The Role of CD5 in B-Cell Development and Autoimmunity

CD5 在 B 细胞发育和自身免疫中的作用

• 批准号: 7878060
• 负责人: Chander Raman
• 金额: $ 35.89万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878060
• 关键词: Address; Affect; Animal Model; Antibodies; Antibody Formation; Antigen Receptors; Antigens; Apoptotic; Attenuated; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B cell differentiation; B lymphoid malignancy; B-Cell Activation; B-Cell Development; B-Lymphocytes; Binding; Biological; Biology; Cell Death; Cell Survival; Cell Wall; Cellular biology; Characteristics; Chickens; Chimera organism; Choline; Chromosomes, Human, Pair 4; Chronic; Chronic Lymphocytic Leukemia; Clinical; Coupled; Cytoplasmic Tail; Data; Development; Equilibrium; Ficoll; Gene Targeting; Generations; Genes; Genetic Recombination; Globulins; Glycoproteins; Goals; Greater sac of peritoneum; HIV; Human; Hyperactive behavior; Immune; Immune Tolerance; Immune response; Immune system; Immunoglobulin M; Individual; Lead; Lymphocyte; Maintenance; Mediating; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Natural Immunity; Neonatal; Outcome; Pathogenesis; Pathway interactions; Patients; Play; Population; Positioning Attribute; Process; Progressive Disease; Protein-Serine-Threonine Kinases; Receptor Activation; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Regulatory Pathway; Rheumatoid Arthritis; Role; SLEB2 gene; Serum; Shapes; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Stimulus; Systemic Lupus Erythematosus; T-Independent Antigens; T-Lymphocyte; TNP-ficoll; Tail; Testing; Tyrosine; Up-Regulation; Viral; Virus Diseases; Work; age related; arm; autoreactive B cell; casein kinase II; design; in vivo; irradiation; leukemia; lupus prone mice; mutant; novel; pathogen; public health relevance; receptor; research study; response; systemic autoimmune disease

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.

描述（由申请人提供）：B1A（CD5+）B细胞是自然抗体的主要产生者，它们具有自反应性和多反应性但通常是非致病性。但是，在某些情况下，B1A B细胞对慢性全身性自身免疫性疾病（如类风湿关节炎（RA），Sjogren综合征和全身性狼疮的红蛋白症状性疾病（SLE）的免疫致病作用。 B1A B细胞是先天免疫系统的关键部门，并为各种细菌和病毒感染提供了第一道防线。最普遍的B细胞恶性肿瘤，慢性淋巴细胞性白血病（CLL）的起源是CD5+ B细胞。奇怪的是，患有进行性疾病的HIV患者缺乏CD5+ B细胞。相比之下，患有非促进疾病的血清阳性个体的B1a B细胞水平正常。这表明CD5+ B细胞产生的天然抗体可能在HIV中具有保护性。 CD5在B1A B细胞的开发，功能和/或持久性中的作用仍然是一个尚未解决且有争议的问题。由于当B细胞抗原受体（BCR）与抗原接合时，CD5可以负调节信号，因此据信，其在B1A B细胞中的主要作用是控制B细胞受体激活，从致病性地反应自我抗原。但是，这种教条受到CD5 - / - 小鼠不会自发自身免疫性疾病的挑战。我们最近的研究导致发现，除了其抑制活性外，CD5的主要起作用是主要的，可能是主要的作用，是促进生存。 CD5的存活活性介导了其与CK2的独特相互作用，CK2是一种丝氨酸/苏氨酸激酶，是多个细胞Prosurvival信号级联的主要阳性调节剂。在与CK2激活介导的验证活性的对立中，CD5还具有免疫受体酪氨酸抑制基序（ITIM），用于负调控B细胞激活。 ITIM结构域还通过衰减B细胞激活并因此激活诱导的细胞死亡提供了生存信号。我们建议CD5通过两种独立但免费的途径调节B细胞响应。为了测试该模型，我们通过基因靶向方法的小鼠产生了表达CD5具有选择性无法激活CD5-CK2依赖性Proservival信号级联和缺乏CD5-ITIM依赖性负调控活性的小鼠的小鼠。使用这些独特的动物模型以及我们建议开发的新模型，我们将有能力（1）确定CD5在B1A B细胞发展中的作用及其对自身免疫性的贡献，（2）CD5阐明B-cell对T-独立抗原和T依赖性抗原和（3）cd依赖性抗原和（3）的质疑的响应方式B细胞。这些使用新型动物模型的研究将使我们能够在B细胞中解决CD5生物学。拟议的研究的一个重要结果将是我们理解对细菌和病毒病原体的先天B细胞反应的调节途径的重大进步，以及用于治疗自身免疫性疾病和白血病的靶向方法的发展。公共卫生相关性：CD5+ B细胞（B1A）B细胞在先天免疫中很重要，塑造适应性的免疫曲目和自身免疫性疾病的免疫发病发生。 CD5在B细胞发展中的作用已被广泛审问，但仍未解决。该提案的目的是在我们的理解中填补这一空白。