The Role of CD5 in B-Cell Development and Autoimmunity

描述（由申请人提供）：B1 a（CD 5+）B细胞是天然抗体的主要生产者，天然抗体具有自反应性和多反应性，但通常是非致病性的。然而，在某些情况下，B1 a B细胞在慢性系统性自身免疫性疾病如类风湿性关节炎（RA）、干燥综合征和系统性红斑狼疮（SLE）的免疫发病机制中起重要作用。B1 a B细胞是先天免疫系统的重要组成部分，是抵御各种细菌和病毒感染的第一道防线。最普遍的B细胞恶性肿瘤，慢性淋巴细胞白血病（CLL）是CD 5 + B细胞起源。奇怪的是，进行性疾病的HIV患者缺乏CD 5 + B细胞;相反，非进行性疾病的血清阳性个体具有正常水平的B1 a B细胞。这表明由CD 5 + B细胞产生的天然抗体可能对HIV具有保护作用。CD 5在B1 a B细胞的发育、功能和/或持久性中的作用仍然是一个未解决和有争议的问题。由于CD 5可以负调节当B细胞抗原受体（BCR）被抗原接合时启动的信号，因此认为其在B1 a B细胞中的主要作用是控制B细胞受体活化以防止对自身抗原的病原性应答。然而，这一教条受到了CD 5-/-小鼠不发生自发性自身免疫性疾病的事实的挑战。我们最近的研究发现，除了其抑制活性外，CD 5的主要和可能占主导地位的作用是促进生存。CD 5的存活活性是通过其与CK 2的独特相互作用介导的，CK 2是一种丝氨酸/苏氨酸激酶，是多种细胞促存活信号级联的主要正调节因子。与CK 2激活介导的促生存活性相反，CD 5也具有B细胞激活负调控所必需的免疫受体酪氨酸抑制基序（ITIM）。ITIM结构域还通过减弱B细胞活化并因此减弱活化诱导的细胞死亡来提供促存活信号。我们认为CD 5通过两条独立但互补的途径调节B细胞反应。为了测试该模型，我们通过基因靶向方法产生了表达CD 5的小鼠，其选择性不能激活CD 5-CK 2依赖性促存活信号级联，以及缺乏CD 5-ITIM依赖性负调节活性的小鼠。使用这些独特的动物模型和我们提出开发的新模型，我们将能够（1）确定CD 5在B1 a B细胞发育中的作用及其对自身免疫的贡献，（2）阐明CD 5如何调节B细胞对T非依赖性抗原和T依赖性抗原的应答，（3）剖析正常B-细胞中CD 5依赖性存活和抑制信号的分子机制。细胞这些使用新型动物模型的研究将使我们能够解析B细胞中的CD 5生物学。拟议的研究的一个重要成果将是我们对先天性B细胞对细菌和病毒病原体反应的调控途径的理解以及治疗自身免疫性疾病和白血病的靶向方法的发展的重大进展。公共卫生相关性：CD 5 + B细胞（B1 a）B细胞在先天免疫中很重要，形成了适应性免疫库，并在自身免疫性疾病的免疫发病机制中。CD 5在B细胞发育中的作用已被广泛质疑，但仍未得到解决;这项建议的目标是填补我们理解中的这一空白。

DESCRIPTION (provided by applicant): The B1a (CD5+) B-cells are the primary producers of natural antibodies that are self-reactive and polyreactive but usually non-pathogenic. However, in some circumstances, B1a B-cells contribute substantially to the immunopathogenesis of chronic systemic autoimmune diseases such as rheumatoid arthritis (RA), Sjogren's syndrome and systemic lupus erythematosus (SLE). B1a B-cells are a critical arm of the innate immune system and provides the first line of defense against a variety of bacterial and viral infections. The most prevalent B-cell malignancy, chronic lymphocytic leukemia (CLL) is CD5+ B-cell in origin. Curiously, HIV patients with progressive disease have paucity of CD5+ B-cells; in contrast, seropositive individuals with non-progressive disease have normal levels of B1a B-cells. This suggests the possibility that natural antibodies produced by CD5+ B-cells may be protective in HIV. The role of CD5 in the development, function and/or persistence of B1a B-cells remains an unresolved and controversial question. Since CD5 can negatively regulate signals initiated when the B-cell antigen receptor (BCR) is engaged by antigen, it is believed that its primary role in B1a B-cells is to control B-cell receptor activation from responding pathogenically to self antigen. However, this dogma is challenged by the fact that that CD5-/- mice do not develop spontaneous autoimmune disease. Our recent studies have led to that discovery that a major and probably dominant role of CD5, in addition to its inhibitory activity, is to promote survival. The survival activity of CD5 is mediated its unique interaction with CK2, a serine/threonine kinase that is a major positive regulator of multiple cellular prosurvival signaling cascades. In a counterpoint to the prosurvival activity mediated by activation of CK2, CD5 also has an immunoreceptor tyrosine inhibitory motif (ITIM) necessary for negative regulation of B-cell activation. The ITIM domain also provides prosurvival signals by attenuating B-cell activation and therefore activation-induced cell death. We suggest that CD5 regulates the B-cell response by two independent but complimentary pathways. To test this model, we have generated by gene targeting approach mice expressing CD5 with selective inability to activate the CD5-CK2 dependent prosurvival signaling cascade and mice lacking CD5-ITIM dependent negative regulatory activity. Using these unique animal models, and the new model we propose to develop, we will be in a position to (1) determine the role of CD5 in the development of B1a B-cells and its contribution to autoimmunity, (2) elucidate how CD5 regulates B-cell responses to T-independent antigens and T-dependent antigens and (3) dissect the molecular mechanism of CD5-dependent survival and inhibitory signals in normal B-cells. These studies using the novel animal models will enable us to resolve CD5 biology in B-cells. An important outcome of the proposed studies will be a major advancement in our understanding of regulatory pathways in innate B-cell responses to bacterial and viral pathogens and the development of targeting approaches for treatment of autoimmune diseases and leukemia. PUBLIC HEALTH RELEVANCE: CD5+ B-Cells (B1a) B-cells are important in innate immunity, shaping the adaptive immune repertoire and in the immunopathogenesis of autoimmune diseases. The role of CD5 in the development of B-cells has been extensively interrogated, but remains unresolved; the goal of this proposal is to fill this gap in our understanding.