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，但同时保持对自身抗原的无反应或耐受性。对自身抗原耐受性的崩溃会导致自身免疫。自身免疫性疾病包括70多种慢性疾病，在西方人口中，约每20人中就有1人受到影响。提高我们对自身免疫性疾病背后的机制的理解对于设计更有效的治疗方法是至关重要的。Lyn酪氨酸激酶是参与通过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，并参与感染、免疫和过敏反应的机制。为了进一步了解这种酶在整个动物中的作用，我们培育了两个品系的小鼠，一个不能产生LYN(LYN缺陷小鼠)，另一个表达LYN酶的激活形式(LYN-UP小鼠)。我们发现，这两个品系的小鼠都会患上与人类自身免疫性疾病系统性红斑狼疮(SLE)相似的特征的自身免疫性疾病。这些研究表明，Lyn是自身免疫中一个重要的严重基因。在这项研究中，我们将详细研究Lyn在B细胞发育、功能和自身免疫中所起的作用，并试图确定导致Lyn突变小鼠自身免疫性疾病的途径。在这些研究完成后，我们将开发出一份LYN突变小鼠中受干扰的分子和途径的目录。这些研究将极大地提高我们对某些自身免疫性疾病背后的机制的认识和理解，并可能确实导致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.