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: 8395959
• 负责人: Justin Richner
• 金额: $ 4.92万
• 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/8395959
• 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. PUBLIC HEALTH RELEVANCE: This study will advance our knowledge of the age-dependent decline in immune system effectiveness and help explain the age-related vulnerability to WNV infection. A better understanding of the causes and consequences of these processes may facilitate the generation of new strategies that improve vaccine responses, and thus limit the morbidity of infectious diseases.

描述（由申请人提供）：西尼罗河病毒（WNV）是一种新兴的蚊媒黄病毒，可导致多种脊椎动物物种致命的脑炎。老年人特别容易感染西尼罗河病毒，其发病率和死亡人数也会增加。尽管众所周知，老年人在使用候选抗病毒疫苗免疫后往往无法产生保护性体液免疫反应，但其背后的机制却知之甚少。事实上，人们对于塑造 B 细胞介导的记忆的年龄相关变化知之甚少。与人类一样，老年小鼠在感染西尼罗河病毒后表现出对严重疾病的易感性增加。为了了解这些观察结果的潜在机制，我们将评估成年（4-6 个月大）和老年（> 18 个月）小鼠的 B 细胞库和功能。我们将比较成年和老年小鼠感染西尼罗河病毒后记忆发育的程度和质量以及继发感染后的记忆反应。我们假设老年小鼠针对 WNV 感染会产生较低的定性和定量 B 细胞介导的免疫反应，表现为中和抗体水平降低、抗体分泌细胞减少，并最终在继发感染后记忆反应降低。这项研究的结果应该有助于我们了解导致体液反应免疫衰老的机制，并为老年人开发针对西尼罗河病毒和其他全球相关传染病的疫苗奠定基础。 公共卫生相关性：这项研究将增进我们对免疫系统有效性随年龄下降的认识，并有助于解释与年龄相关的西尼罗河病毒感染脆弱性。更好地了解这些过程的原因和后果可能有助于制定改善疫苗反应的新策略，从而限制传染病的发病率。