Mouse C4b-binding Protein in Adaptive Immunity

适应性免疫中的小鼠 C4b 结合蛋白

• 批准号: 7426383
• 负责人: RICK A. WETSEL
• 金额: $ 7.21万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2008-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7426383
• 关键词: Allergic; Animal Model; Antibodies; Antibody Formation; Antigens; Apoptosis; Autoimmune Diseases; B-Cell Development; B-Lymphocytes; Binding; Binding Sites; Biological; CD34 gene; CD4 Positive T Lymphocytes; CD40 Ligand; Cell Maturation; Complement 4b; Development; Disease; Exhibits; Extrinsic asthma; Generations; Goals; Human; Humoral Immunities; ICAM1 gene; IgE; Immune; Immune response; Immune system; Immunity; Immunoglobulin Class Switching; Immunoglobulins; Impairment; Investigation; Knockout Mice; Ligands; Ligation; Lymphocyte; Lymphocyte Count; Mediating; Mediator of activation protein; Membrane Glycoproteins; Molecular; Mus; Pathogenesis; Phenotype; Physiological; Pilot Projects; Production; Protein Binding; Reaction; Regulation; Research; Research Proposals; Site; Staging; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; T-Independent Antigens; TNFRSF5 gene; TNFSF5 gene; Testing; Thymus Gland; Transcriptional Activation; Tyrosine Phosphorylation; Up-Regulation; Wild Type Mouse; complement 4b-binding protein; complement pathway; human C4BPA protein; in vivo Model; inhibitor/antagonist; insight; progenitor; receptor; response

DESCRIPTION (provided by applicant): The objective of this research proposal is to evaluate the mouse complement C4b binding protein (C4BP) "knock-out" mouse as an in vivo model to delineate the overall contribution of human C4BP in adaptive immunity. The aims of this proposal are driven the the central hypothesis that C4BP on binding CD40 expressed on B cells mediates many important biological responses important in immune regulation, including immunoglobulin class switching in response to T-dependent antigens, and proliferation and rescue of germinal center B cells. Our recent generation of a C4BP "knock-out" mouse provides a unique opportunity to evaluate the physiological impact of C4BP as a significant contributor to adaptive immunity. The results from this proposal will significantly advance the understanding of how the innate and adaptive immune systems interact in providing a robust immune response. Moreover, these studies will also provide basic information that will facilitate a better understanding of B-cell maturation and immunoglobulin production, and thereby provide significant insights into the pathogenesis of autoimmune diseases such as systemic lupus erythematosus as well as IgE associated allergic diseases, including atopic asthma. To accomplish the overall objective of the proposal, three aims are proposed. Aim one will evaluate the binding interactions between mouse C4BP and CD40 expressed on mouse B cells. Aim two will examine lymphocyte development in C4BP-deficient (-/-) mice compared to wild-type mice. Aim three will determine the antibody response to T-dependent and T-independent antigens in C4BP-deficient (-/-) mice compared to wild-type mice, as well as to examine germinal center formation in C4BP-deficient (-/-) mice compare to wild- type mice.

描述（由申请人提供）：该研究建议的目的是评估小鼠补体C4B结合蛋白（C4BP）“敲除”小鼠作为体内模型，以描述人类C4BP在适应性免疫中的总体贡献。该提案的目的驱动了一个中心假设，即在B细胞上表达的C4BP在结合CD40上介导了在免疫调节中重要的许多重要生物学反应，包括对T依赖性抗原的免疫球蛋白类切换，以及对T依赖性抗原的响应，以及Germinal Center B细胞的增殖和营救。我们最近一代的C4BP“敲除”小鼠为评估C4BP的生理影响提供了一个独特的机会，作为适应性免疫的重要原因。该提案的结果将大大提高对先天和适应性免疫系统如何相互作用在提供强大的免疫反应方面相互作用的理解。此外，这些研究还将提供基本信息，从而有助于更好地了解B细胞成熟和免疫球蛋白的产生，从而为自身免疫性疾病的发病机理提供了重要的见解，例如全身性红斑狼疮，例如IgE相关的过敏性疾病，包括患有植物的疾病。为了实现该提案的总体目标，提出了三个目标。 AIM ONE将评估小鼠C4BP和在小鼠B细胞上表达的CD40之间的结合相互作用。与野生型小鼠相比，目标两个将检查C4BP缺陷型（ - / - ）小鼠的淋巴细胞发育。 AIM三将确定与野生型小鼠相比，C4BP缺陷型（ - / - ）小鼠中对T依赖性和T非依赖性抗原的抗体反应，以及与野生型小鼠相比，在C4BP缺陷型（/ - ）小鼠中检查了C4BP缺乏（/ - ）小鼠的生发中心形成。

项目成果

Epididymal C4b-binding protein is processed and degraded during transit through the duct and is not essential for fertility.

• DOI: 10.1016/j.imbio.2014.11.001
• 发表时间: 2015-04
• 期刊: IMMUNOBIOLOGY
• 影响因子: 2.8
• 作者: Nonaka, Mayumi I.;Zsigmond, Eva;Kudo, Akihiko;Kawakami, Hayato;Yoshida, Kaoru;Yoshida, Manabu;Kawano, Natsuko;Miyado, Kenji;Nonaka, Masaru;Wetsel, Rick A.
• 通讯作者: Wetsel, Rick A.