FAIM in Immunity and Autoimmunity

描述(申请人提供)：就像Janus的两张脸一样，抗体可以是抗微生物免疫或自身抗体相关疾病的门户。最近成功地使用抗CD20治疗自身免疫性营养不良患者，使人们重新关注B细胞作为治疗靶点的作用。成熟的B细胞通过一个复杂的过程成为分泌抗体的浆细胞，这个过程始于生发中心，涉及多种转录因子的变化。该实验室的工作已经确定了B细胞激活和分化的新参与者，即新基因Faim.FAIM是独一无二的；它在进化上高度保守，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扮演着力量倍增器的角色。它通过增强CD40L刺激的NF-：B和IRF4的增加来增强CD40信号，并增强CD40L刺激的bcl6的下降。正如预期的那样，IRF4的额外增加和bcl6的减少(以及它在生发中心的位置)使嵌合体小鼠的浆细胞隔间增加。FIM的表达受IRF4的刺激，因此一旦被触发，FIM就参与了一种“前馈”的正向再增强机制。这项建议的长期目标有两个：了解正常的B细胞生物学，重点是“静止的”B细胞如何成为效应者，并确定这些过程出错导致自身抗体产生和自身免疫的点。这项工作的近期目标是确定FAIM在促进免疫和调节自身免疫中的作用，目的是确定新的治疗靶点。这项建议的具体目的是：1)进行仔细的分子结构/功能分析，以确定和表征独特的FAIM效应基序；以及，2)评估FAIM对正常免疫反应模型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FAIM在生发中心表达的生理学。这项工作的结果很有可能提供关于B细胞中的信号如何被促进，以及关于浆细胞分化如何被调控的全新的基本信息。此外，其他研究人员最近的发现(未发表)表明，FAIM序列附近和内部的SNP与人类狼疮疾病密切相关，表明本研究揭示的机制很可能与理解临床自身免疫有关，并可能为治疗操作提供新的靶点。 与公共卫生相关：抗体是血液中的蛋白质，由B淋巴细胞制造，B淋巴细胞是一种白细胞。抗体结合并帮助战胜细菌和病毒感染。然而，抗体并不总是有益的；有时B淋巴细胞会产生针对自身的抗体，这些自身反应性抗体或自身抗体会导致严重的自身免疫性疾病，如系统性红斑狼疮。最近，我们发现了由10年前发现的一种基因产生的新的重要活动。这种基因被称为faim，它使B细胞对某些类型的激活信号产生高度反应，并增加产生抗体的细胞的数量。这种基因之所以令人着迷，是因为在高等和低等生物的进化过程中都能发现它(甚至海绵也有类似的基因)，但它的作用机制尚不清楚。我们发现FAIM是B淋巴细胞反应性和发育为抗体产生细胞的力量倍增器。因此，FAIM很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：通过确定蛋白的活性区域来确定FAIM如何影响B淋巴细胞，FAIM对抗体产生细胞的影响是否改变了产生抗体的细胞，以及FAIM是否影响自身免疫病期间自发自身抗体的水平。如果我们的工作成功，我们将确定一个新的分子靶点，通过它应该可以调节B细胞的活动和抗体的产生，上到治疗免疫缺陷，下到治疗自身免疫性疾病。

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.