CD138 Regulates Competition of Antibody Secreting Cells for Survival

CD138 调节抗体分泌细胞的生存竞争

• 批准号: 9906270
• 负责人: David R Fooksman
• 金额: $ 50.18万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906270
• 关键词: Address; Adjuvant; Antibodies; Antibody Affinity; Antibody Formation; Antibody Response; Antibody titer measurement; Antigens; Apoptosis; Attenuated; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Binding; Blood; Bone Marrow; Cell Maturation; Cell Survival; Cells; Chronic; Cytokine Signaling; Disease; Disease Progression; Effector Cell; Engraftment; Genetic Transcription; Genus Mentha; Grant; Growth; Hematopoietic; Heparitin Sulfate; Human; IL6 gene; Immune; Immune response; Immunity; Immunization; Immunoglobulin-Secreting Cells; Infection; Inflammation; Interleukin 6 Receptor; Interleukin-6; Lupus; Lymphoid Tissue; Malignant Neoplasms; Mediating; Modeling; Multiple Myeloma; Mus; Pathogenicity; Pathologic; Patients; Phenotype; Plasmablast; Population; Production; Prophylactic treatment; Proteins; Publishing; Receptor Signaling; Rheumatoid Arthritis; Role; Signal Pathway; Stress; Surface; TLR4 gene; Testing; Time; Vaccination; Vaccines; Virus; adoptive B cell transfer; autoreactivity; base; cytokine; human model; immune function; improved; in vivo; migration; mouse model; prevent; transcription factor; vaccine efficacy; vaccine response

Long-lived antibody secreting cells (LLASCs) are critical immune effector cells constitutively secreting high affinity antibody providing prophylaxis against infections. In contrast to live attenuated viruses which can provide lifelong immunity, protein-based vaccines are known to poorly induce LLASCs, often requiring multiple boosting to generate sufficient antibody titer. The factors that control LLASC production are poorly understood, but are critically important for all humoral-based vaccines. Survival of LLASCs is chiefly mediated by soluble cytokines, such as APRIL in the BM, and IL-6 in secondary lymphoid tissues. After immunization, antibody secreting cells (ASCs) express variable levels of CD138, and its function was unclear, since it can bind 100+ proteins, and CD138-/- have no overt phenotype. However, we have recently published a study that finally details a direct role for CD138 for potent antibody responses, by controlling ASC maturation and survival after immunization. LLASCs express the highest level of CD138 among all cells, in comparison to newly minted ASCs, which express intermediate levels of CD138. We proposed that high expression of CD138 provides LLASCs with higher binding and accumulation of IL-6 and APRIL, which are limiting, leading to a competitive advantage over new ASCs for survival. In Aim 1, we will test this competition model in this grant, which can explain poor vaccine responses as well as how LLASCs are maintained over time and repeated immune responses. In Aim 2 we will explore ways to increase CD138 after vaccination to enhance ASC survival and long term immunity. In Aims 3 & 4, we will explore CD138 function in pathological conditions.

长寿命抗体分泌细胞 (LLASC) 是关键的免疫效应细胞 分泌高亲和力抗体，预防感染。与直播相比 减毒病毒可以提供终生免疫力，众所周知，基于蛋白质的疫苗可以 LLASC 的诱导效果较差，通常需要多次加强才能产生足够的抗体滴度。这 人们对控制 LLASC 生产的因素知之甚少，但对所有人来说都至关重要 基于体液的疫苗。 LLASCs的存活主要由可溶性细胞因子介导，例如 APRIL 存在于 BM 中，IL-6 存在于次级淋巴组织中。免疫后产生抗体 分泌细胞（ASC）表达不同水平的 CD138，其功能尚不清楚，因为 可以结合 100+ 蛋白质，并且 CD138-/- 没有明显的表型。然而，我们最近 发表了一项研究，最终详细介绍了 CD138 对强效抗体反应的直接作用，作者： 控制免疫后 ASC 的成熟和存活。 LLASCs 表达最高水平 与表达中间体的新生成的 ASC 相比，所有细胞中 CD138 的数量 CD138 的水平。我们提出 CD138 的高表达为 LLASCs 提供了更高的 IL-6 和 APRIL 的结合和积累是有限的，导致竞争性 相对于新 ASC 的生存优势。在目标 1 中，我们将测试这个竞争模型 赠款，这可以解释疫苗反应不佳以及 LLASCs 如何维持 时间和重复的免疫反应。在目标 2 中，我们将探索在之后增加 CD138 的方法 接种疫苗以增强 ASC 存活率和长期免疫力。在目标 3 和 4 中，我们将探索 CD138 在病理条件下发挥作用。