FAIM in Immunity and Autoimmunity

免疫和自身免疫中的 FAIM

• 批准号: 8081080
• 负责人: THOMAS L ROTHSTEIN
• 金额: $ 41.09万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081080
• 关键词: Affect; Affinity; Antibodies; Antibody Formation; Antibody-Producing Cells; Antigens; Apoptosis; Attention; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Autologous; B cell differentiation; B-Cell Activation; B-Lymphocytes; BCL1 Oncogene; Bacterial Infections; Binding; Biological Models; Biology; Blood; Cell physiology; Cellular biology; Clinical; Complex; DNA; Development; Disease; Down-Regulation; Dysplasia; Evolution; Face; Genes; Goals; Grant; Human; IRF4 gene; Immune; Immune response; Immunity; Immunoglobulins; In Vitro; Laboratories; Letters; Leukocytes; Location; Lower Organism; Lupus; Lupus Erythematosus; MS4A1 gene; Mature B-Lymphocyte; Modeling; Molecular Structure; Molecular Target; Mus; Participant; Patients; Personal Communication; Physiology; Plasma Cells; Play; Porifera; Process; Production; Protein Region; Proteins; Publishing; Research Personnel; Rest; Role; Sequence Homology; Signal Transduction; Specificity; Structure; Structure of germinal center of lymph node; System; TNFRSF5 gene; TNFSF5 gene; Time; Virus Diseases; Work; antimicrobial; fascinate; feeding; gene cloning; gene discovery; in vivo; lupus prone mice; new therapeutic target; novel; overexpression; plasma cell differentiation; public health relevance; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Like the two faces of Janus, antibodies can be a gateway to anti-microbial immunity or to autoantibody- associated disease. The recent successful use of anti-CD20 to treat patients with autoimmune dyscrasias has re-focused attention on the role of B cells as therapeutic targets. Mature B cells become antibody secreting plasma cells through a complex process that begins in the germinal center and involves alterations in multiple transcription factors. Work from this laboratory has identified a new player in B cell activation and differentiation, namely the novel gene, Faim. FAIM is unique; it is highly evolutionarily conserved, yet does not contain sequence homology, or structural homology, with any other protein. In B cells FAIM acts as a force multiplier. It boosts CD40 signaling by enhancing CD40L-stimulated increases in NF-:B and IRF4, and, it enhances the CD40L-stimulated decline in BCL-6. As expected from the extra increase in IRF4 and decline in BCL-6 (as well as its location in the germinal center) FAIM overexpression augments the plasma cell compartment in chimeric mice. FAIM expression is stimulated by IRF4 and so once triggered FAIM is involved in a "feed-forward" positive re-inforcing mechanism. The long term objective of this proposal is two-fold: to understand normal B cell biology focusing on how "resting" B cells become effectors, and to determine the points at which these processes go awry resulting in autoantibody production and autoimmunity. The near term objective of this work is to define the role of FAIM in facilitating immunity and regulating autoimmunity, with the goal of identifying a new therapeutic target. The specific aims of this proposal are to: 1) conduct a careful molecular structure/function analysis to identify and characterize the unique FAIM effector motif; and, 2) evaluate the influence of FAIM on the quality and selection of antibody produced in a model normal immune response, and on checkpoint integrity in a model system of spontaneous autoantibody production, and elucidate the physiology of FAIM expression in the germinal center. The results of this work are highly likely to provide completely new and fundamental information about how signaling in B cells is promoted, and about how plasma cell differentiation is regulated. Moreover, the recent finding by other investigators (unpublished) that SNPs proximal to, and within, the FAIM sequence are strongly associated with human lupus disease indicates that the mechanisms revealed by this study are highly likely to be relevant to understanding clinical autoimmunity and may provide a new target for therapeutic manipulation. PUBLIC HEALTH RELEVANCE: Antibodies are proteins in the blood that are made by B lymphocytes, which are a kind of white blood cell. Antibodies bind to and help defeat bacterial and viral infections. However, antibodies are not always beneficial; sometimes B lymphocytes make antibodies against self, and these autoreactive antibodies, or autoantibodies, can cause serious autoimmune diseases such as system lupus erythematosus. Recently we found new and important activities produced by a gene that we discovered 10 years ago. This gene, termed FAIM, makes B cells hyperresponsive to some kinds of activation signals and increases the number of antibody producing cells. This gene is fascinating because it is found throughout evolution in both higher and lower organisms (even sponge has a similar gene), but its mechanism of action is unknown. We have found that FAIM is a force multiplier for B lymphocyte responsiveness and development into antibody producing cells. As such, FAIM is likely to play a role in autoimmune disease. Our goal in this work is to determine: how FAIM affects B lymphocytes by identifying the active region of the protein, whether effect of FAIM on antibody producing cells alters which cells produce antibody, and whether FAIM influences the level of spontaneous autoantibodies during autoimmune disease. If our work is successful, we will identify a new molecular target through which it should be possible to regulate B cell activity and antibody production, up to treat immune deficiency, and down to treat autoimmune disease.

