Genetic Control of Autoimmune Exocrinopathy in NOD Mice

描述(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，会导致口腔严重干燥。口干被认为是遗传易感性的结果，与环境刺激相关联，导致对唾液腺组织中表达的特定(自身)抗原的慢性免疫攻击。虽然人类白细胞抗原的遗传已经被认为是大多数自身免疫性疾病的重要危险因素，但到目前为止还没有发现人类白细胞抗原基因与干燥综合征发病风险的增加有关。非人类白细胞抗原基因似乎也有助于人类的遗传易感性，但识别非人类白细胞抗原基因只会使人们更难理解干燥综合征的遗传基础。自身免疫性疾病的动物模型为识别潜在发病机制的遗传途径提供了极好的资源。我们推广NOD小鼠作为干燥综合征的模型，因为这种小鼠在伴随着外分泌腺分泌减少的情况下，在外分泌腺中出现逐渐的淋巴细胞渗透、细胞因子和自身抗体的产生。利用已有的多个NOD同源菌株，已鉴定出两个NOD衍生的基因座，分别为Aec1和Aec2(自身免疫性外分泌病遗传区1和2)，它们分别包含位于染色体3的胰岛素依赖型糖尿病基因座Idd3和位于染色体1的Idd5。这两个间期似乎以相加和分级的方式作用，以控制NOD小鼠的上皮细胞病理，随后淋巴细胞浸润的聚集，以及最终唾液腺(和泪腺)分泌功能的丧失。我们成功地培育了C57BL/6.NOD-AECL Aec2小鼠，它概括了亲本NOD小鼠观察到的完整疾病表型。为了进一步定位染色体区间，我们建议构建重组近交系C57BL/6.NOD-AECL Aec2小鼠。为了达到特定的目的，将产生C57BL/6的RI品系的ASET，以精细定位Aecf和Aec2基因区域，以确定与NOD小鼠自身免疫性外分泌病发生相关的特定间隔。对于特定的目的2，将使用基因芯片技术，通过比较疾病易感和非易感RI小鼠转录本的表达水平，在这些间隔内识别与免疫和非免疫成分有关的候选基因，从而导致自身免疫性外分泌病。这些研究的结果将为深入了解干燥综合征发病的遗传机制(S)提供洞察，这对开发有针对性的预防或准备好的干预策略的长期目标非常重要。

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.