Ozaki Akemi, Seki Yoh-ichi, Fukushima Atsuki, Kubo Masato
Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Kanagawa, Japan.
J Immunol. 2005 Oct 15;175(8):5489-97. doi: 10.4049/jimmunol.175.8.5489.
Allergic conjunctivitis (AC) is a common allergic eye disease characterized by clinical symptoms such as itchiness, conjunctival congestion, elevated Ag-specific IgE, mast cell activation, and local eosinophil infiltration. In this study we established a murine model for Ag-induced AC to understand the pathogenesis of the disease. Cell transfer experiments indicated that AC can be divided into early and late phase responses (EPR and LPR). EPR was associated with IgE responses, leading to itchiness, whereas LPR was characterized by local eosinophil infiltration. Both EPR and LPR were significantly inhibited in STAT6-deficient mice, and adoptive transfer of Th2 cells reconstituted LPR. Furthermore, SOCS3 was highly expressed at the disease site, and T cell-specific expression of SOCS3 deteriorated clinical and pathological features of AC, indicating that Th2-mediated SOCS3 expression controls the development and persistence of AC. Reduction of the expression level in SOCS3 heterozygous mice or inhibition of function in dominant-negative SOCS3 transgenic mice clearly reduced the severity of AC. In contrast, constitutive expression of SOCS5, a specific inhibitor of IL-4 signaling, resulted in reduced eosinophil infiltration. These results suggest that negative regulation of the Th2-mediated response by dominant-negative SOCS3 and SOCS5 could be a target for therapeutic intervention in allergic disease.
过敏性结膜炎（AC）是一种常见的过敏性眼病，其特征为瘙痒、结膜充血、特异性抗原IgE升高、肥大细胞活化及局部嗜酸性粒细胞浸润等临床症状。在本研究中，我们建立了抗原诱导的AC小鼠模型以了解该疾病的发病机制。细胞转移实验表明，AC可分为早期和晚期反应（EPR和LPR）。EPR与IgE反应相关，导致瘙痒，而LPR的特征是局部嗜酸性粒细胞浸润。在STAT6缺陷小鼠中，EPR和LPR均受到显著抑制，过继转移Th2细胞可重建LPR。此外，SOCS3在疾病部位高表达，SOCS3在T细胞中的特异性表达使AC的临床和病理特征恶化，这表明Th2介导的SOCS3表达控制着AC的发展和持续。在SOCS3杂合小鼠中降低表达水平或在显性阴性SOCS3转基因小鼠中抑制功能，均明显降低了AC的严重程度。相反，IL-4信号的特异性抑制剂SOCS5的组成型表达导致嗜酸性粒细胞浸润减少。这些结果表明，显性阴性SOCS3和SOCS5对Th2介导的反应的负调控可能是过敏性疾病治疗干预的靶点。
