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.

许多免疫应答基因的调节依赖于称为kappaB的10 bp DNA序列。该序列被与Rel癌基因相关的蛋白质因子家族结合。 与该序列结合的原型转录复合物，称为NF-κ B，通常被定义为P50 DNA结合蛋白和P65（RelA）活化蛋白之间的异二聚体，其通常被称为I-kappaB的蛋白质隔离在细胞质中。在对细胞进行某些类型的刺激后，一种称为I-kappaB激酶的特异性蛋白激酶复合物引起I-kappaB的磷酸化，随后是其泛素化和降解。在能够释放NF-κ B的刺激物中，有一种是在免疫应答过程中抗原对T细胞受体（TCR）或B细胞受体（BCR）的触发。然而，这种转录因子在全身不同基因组的诱导中起作用，以响应数百种不同的诱导剂。在研究一种罕见的免疫缺陷临床病症时，我们还发现了CARD 11中的第一个种系突变，CARD 11是一种在B和T淋巴细胞中的抗原受体之间形成重要信号联系的蛋白质，在一个患有先天性淋巴样增生的家庭中首次报道于1971年的《新英格兰医学杂志》，以及在第二个家庭中从中国收养的儿童中。 受影响的家族成员表现出B淋巴细胞的过度积累和分化缺陷，但不是T淋巴细胞。鉴定的显性错义突变将组成性激活B和T细胞中的NF-κ B，从而促进B细胞中的下游增殖。 然而，它导致T细胞中明显的无反应性或无反应性，导致IL-2产生和增殖不良。因此，我们已经确定了这种遗传性B细胞疾病的潜在遗传原因，并揭示了为什么CARD 11突变可能易患B而不是T淋巴恶性肿瘤的潜在分子解释。这可以根据2信号模型来理解，其中T淋巴细胞需要T细胞增殖所需的抗原受体（信号1）以及共刺激（信号2），而仅提供信号1导致反应性差或无反应性。我们在我们的患者中观察到这种现象，因为E127 G CARD 11在没有伴随信号2的情况下引起NF-κ B的内部组成性激活，NF-κ B是信号1的重要特征成分。相反，B细胞增殖可由单独的BCR交联触发，其由突变CARD 11驱动的NF-κ B活性模拟。我们证实，当专职抗原呈递细胞提供适当的共刺激（信号2）时，通过突变CARD 11提供的慢性TCR样信号1可以转化为患者体内T细胞的增殖信号。T细胞对B细胞的辅助功能缺陷，与T细胞低反应性有关，可能部分解释了这些患者中生殖中心的缺乏和自身免疫表现。另一方面，对多糖抗原的T细胞非依赖性体液应答的缺陷也表明E127 G CARD 11存在的B细胞信号传导和效应子功能的内在缺陷。我们在CARD 11中发现种系功能获得性突变，阐明了抗原受体信号传导如何在B和T细胞中受到不同的调节，尽管近端信号传导机制几乎相同。 弥漫性大细胞B细胞淋巴瘤中的体细胞CARD 11突变尚未揭示这种令人惊讶的差异，其中只有B细胞具有突变，并且可以潜在地解释与该基因激活突变相关的B细胞而不是T细胞淋巴瘤的优势。我们对这种常染色体显性淋巴增生性疾病的分子分析，可能代表了B细胞恶性肿瘤（如B-慢性淋巴细胞白血病）的一种新的前体状态，揭示了通过CARD 11选择性调节NF-κ B如何可能使B细胞选择性增殖和分化停滞，但T细胞的增殖和功能缺陷。通过重新研究几十年前首次报道的罕见遗传性疾病的分子基础，我们的发现可能为治疗这种淋巴组织增生性疾病开辟新的途径，并通过阻断NF-kB的药物预防淋巴瘤的发展。