Genetic Control of Autoimmune Exocrinopathy in NOD Mice

描述（由申请人提供）：干燥综合征是一种自身免疫性疾病，是唾液腺炎症和功能障碍的主要原因之一，导致口腔严重干燥。口干被认为是由遗传易感性引起的，该遗传易感性与环境刺激相关联，导致针对唾液腺组织中表达的特异性（自身）抗原的慢性免疫攻击。尽管HLA遗传已被认为是大多数自身免疫性疾病的重要危险因素，但迄今为止还没有HLA基因型被鉴定为与发生干燥综合征的风险增加相关。非HLA基因似乎也有助于人类的遗传易感性，但非HLA基因的鉴定只会使理解干燥综合征遗传基础的能力复杂化。自身免疫性疾病的动物模型提供了一个很好的资源，以确定遗传途径负责潜在的发病机制。我们已经推广NOD小鼠作为干燥综合征的模型，因为这种小鼠在外分泌腺中发展进行性淋巴细胞浸润、细胞因子和自身抗体产生，伴随外分泌腺分泌减少。使用现在可用的NOD的多个同源菌株，已经鉴定了两个NOD衍生的基因座，分别命名为Aec 1和Aec 2（自身免疫性外分泌蛋白病遗传区域1和2），其含有3号染色体上的胰岛素依赖性糖尿病基因座Idd 3和1号染色体上的Idd 5。这两个时间间隔似乎以相加和分层的方式起作用，以控制上皮细胞病理学、随后淋巴细胞浸润的积累以及NOD小鼠中唾液腺（和泪腺）分泌功能的最终丧失。我们已经成功地开发了C57 BL/6. NOD-AeclAec 2小鼠，其重现了在亲本NOD小鼠中观察到的完整疾病表型。为了进一步定位染色体间隔，我们提出产生C57 BL/6. NOD-AeclAec 2小鼠的重组近交（RI）品系。对于特定目标，将产生C57 BL/6. NOD-Aecl Aec 2小鼠的RI品系的集合以精细映射Aecf和Aec 2遗传区域，以鉴定与NOD小鼠中自身免疫性外分泌蛋白病的发展相关的特定间隔。对于特定目标2，将使用cDNA微阵列技术，通过比较疾病易感与非易感RI小鼠的转录物表达水平，鉴定这些间隔内负责导致自身免疫性外分泌病的免疫和非免疫组分的候选基因。这些研究的结果将提供深入了解干燥综合征发病机制的遗传机制，这对制定有针对性的预防或即时干预策略的长期目标至关重要。

DESCRIPTION (provided by applicant): Sjogren's syndrome, an autoimmune disease that is one of the leading causes of salivary gland inflammation and dysfunction, leads to severe dryness of the oral cavity. Dry mouth is thought to result from a genetic predisposition that, in association with environmental stimuli, results in a chronic immune attack against specific (auto)-antigens expressed in salivary gland tissue. Although HLA inheritance has been recognized as an important risk factor for most autoimmune diseases, as yet no HLA genotype has been identified as being associated with an increased risk for developing Sjogren's syndrome. Non-HLA genes also appear to contribute to the genetic predisposition in humans, but identification of non-HLA genes only complicates5ability to understand the genetic basis of Sjogren's syndrome. Animal models of autoimmune disease provide an excellent resource for identifying genetic pathways responsible for underlying pathogenesis. We have popularized the NOD mouse as a model for Sjogren's syndrome as this mouse develops progressive lymphocytic infiltration, cytokine and autoantibody production in the exocrine glands concomitant with decreased exocrine gland secretions. Using the multiple congenic strains of NOD now available, two NOD-derived loci, designated Aec1 and Aec2 (autoimmune exocrinopathy genetic regions 1 and 2) containing insulin dependent diabetic loci Idd3 on chromosome 3 and Idd5 on chromosome 1, respectively, have been identified. These two intervals appear to act in an additive and hierarchical manner to control the epithelial cell pathology, subsequent accumulation of lymphocytic infiltrates, and the eventual loss of secretory function of the salivary (and lachrymal) glands in the NOD mouse. We have successfully developed the C57BL/6.NOD- Aecl Aec2 mouse which recapitulates the complete disease phenotype observed in the parental NOD mouse. To further map the chromosomal intervals, we propose to generate recombinant inbred (RI) strains of the C57BL/6.NOD- Aecl Aec2 mouse. For Specific Aim t, aset of RI strains of C57BL/6.NOD- Aecl Aec2 mice will be generated to fine-map the Aecf and Aec2 genetic regions to identify specific intervals associated with the development of autoimmune exocrinopathy in the NOD mouse. For Specific Aim 2, cDNA microarray technology will be used to identify candidate genes within these intervals responsible for immune and non-immune components resulting in autoimmune exocrinopathy by comparing expression levels of transcripts from disease-susceptible versus non-susceptible RI mice. Results from these studies will provide insight into the genetic mechanism(s) underlying the pathogenesis of Sjogren's syndrome important to the long-term goal of developing targeted preventive or ready intervention strategies.