Regulation of SIGNALLING PATHWAYS INVOLVING NUCLEAR FACTOR KAPPA B

涉及核因子 KAPPA B 的信号通路的调控

• 批准号: 8745314
• 负责人: michael j lenardo
• 金额: $ 27.93万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8745314
• 关键词: Adjustment Disorders; Affect; Antigen Receptors; Antigen-Presenting Cells; Antigens; Autoimmune Process; B Cell Proliferation; B cell differentiation; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; Binding; Biochemical; Biochemical Genetics; Biology; Cells; China; Chronic; Chronic Lymphocytic Leukemia; Clinical; Complex; Cytoplasm; DNA Sequence; DNA-Binding Proteins; Defect; Development; Diffuse; Disease; Exhibits; Family; Family member; Gene Components; Gene Expression; Gene Family; Genes; Genetic; Genetic Transcription; Germ-Line Mutation; HIV; Hereditary Disease; Human Pathology; Immune; Immune Response Genes; Immune response; Immunologic Deficiency Syndromes; Infectious Agent; Inflammatory; Inherited; Interleukin-2; Journals; Lead; Link; Lymphocyte; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Malignant lymphoid neoplasm; Medicine; Missense Mutation; Modeling; Molecular; Molecular Analysis; Mutation; NF-kappa B; New England; Nuclear; Output; Pathway interactions; Patients; Pharmacologic Substance; Phosphorylation; Phosphotransferases; Play; Polysaccharides; Production; Protein Family; Protein Kinase; Proteins; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Regulator Genes; Reporting; Role; Signal Pathway; Signal Transduction; Stimulus; Structure of germinal center of lymph node; T-Cell Lymphoma; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; TNFRSF5 gene; Ubiquitination; adopted child; anergy; base; combat; crosslink; gain of function mutation; gene induction; genetic regulatory protein; human disease; in vivo; insight; interest; lymphoid hyperplasia; metaplastic cell transformation; mutant; novel; novel strategies; p65; prevent; programs; protein activation; protein complex; prototype; response; transcription factor; v-rel Oncogenes

Regulation of many immune response genes depend on a 10 bp DNA sequence termed kappaB. This sequence is bound by a family of protein factors related to the Rel oncogene. The prototype transcription complex binding to the sequence, termed NF-kappaB, has been conventionally defined as a heterodimer between a P50 DNA binding protein and a P65 (RelA) activation protein that is typically sequestered in the cytoplasm by a protein called I-kappaB. Following certain types of stimulation to the cell, a specific protein kinase complex called I-kappaB kinase causes the phosphorylation of I-kappaB followed by its ubiquitination and degradation. Among the stimuli that can release NF-kappaB is the triggering of the T cell receptor (TCR) or B cell receptor (BCR) by antigen during an immune response. However, this transcription factor plays a role in the induction of diverse sets of genes throughout the body in response to hundreds of different inducers. While studying a rare clinical condition of immunodeficiency, We have also discovered the first germline mutation in CARD11, a protein that forms a vital signaling link between the antigen receptor in both B and T lymphocytes, in one family with congenital lymphoid hyperplasia first reported in The New England Journal of Medicine in 1971 as well as in a child adopted from China in a second family. The affected family members exhibit excessive accumulation and defective differentiation of B lymphocytes but not T lymphocytes. The dominant missense mutations identified will constitutively activate NF-kappaB in both B and T cells contributing to downstream proliferation in B cells. However,it causes apparent non-responsivenes or anergy in T cells resulting in poor IL-2 production and proliferation. Thus, we have identified the underlying genetic cause of this hereditary B cell disorder and have uncovered a potential molecular explanation for why CARD11 mutations may predispose to B but not T lymphoid malignancies. This can be understood in terms of the 2 signal model in which T lymphocytes require antigen receptor(signal 1) as well as costimulatory (signal 2)both required for T cell proliferation, whereas the provision solely of signal 1 leads to poor responsiveness or anergy. We observed this phenomenon in our patients, since E127G CARD11 causes internal constitutive activation of NF-kappaB, an important feature component of signal 1, in the absence of a concomitant signal 2. In contrast, B cell proliferation can be triggered by BCR crosslinking alone, which is mimicked by mutant CARD11-driven NF-kappaB activity. We posit that a chronic TCR-like signal 1 provided through mutant CARD11 can be converted to a proliferative signal for the patients T cells in vivo when proper costimulation (signal 2) is provided by professional antigen presenting cells. Defects in T cell help to B cells, related to T cell hyporesponsiveness, may partly explain the paucity of germinal centers and autoimmune manifestations in these patients. On the other hand, deficiencies in T cell-independent humoral responses to polysaccharide antigens also point to intrinsic defects in B cell signaling and effector function with E127G CARD11 present. Our discovery of a germline gain-of-function mutation in CARD11 illuminates how antigen receptor signaling is regulated differently in B and T cells, even though the proximal signaling machinery is nearly identical. This surprising difference has not been revealed by somatic CARD11 mutations in diffuse large cell B cell lymphoma, in which only B cells harbor the mutation and can potentially explain the preponderance of B cell rather than T-cell lymphomas associated with activating mutations in this gene. Our molecular analysis of this autosomal dominant lymphoproliferative disorder, which may represent a novel precursor state for B cell malignancies like B-chronic lymphocytic leukemia, reveals how selective dysregulation of NF-kappaB via CARD11 may predispose to selective proliferation and differentiation arrest in B cells, but defective proliferation and function of T cells. By re-examining the molecular basis of a rare genetic disorder first reported for decades ago, our discovery may open new avenues to treat this lymphoproliferative disease and prevent development of lymphoma by agents that can block NF-kB.

