BASAL/LATERAL--ENDOMEMBRANE TRAFFIC IN LACRIMAL ACINI

由泪液不足引起的干眼症是最常见的眼科疾病。 发达国家的发病率。它是由淋巴细胞引起的。 干燥S综合征泪腺的浸润性改变 200万美国人，以及某些其他免疫系统疾病。更多 细微形式的淋巴细胞渗透可能有助于分泌 原发性泪液缺乏症，与干燥S综合征一样， 主要发生在女性身上。这项提议背后的论点是 泪液分泌上皮细胞功能的特点 它们激发自身免疫反应是一种以前鲜为人知的 内膜室和基底侧之间的循环交通 膜(BLM)，即接触间质的膜域。 这种流量分泌免疫调节因子和潜在的自身抗原 进入间质，当细胞被诱导表达主要 组织相容性复合体II类分子(MHC II)，它允许它们 以与专业抗原呈递相同的方式呈递自身抗原 细胞呈递外来抗原。另一个前提是，正常的 分泌和展示的自身抗原的光谱受外周影响 容忍度，但当BLM发生变化时，这种容忍度被克服- 膜内交通干扰自身抗原谱。初步数据 表明这种变化发生在持续的分泌运动过程中 刺激，一种可能模拟体内情况的实验情况 眼表-泪腺反馈环的手术治疗 弥补荷尔蒙引起的腺体萎缩。因此，这 该项目将结合亚细胞分离分析的方法， 是唯一能够分辨博莱姆-内膜的隔室的 交通与广泛使用的免疫细胞化学方法来：1)勾画 在限定的BLM-内膜交通间隔之间的通道。 2)绘制MHC II，La抗原的流量图，这是一个突出的 干燥S综合征及其他自身免疫反应的靶点 潜在的自身抗原。3)调查负责的机制 刺激诱导的博莱姆-膜-膜交通的加速。4) 研究刺激引起的脑电活动变化的机制 靶向和/或分离导致高尔基体和溶酶体蛋白 进入BLM路径。

Dry eye caused by lacrimal insufficiency is the most common form of ocular morbidity in the developed countries. It is caused by lymphocytic infiltration of the lacrimal glands in Sjogren s syndrome, which affects two million Americans, and in certain other immune system disorders. More subtle forms of lymphocytic infiltration may contribute to the secretory defect in primary lacrimal deficiency, which, like Sjogren s syndrome, occurs primarily in women. The thesis underlying this proposal is that the feature of lacrimal secretory epithelial cell function which causes them to provoke autoimmune responses is a previously little-appreciated recycling traffic between endomembrane compartments and the basal-lateral membrane (BLM), i.e., the membrane domain that contacts the interstitium. This traffic secretes immunomodulatory factors and potential auto antigens into the interstitium, and when cells have been induced to express major histocompatibility complex Class II molecules (MHC II), it allows them to present autoantigens in the same way that professional antigen presenting cells present foreign antigens. A further premise is that the normal spectra of secreted and displayed autoantigens are subject to peripheral tolerance, but that tolerance is overcome when changes in the BLM - endomembrane traffic perturb the autoantigenic spectra. Preliminary data indicate that such changes occur during sustained secretomotor stimulation, an experimental situation that may mimic the in vivo operation of the ocular surface - lacrimal gland feedback loop working to compensate for hormonally-induced glandular atrophy. Therefore, this project will combine methods of subcellular fractionation analysis that are uniquely capable of resolving compartments of the BLM -endomembrane traffic with widely used immunocytochemical methods to: 1) Delineate pathways between defined compartments of the BLM - endomembrane traffic. 2) Map the traffic of MHC II, of the La antigen, which is a prominent target of autoimmune reactions in Sjogren s syndrome, and of other potential autoantigens. 3) Investigate mechanisms responsible for stimulation-induced acceleration of BLM - endomembrane traffic. 4) Investigate mechanisms responsible for the stimulation-induced changes in targeting and/or segregation that cause Golgi and lysosomal proteins to enter the BLM pathway.