Dysregulation of autophagy has been implicated in the development of various disease indications including autoimmune diseases. Here we identified hitherto unsuspected molecular alterations of autophagy occurring at an early stage of the macroautophagy pathway in the salivary glands and spleen of NOD.H-2h4 mice that develop a primary Sjögren's-like syndrome. In this study we investigated the capacity of phosphopeptide P140 to correct immune alteration in NOD.H-2h4 mice and the effect on neogenesis of tertiary lymphoid structures in salivary glands, which is hallmark characteristic of SS. Phosphopeptide P140 known to lower excessive autophagy processes, rescued sick NOD.H-2h4 mice from some autophagy defects and significantly reduced formation of tertiary lymphoid structures in salivary glands. Mechanistically, the frequency of activated CD44^high/CD62L^low CD4⁺ T cell populations was significantly decreased and this reduction was correlated with an increased number of CD44^low/CD62L^high resting T cells. The CD8 T cell compartment was not affected. P140 down-regulated the maturation and differentiation of B cells into plasma cells, and decreased IgG and autoantibody secretion. It had no effect on germinal centers B cells (B220⁺ FAS⁺GL-7⁺) that are an important compound of the B cell humoral immune response. Together with previous data generated in MRL/lpr mice that develop some features of Sjögren's syndrome associated to other inflammatory and autoimmune defects, our present findings strongly reinforce the potential of autophagy modulators, such as P140, for treating patients with Sjögren's syndrome.

自噬失调与多种疾病适应症的发展有关，包括自身免疫性疾病。在这里，我们确定了自噬的迄今为止从未想到的分子改变，发生在唾液腺和NOD.H-2h4小鼠唾液腺和脾的巨自噬途径的早期阶段，这些小鼠发展为原发性Sjögren's综合征。在这项研究中，我们研究了磷酸肽P140纠正NOD.H-2h4小鼠免疫改变的能力以及对唾液腺第三级淋巴结构新生的影响，这是SS的标志性特征。已知磷酸肽P140可以降低过度的自噬过程，从某些自噬缺陷中拯救患病的NOD.H-2h4小鼠，并显着减少唾液腺中三级淋巴结构的形成。从机制上讲，激活的CD44的频率^高/ CD62L^高/^低CD4 ⁺ T细胞群体显着减少，这种减少与CD44^低/ CD62L^高/静息T细胞数量增加相关。CD8 T细胞区室不受影响。P140下调B细胞向浆细胞的成熟和分化，并降低IgG和自身抗体的分泌。它对生发中心B细胞（B220 ⁺ FAS ⁺ GL-7 ⁺）是B细胞体液免疫反应的重要化合物。连同在MRL / lpr小鼠中产生的，发展出与其他炎症和自身免疫缺陷相关的干燥综合征的某些特征的先前数据一起，我们目前的发现强烈增强了自噬调节剂（例如P140）在治疗干燥综合征中的潜力。