Functional Genomic Analysis of NK and NKT Cell Immune Control of Autoimmunity

负责习得性免疫的主要白细胞群是B细胞和T细胞，B细胞产生针对细菌等微生物的抗体，T细胞杀死病毒感染的细胞并帮助B细胞产生抗体。T细胞和B细胞偶尔会攻击人体自身组织，导致自身免疫性疾病。这些疾病包括1型糖尿病、狼疮和贫血，是人类发病和死亡的第三大常见原因。自身免疫发生的主要原因被认为是由于负责控制这些不必要反应的机制失效。另外两种被称为NK细胞和NKT细胞的白细胞群也参与了这种调节，它们各自释放重要的细胞激素。目前的项目旨在测试NK和NKT细胞的缺陷是否会导致自身免疫性疾病。为此，将使用一种特殊的小鼠品系（NOD小鼠）。选择他们的原因是：1)他们对一系列自身免疫性疾病非常敏感，包括糖尿病、狼疮和贫血，2)我们和其他人发现他们缺乏NK和NKT细胞。拟议中的实验分为两组，一组旨在描述这些细胞缺陷的性质，另一组旨在识别导致这些缺陷的基因。通过这种方式，应该有可能阐明自身免疫性疾病的遗传基础。使用的方法涉及复杂的基因分析技术，这需要生产特殊的同源小鼠系。这些小鼠与NOD小鼠相似，但除了携带NOD基因外，还携带来自非自身免疫品系的遗传区域，具有纠正NK和NKT细胞缺陷的潜力。通过这种方式，应该有可能查明与自身免疫引起有关的疾病易感基因，并弄清楚它们如何影响NK和NKT细胞。

The major populations of white blood cells responsible for learned immunity to are the B cells, which make antibody against microorganisms like bacteria, and the T cells, which kill virally infected cells and help B cells produce antibody. The T and B cells occasionally attack the body s own tissues, resulting in autoimmune disease. These diseases include type 1 diabetes, lupus, and anaemia, and collectively represent the third commonest cause of morbidity and mortality in humans. The major reason why autoimmunity occurs is thought to be due to a failure in the mechanisms responsible for controlling such unwanted responses. Two other populations of white blood cells are involved in this regulation, termed NK and NKT cells, each of which release important cell hormones. The current project is designed to test whether defects in NK and NKT cells lead to autoimmune disease. For this purpose a special strain of mice (NOD mice) will be used. The reasons for their selection are: 1) they are highly susceptible to a range of autoimmune diseases including diabetes, lupus and anaemia, and 2) we and others have found that they are deficient in both NK and NKT cells. The proposed experiments are divided into two groups, one designed to characterise the nature of the defects in these cells and the other to identify the genes responsible for them. In this way it should be possible to shed light on the genetic basis of autoimmune diseases in general. The approach to be used involves sophisticated techniques of genetic analysis, which require production of special congenic lines of mice. These mice are like NOD mice but carry in addition to NOD genes genetic regions from a non-autoimmune strain with the potential to correct the defects in NK and NKT cells. In this way, it should be possible to pinpoint the disease susceptibility genes involved in causation of autoimmunity and to work out how they affect NK and NKT cells.