许多免疫反应基因的调节取决于称为Kappab的10 bp DNA序列。该序列由与REL癌基因有关的蛋白质因子系列结合。 原型转录复合物与序列的结合称为NF-kappab，通常被定义为P50 DNA结合蛋白与p65（rela）激活蛋白之间通常被称为I-kappab蛋白质的细胞质中隔离的p65（rela）激活蛋白。遵循对细胞的某些类型的刺激，一种称为I-kappab激酶的特定蛋白激酶复合物会导致I-kappab的磷酸化，然后其泛素化和降解。在可以释放NF-kappab的刺激中，在免疫反应过程中，抗原触发了T细胞受体（TCR）或B细胞受体（BCR）。然而，该转录因子在响应数百种不同诱导剂的诱导中诱导各种基因集中起作用。在研究罕见的免疫缺陷临床状况的同时，我们还发现了Card11中的第一个种系突变，这种蛋白质在B和T淋巴细胞中构成了抗原受体之间的重要信号连接，在1971年新英格兰医学杂志上首次在中国采用的一家人中，在新英格兰医学杂志上首次在中国采用了一家人，在一家人中，在一家人中首次获得了一个在新英格兰医学杂志上，并在Childry in Chernecy in Seccence Family in Seccences in Seccence。 受影响的家庭成员表现出B淋巴细胞的过度积累和有缺陷的分化，而不是T淋巴细胞。所鉴定的主要错义突变将组成性激活B和T细胞中有助于B细胞下游增殖的NF-kappab。 然而，它会导致T细胞中明显的非反应或厌食，从而导致IL-2产生和增殖差。因此，我们已经确定了这种遗传性B细胞疾病的根本遗传原因，并发现了为什么Card11突变可能易感B而不是T淋巴性恶性肿瘤的潜在分子解释。这可以通过2个信号模型来理解，其中T淋巴细胞需要抗原受体（信号1）以及Costimulatory（信号2），这都是T细胞增殖所需的，而信号1的提供仅导致反应性或消极性不佳。我们在患者中观察到了这种现象，因为E127G card11导致NF-kappab的内部组成型激活，这是信号1的重要特征成分，在没有伴随的信号2的情况下。相反，B单独使用BCR链接触发B细胞增殖，这是由BCR交叉触发的，这是由突变的Cardant cardant cardant cardant-cardant nivienniven nivienniveniveniver nivientiver nfiven niviennivenivenive nf-kappab启用。我们认为，当适当的共刺激（信号2）由专业抗原呈递细胞提供时，可以将通过突变card11提供的慢性TCR样信号1转换为患者T细胞的增生信号（信号2）。与T细胞低调有关的T细胞的缺陷有助于B细胞，可能部分解释了这些患者的生发中心和自身免疫性表现的缺乏。另一方面，对多糖抗原的T细胞无关的体液反应缺陷也表明存在E127G Card11的B细胞信号传导和效应子功能中的固有缺陷。我们发现Card11种系功能收益突变的发现，即使近端信号机制几乎相同，在B和T细胞中抗原受体信号的调节方式都不同。 这种令人惊讶的差异尚未通过弥漫性大细胞B细胞淋巴瘤中的体细胞card11突变揭示，其中只有B细胞含有突变，并有可能解释B细胞的优势，而不是与该基因激活突变相关的T细胞淋巴瘤。我们对这种常染色体显性淋巴细胞增生性疾病的分子分析，它可能代表了B细胞恶性肿瘤（如B奇妙的淋巴细胞性白血病）的新型前体状态，揭示了NF-kappab通过Card11的选择性失调可能会在B细胞中选择性地扩散和分化在B细胞中，但有缺陷的细胞，而不是在blifififififififififififififififs和Fightififififififififififififififififs和Fightififififififififififififififif-kappab中。通过重新研究几十年前首次报道的罕见遗传疾病的分子基础，我们的发现可能打开了新的途径来治疗这种淋巴增生性疾病并防止可以阻止NF-KB的药物对淋巴瘤的发展。