构信息
Department of Ophthalmology, Otolaryngology, Head and Neck Surgery, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
Ophthalmology, Otolaryngology, Head and Neck Surgery Department, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, SP, 14.040-900, Brazil.
出版信息
Adv Rheumatol. 2025 Jan 8;65(1):2. doi: 10.1186/s42358-024-00430-7.
BACKGROUND
Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are adaptive mechanisms for conditions of high protein demand, marked by an accumulation of misfolded proteins in the endoplasmic reticulum (ER). Rheumatic autoimmune diseases (RAD) are known to be associated with chronic inflammation and an ERS state. However, the activation of UPR signaling pathways is not completely understood in Sjögren's disease (SD). This study evaluated the expression of ERS-related genes in glandular tissue of patients with primary SD (pSD), associated SD (aSD) with other autoimmune diseases, and non-Sjögren sicca syndrome (NSS).
METHODS
In a cross-sectional study, minor salivary gland biopsies were obtained from 44 patients with suspected SD and 13 healthy controls (HC). Patients were classified as pSD, aSD, or NSS based on clinical, serological, and histological assessment. Histopathological analysis and mRNA expression analysis of genes associated with ERS and UPR (PERK, XBP1, ATF-6, ATF-4, CANX, CALR, CHOP, and BIP) were performed on the samples. Differences between groups (pSD, aSD, NSS, and HC) were assessed. The influence of chloroquine (CQ) on the ER was also investigated.
RESULTS
Twenty-eight SD patients showed increased expression of PERK (p = 0.0117) and XBP1 (p = 0.0346), and reduced expression of ATF-6 (p = 0.0003) and CHOP (p = 0.0003), compared to the HC group. Increased expression of BIP (p < 0.0001), PERK (p = 0.0003), CALR (p < 0.0001), and CANX (p = 0.0111) was also observed in the SD group compared to the NSS group (n = 16). Patients receiving CQ (n = 16) showed a significant increase in ATF-6 (p = 0.0317) compared to patients not taking the medication (n = 29).
CONCLUSIONS
Altogether, the results suggest a greater activation of the ERS and UPR genes in patients with SD, especially in the pSD group. Antimalarial drugs, like CQ, used to treat RAD, may affect the ER function in exocrine glands.
背景
内质网应激（ERS）和未折叠蛋白反应（UPR）是针对高蛋白需求状况的适应性机制，其特征是内质网（ER）中错误折叠蛋白的积累。已知风湿性自身免疫性疾病（RAD）与慢性炎症和ERS状态有关。然而，在干燥综合征（SD）中，UPR信号通路的激活尚未完全明确。本研究评估了原发性干燥综合征（pSD）、合并其他自身免疫性疾病的继发性干燥综合征（aSD）以及非干燥综合征性口干症（NSS）患者腺体组织中ERS相关基因的表达。
方法
在一项横断面研究中，从44例疑似干燥综合征患者和13名健康对照（HC）中获取小唾液腺活检样本。根据临床、血清学和组织学评估将患者分为pSD、aSD或NSS。对样本进行组织病理学分析以及与ERS和UPR相关基因（PERK、XBP1、ATF-6、ATF-4、CANX、CALR、CHOP和BIP）的mRNA表达分析。评估各组（pSD、aSD、NSS和HC）之间的差异。还研究了氯喹（CQ）对内质网的影响。
结果
与HC组相比，28例干燥综合征患者的PERK（p = 0.0117）和XBP1（p = 0.0346）表达增加，而ATF-6（p = 0.0003）和CHOP（p = 0.0003）表达降低。与NSS组（n = 16）相比，干燥综合征组中BIP（p < 0.0001）、PERK（p = 0.0003）、CALR（p < 0.0001）和CANX（p = 0.0111）的表达也增加。与未服用药物的患者（n = 29）相比，接受CQ治疗的患者（n = 16）的ATF-6显著增加（p = 0.0317）。
结论
总体而言，结果表明干燥综合征患者，尤其是pSD组中，ERS和UPR基因的激活程度更高。用于治疗RAD的抗疟药物，如CQ，可能会影响外分泌腺的内质网功能。
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