Cpdm: Cloning a Gene That Regulates Eosinophil Function

描述(由申请人提供)： 嗜酸性粒细胞在多种人类疾病的发病机制中起着重要作用。淋巴细胞产生的细胞因子的失调导致嗜酸性粒细胞增多，通过单个基因突变影响多个器官，为定义健康和疾病中的嗜酸性粒细胞提供了一个独特而有价值的模型。自发、常染色体、隐性、慢性增殖性皮炎突变小鼠(基因符号：CPDM)就是这样一个模型。Cpdm基因座位于小鼠15号染色体中部。纯合子(cpdm/cpdm)表现出明显的进行性表皮增殖，并伴有嗜酸性粒细胞、肥大细胞和MHC II+细胞的渗透。皮肤和其他器官的嗜酸性粒细胞增多症伴有ILl2分泌缺陷和淋巴器官发育异常。候选基因已经确定，并将对这些基因进行核苷酸变化测序。测序的优先顺序将基于使用定量RT-PCR方法的表达水平的变化。根据外源性重组ILl2治疗后cpdm皮肤病的复杂表型、功能分析和解决方案，我们假设cpdm的功能包括但不限于调节ILl2的产生。我们推测，这种缺陷导致的细胞因子的失调增加了Th2细胞因子(IL4、IL5、IL13和GMCSF)的产生，导致血液和组织嗜酸性粒细胞增多和嗜酸性粒细胞诱导的组织损伤。对嗜酸性皮炎机制的研究最初将通过产生cpdm/cpdm小鼠与缺乏IL12b、11Ara或IL5的小鼠的杂交来集中在这一可能的途径上。由于cpdm/cpdm小鼠除皮肤外还有许多器官受到影响，我们相信明确嗜酸性皮肤病的遗传学和发病机制将使我们能够更好地了解肺部和其他组织的嗜酸性疾病。

DESCRIPTION (provided by applicant): Eosinophils play a major role in the pathogenesis of a variety of human diseases. Dysregulation of cytokines produced by lymphocytes that result in eosinophilia affecting multiple organs by a single gene mutation provides a unique and valuable model to define eosinophils in health and disease. The spontaneous, autosomal, recessive, chronic proliferative dermatitis mouse mutation (gene symbol: cpdm) is such a model. The cpdm locus maps to the middle of mouse Chromosome 15. Homozygotes (cpdm/cpdm) show marked, progressive, epidermal proliferation associated with infiltration of eosinophils, mast cells, and MHC II+ cells. Eosinophilia in the skin and other organs is accompanied by a defect in the secretion of ILl2 and abnormalities in the development of lymphoid organs. Candidate genes have been identified and these will be sequenced for nucleotide changes. Sequencing priority will be based upon changes in expression levels using quantitative RT PCR methods. Based on the complex phenotype, functional assays, and resolution of the cpdm skin disease following exogenous recombinant ILl2 treatment, we postulate that the function of cpdm includes but is not limited to the regulation of ILl2 production. We hypothesize that dysregulation of cytokines resulting from this defect augments Th2 cytokine production (IL4, IL5, ILl3, and GMCSF) causing blood and tissue eosinophilia and eosinophil-induced tissue damage. Studies on the mechanism of eosinophilic dermatitis will initially focus on this potential pathway by generating crosses of cpdm/cpdm mice with mice lacking IL12b, llAra, or IL5. Since many organs in addition to the skin are affected in cpdm/cpdm mice, we believe that defining the genetics and mechanisms of eosinophilic skin disease will enable us to better understand eosinophilic diseases in the lung and other tissues.