描述（由申请人提供）：就像Janus的两个面一样，抗体可以成为抗微生物免疫的门户或与自身抗体相关的疾病。最近成功使用抗CD20来治疗自身免疫性障碍患者，重新集中注意力细胞作为治疗靶标的作用。成熟的B细胞通过复杂的过程从生发中心开始，将浆细胞分泌，并涉及多种转录因子的改变。该实验室的工作已经确定了B细胞激活和分化方面的新玩家，即新颖的基因Faim。 Faim是独一无二的；它在进化上是高度保守的，但不包含与任何其他蛋白质的序列同源性或结构同源性。在B细胞中，FAIM充当力乘数。它通过增强NF-：B和IRF4的CD40L刺激的增加来增强CD40信号传导，并增强了BCL-6的CD40L刺激下降。正如预期的那样，IRF4的额外增加和Bcl-6（及其在生发中心的位置）FAIM过表达增加了嵌合小鼠的浆细胞室。 FAIM表达受到IRF4的刺激，因此一旦触发了FAIM，FAIM就参与了“前进”阳性重新启动机制。该提案的长期目标是两个方面：了解正常的B细胞生物学，重点是“静止” B细胞如何成为效应子，并确定这些过程出现问题的点，从而导致自身抗体的产生和自身免疫性。这项工作的近期目标是定义FAIM在促进免疫力和调节自身免疫性方面的作用，以确定新的治疗靶标。该提案的具体目的是：1）进行仔细的分子结构/功能分析，以识别和表征唯一的FAIM效应子基序； 2）评估FAIM对模型正常免疫反应中产生的抗体的质量和选择的影响，以及对自发自身抗体产生模型系统中检查点完整性的影响，并阐明了生发中心中FAIM表达的生理学。这项工作的结果极有可能提供有关如何促进B细胞信号传导以及如何调节浆细胞分化的全新和基本信息。此外，其他研究者（未发表）的最新发现，SNP靠近FAIM序列与人类狼疮疾病密切相关，表明，这项研究揭示的机制极有可能与理解临床自身免疫性有关，并且可能为治疗操作提供了新的靶标。 公共卫生相关性：抗体是由B淋巴细胞产生的血液中的蛋白质，这是一种白细胞。抗体结合并有助于击败细菌和病毒感染。但是，抗体并不总是有益的。有时，B淋巴细胞会产生反对自我的抗体，而这些自动反应性抗体或自身抗体可能会引起严重的自身免疫性疾病，例如系统狼疮红斑eRythematosus。最近，我们发现了10年前发现的基因产生的新的重要活动。该基因称为FAIM，使B细胞对某些激活信号的反应性过高，并增加产生抗体细胞的数量。该基因引人入胜，因为它在较高和较低的生物体中都可以在整个进化中发现（甚至海绵具有相似的基因），但其作用机理尚不清楚。我们发现，FAIM是B淋巴细胞反应性并发育到产生抗体细胞中的力乘数。因此，FAIM可能在自身免疫性疾病中发挥作用。我们在这项工作中的目标是确定：FAIM如何通过识别蛋白质的活性区域来影响B淋巴细胞，FAIM对产生细胞的抗体的影响是否会改变产生抗体的细胞，以及FAIM是否影响自身免疫性疾病期间自发性自身抗体的水平。如果我们的工作成功，我们将确定一个新的分子靶标，应该通过该靶标调节B细胞活性和抗体产生，以治疗免疫缺乏，并下降以治疗自身免疫性疾病。