Functional genomic analysis of the NKT cell control locus Nkt1 and the Bana3/Babs2 lupus susceptibility locus

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，导致红斑狼疮等自身免疫性疾病，其中抗体沉积在组织中，导致大脑、皮肤，尤其是肾脏等器官发炎。另一种被称为NKT细胞的白细胞群在控制T细胞和B细胞方面起着重要作用，我们发现这些细胞在一种近亲繁殖的小鼠品系NOD小鼠中缺乏，这种小鼠在接触一种叫做分枝杆菌的特殊细菌后会患上狼疮。我们发现，在这些小鼠中，赋予狼疮易感性的主要基因之一与控制NKT细胞数量的主要基因位于相同的遗传区域，这增加了该品系中NKT细胞缺乏使其易患狼疮的可能性。本项目拟进行的实验分为两组。第一组测试是否通过注射增加NKT细胞数量，或者通过转移允许更多细胞自然发育的基因来增加NKT细胞数量，可以影响患狼疮的风险。第二组实验检查了两个特定基因的潜在作用，这两个基因位于感兴趣的遗传区域，我们认为它们可能控制NKT细胞数量和狼疮易感性。使用的方法涉及复杂的遗传分析技术，例如使用携带相关基因附近基因突变的突变小鼠和同源小鼠，它们与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。

The major populations of white blood cells responsible for learned immunity 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 diseases such as lupus, in which antibodies are deposited in the tissues causing inflammation in organs such as the brain, skin and especially the kidneys. Another population of white blood cells, termed NKT cells, plays an important role in keeping the T and B cells in check, and we have found that these cells are deficient in an inbred mouse strain, NOD mice, which develop lupus after exposure to a particular type of bacteria, called mycobacteria. We have found that one of the major genes conferring susceptibility to lupus in these mice lies in the same genetic region as the major gene controlling NKT cell numbers, raising the possibility that the deficiency in NKT cells in this strain predisposes it to developing lupus. The experiments proposed for this project are divided into two groups. The first group test whether increasing NKT cell numbers by either injecting them, or else transferring genes that allow more to develop naturally, can affect the risk of developing lupus. The second group of experiments examine the potential roles of two specific genes which are in the genetic region of interest, and which we think might control both NKT cell numbers and lupus susceptibility. The approach to be used involves sophisticated techniques of genetic analysis, such as the use of mutant mice which carry genetic mutations near the relevant genes, and congenic mice, which are like NOD mice, but carry in addition to NOD genes, genetic regions from a non-autoimmune strain.