Defining the Impact of Aging on Memory B Cell Development and Humoral Immunity fo

确定衰老对记忆 B 细胞发育和体液免疫的影响

• 批准号: 8701210
• 负责人: Justin Richner
• 金额: $ 5.51万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701210
• 关键词: Adoptive Transfer; Adult; Age; Age-Months; Aging; Animals; Antibodies; Antibody Affinity; Antibody Repertoire; Antigens; Antiviral Agents; B cell repertoire; B-Cell Development; B-Lymphocytes; Bone Marrow; Cells; Cessation of life; Communicable Diseases; Culicidae; Defect; Development; Disease; Effectiveness; Elderly; Encephalitis; Flavivirus; Generations; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunoglobulin-Secreting Cells; Immunologic Memory; Incidence; Infection; Knowledge; Lead; Life; Lymphoid Tissue; Mediating; Memory; Memory B-Lymphocyte; Morbidity - disease rate; Mus; Nature; Plasma Cells; Plasmablast; Population; Predisposition; Process; Relative (related person); Research; Rest; Serum; Shapes; Specificity; Structure of germinal center of lymph node; Vaccination; Vaccines; Variant; Vertebrates; Virion; Virus; Virus Diseases; West Nile virus; age related; aged; arm; attenuation; base; cell mediated immune response; immunosenescence; improved; neutralizing antibody; response; secondary infection; senescence; vaccine development; vaccine effectiveness

DESCRIPTION (provided by applicant): West Nile Virus (WNV) is an emerging mosquito-born flavivirus that can lead to fatal encephalitis in several vertebrate animal species. The elderly ar especially vulnerable to WNV infection with increased incidence of disease and death. Although it is well characterized that elderly humans often fail to mount protective humoral immune response after immunization with candidate antiviral vaccines, the mechanistic causes behind this are poorly understood. Indeed, little is known regarding the age-related changes which shape B cell-mediated memory. Like humans, aged-mice show increased susceptibility to severe disease after WNV infection. To understand the underlying mechanisms of these observations we will assess the B cell repertoire and function in adult (4-6 month of age) and old (>18 months) mice. We will compare the magnitude and quality of the memory development in adult and aged mice following WNV infection and the memory response following a secondary infection. We hypothesize that old mice will develop lower qualitative and quantitative B cell-mediated immune responses against WNV infections that manifests as reduced levels of neutralizing antibodies, fewer antibody secreting cells, and ultimately decreased memory responses following secondary infections. The results of this study should inform our understanding of the mechanisms leading to immunosenescence of the humoral response and frame the development of vaccines for the elderly against WNV and other globally relevant infectious diseases.

描述（由申请人提供）：西尼罗河病毒（WNV）是一种新出现的蚊媒黄病毒，可导致几种脊椎动物致命性脑炎。老年人尤其容易感染西尼罗河病毒，发病率和死亡率增加。尽管老年人在用候选抗病毒疫苗免疫后通常不能产生保护性体液免疫应答，但这背后的机制原因知之甚少。事实上，关于年龄相关的变化，形状B细胞介导的记忆知之甚少。像人类一样，老年小鼠在感染西尼罗河病毒后对严重疾病的易感性增加。为了理解这些观察结果的潜在机制，我们将评估成年（4-6月龄）和老年（>18月龄）小鼠中的B细胞库和功能。我们将比较WNV感染后成年和老年小鼠记忆发育的幅度和质量以及继发感染后的记忆反应。我们假设，老年小鼠将发展较低的定性和定量B细胞介导的免疫反应对西尼罗河病毒感染，表现为减少中和抗体水平，更少的抗体分泌细胞，并最终减少记忆反应后继发感染。这项研究的结果应告知我们的理解的机制，导致免疫衰老的体液反应和框架的发展疫苗的老年人对西尼罗河病毒和其他全球相关的传染病。

项目成果

Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors.

• DOI: 10.1111/acel.12320
• 发表时间: 2015-06
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Metcalf TU;Cubas RA;Ghneim K;Cartwright MJ;Grevenynghe JV;Richner JM;Olagnier DP;Wilkinson PA;Cameron MJ;Park BS;Hiscott JB;Diamond MS;Wertheimer AM;Nikolich-Zugich J;Haddad EK
• 通讯作者: Haddad EK