Dissecting the role of the Lyn tyrosine kinase in B cell differentiation and the development of autoimmunity.

免疫系统必须能够对无限的病原体做出反应，但同时对自身抗原保持无反应或耐受。对自身抗原耐受性的破坏导致自身免疫。自身免疫性疾病包括70多种慢性疾病，影响西方人口中约1/20的人。提高我们对自身免疫性疾病机制的理解对于设计更有效的治疗方法至关重要。林恩酪氨酸激酶是参与跨细胞膜传递信息的基因家族的成员。这种酶在血细胞中表达，并参与与感染、免疫和过敏反应有关的机制。为了进一步理解这种酶在整个动物中的作用，我们产生了两种小鼠品系，一种不能产生林恩（Lyn-deficient mice），另一种表达林恩酶的活化形式（Lyn-up mice）。我们已经发现，这两种品系的小鼠发展自身免疫性疾病的特征类似于人类自身免疫性疾病系统性红斑狼疮（SLE）。这些研究表明，林恩是一个重要的严重性基因在自身免疫。在这项研究中，我们将详细研究林恩在B细胞发育，功能和自身免疫中发挥的作用，我们打算确定导致林恩突变小鼠自身免疫性疾病的途径。完成这些研究后，我们将开发出一个林恩突变小鼠中受干扰的分子和途径的目录。这些研究将大大提高我们对某些自身免疫性疾病背后机制的认识和理解，并可能确实改善这些疾病患者的诊断，预后和治疗。

The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune diseases include more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more effective treatments. The Lyn tyrosine kinase is a member of a family of genes that participate in transmitting information across the cell membrane. This enzyme is expressed in blood cells, and is involved in mechanisms pertaining to infection, immunity and allergic responses. To further our understanding of the role of this enzyme in the context of the whole animal, we have generated two strains of mice, one that is unable to make Lyn (Lyn-deficient mice) and one that expresses an activated form of the Lyn enzyme (Lyn-up mice). We have found that both strains of mice develop autoimmune disease with characteristics similar to the human autoimmune disease systemic lupus erythematosus (SLE). These studies suggest that Lyn is an important severity gene in autoimmunity. In this study we will examine in detail the role that Lyn plays in B cell development, function and autoimmunity, and we intend to identify the pathways that lead to autoimmune disease in Lyn mutant mice. On completion of these studies we will have developed a catalogue of the molecules and pathways perturbed in Lyn mutant mice. These studies will greatly improve our knowledge and understanding of the mechamisms behind certain autoimmune diseases, and may indeed lead to improved diagnosis, prognosis and treatment of patients with these conditions.