The Role of CD5 in B-Cell Development and Autoimmunity

描述(由申请人提供)：B1a(CD5)B细胞是自然抗体的主要产生者，这种抗体具有自我反应和多反应，但通常是非致病性的。然而，在某些情况下，B1a 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着重要作用。B1a B细胞是先天免疫系统的关键武器，是抵御各种细菌和病毒感染的第一道防线。慢性淋巴细胞性白血病(CLL)是最常见的B细胞恶性肿瘤，起源于CD5B细胞。奇怪的是，患有进展性疾病的HIV患者缺乏CD5B细胞；相比之下，血清阳性的非进展性疾病患者的B1AB细胞水平正常。这表明CD5B细胞产生的天然抗体可能对HIV具有保护作用。CD5在B1a B细胞的发育、功能和/或持续性中的作用仍然是一个悬而未决且有争议的问题。由于CD5可以负向调节B细胞抗原受体(BCR)与抗原结合时启动的信号，因此认为CD5在B1a B细胞中的主要作用是控制B细胞受体的激活，使其对自身抗原产生病理性反应。然而，CD5-/-小鼠不会患上自发的自身免疫性疾病，这一事实对这一教条提出了挑战。我们最近的研究发现，CD5除了抑制活性外，还有一个主要且可能占主导地位的作用是促进生存。CD5的存活活性是通过其与CK2的独特相互作用实现的，CK2是一种丝氨酸/苏氨酸激酶，是多种细胞生存信号级联的主要正向调节因子。与CK2激活介导的生存活性相反，CD5还具有免疫受体酪氨酸抑制基序(ITIM)，这是负调控B细胞激活所必需的。ITIM结构域还通过减弱B细胞的激活从而减弱激活诱导的细胞死亡来提供生存信号。我们认为CD5通过两条独立但互补的途径来调节B细胞的反应。为了测试这个模型，我们通过基因打靶的方法产生了表达CD5的小鼠，但选择性地无法激活CD5-CK2依赖的生存信号级联反应，以及缺乏CD5-ITIM依赖的负调控活性的小鼠。利用这些独特的动物模型，以及我们建议开发的新模型，我们将能够(1)确定CD5在B1a B细胞发育中的作用及其对自身免疫的贡献，(2)阐明CD5如何调节B细胞对T依赖抗原和T依赖抗原的反应，(3)剖析正常B细胞中CD5依赖的生存和抑制信号的分子机制。这些使用新的动物模型的研究将使我们能够在B细胞中解析CD5生物学。拟议研究的一个重要成果将是我们在理解先天B细胞对细菌和病毒病原体的反应的调节途径方面取得的重大进展，以及为治疗自身免疫性疾病和白血病而开发的靶向方法。公共卫生相关性：CD5B细胞(B1a)B细胞在先天免疫、形成获得性免疫谱系和自身免疫性疾病的免疫发病机制中非常重要。CD5在B细胞发育中的作用已被广泛询问，但仍未得到解决；这项建议的目标是填补我们理解上的空白。

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.