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: 10391544
• 负责人: David R Fooksman
• 金额: $ 41.75万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391544
• 关键词: Address; Adjuvant; Antibodies; Antibody Affinity; Antibody Formation; Antibody Response; Antibody titer measurement; Antigens; Apoptosis; Attenuated; Autoantibodies; Autoimmune; Autoimmune Diseases; 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; antibody test; 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）是组成型免疫系统中重要的免疫效应细胞 分泌高亲和力抗体，提供对感染的预防。对比一下live 减毒病毒可以提供终身免疫，基于蛋白质的疫苗已知 诱导LLASC的能力差，通常需要多次加强以产生足够的抗体滴度。的 控制LLASC生产的因素知之甚少，但对所有人都至关重要。 体液疫苗LLASC的存活主要由可溶性细胞因子介导，如 BM中的APRIL和次级淋巴组织中的IL-6。免疫后，抗体 分泌细胞（ASCs）表达不同水平的CD 138，其功能尚不清楚，因为它 可结合100+蛋白，CD 138-/-无明显表型。然而，我们最近 发表了一项研究，最终详细说明了CD 138对有效抗体应答的直接作用， 控制免疫后ASC的成熟和存活。LLASC表达了最高水平的 在所有细胞中CD 138的表达，与新产生的ASC相比， CD 138的水平。我们认为，高表达的CD 138为LLASC提供了更高的增殖能力。 IL-6和APRIL的结合和积累，这是限制性的，导致竞争性的 比新的ASCs更有利于生存。在目标1中，我们将在此测试此竞争模型 这可以解释疫苗反应不佳以及如何维持LLASC超过 时间和反复的免疫反应。在目标2中，我们将探索增加CD 138的方法， 接种疫苗以增强ASC存活和长期免疫力。在目标3和4中，我们将探讨 CD 138在病理条件下的功能。