Impaired B Cell and Vaccine Responses with Advance Renal Disease

晚期肾病导致 B 细胞和疫苗反应受损

• 批准号: 10563125
• 负责人: Alkesh Harihar Jani
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563125
• 关键词: Adult; Affect; Affinity; Age Years; American; Antibodies; Antibody Formation; Antibody Response; Avidity; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Bacterial Infections; Bacterial Pneumonia; Blood; Caring; Cause of Death; Cell Communication; Cell Maturation; Cell Nucleus; Chronic; Chronic Kidney Failure; Cytoplasm; DNA; Data; Defect; Development; Dialysis patients; Dialysis procedure; End stage renal failure; Enzyme Activation; Frequencies; Gene Mutation; General Population; Genes; Helper-Inducer T-Lymphocyte; Hospitalization; IgA1; IgG1; Immune response; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin Constant Region; Immunoglobulin G; Immunoglobulin Genes; Immunoglobulin M; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Immunoglobulin-Secreting Cells; Impairment; Incidence; Infection; Inflammation; Interleukin-4; Interleukin-6; Kidney Diseases; Lymphoid; Messenger RNA; Mucous Membrane; Mutation; Nasopharynx; Nuclear; Patients; Pattern; Persons; Pneumococcal Pneumonia; Pneumococcal conjugate vaccine; Pneumococcal vaccine; Pneumonia; Polysaccharides; Polyvalent pneumococcal vaccine; Population; Process; Production; Proteins; Respiratory Mucosa; Specificity; Streptococcus pneumoniae; Structure of germinal center of lymph node; Structure of mucous membrane of nose; T-Lymphocyte; TNF gene; TNFSF5 gene; Therapeutic; Vaccination; Vaccines; Veterans; activation-induced cytidine deaminase; antibody and antigen binding; antigen binding; capsule; differential expression; experimental study; fighting; improved; interleukin-21; mortality; novel; novel therapeutics; protein expression; recruit; response; vaccination outcome; vaccine development; vaccine response

Bacterial infections are the second leading cause of death in ESRD. The incidence of pneumonia amongst dialysis patients is increasing and leads to a mortality rate that is 14-16-fold greater than pneumonia in the general population. Little is known regarding the immune response to pneumococcal vaccination in patients with CKD and ESRD. Preliminary data suggests that antibody production and duration in response to pneumococcal vaccines is reduced in CKD and ESRD. The cause of decreased antibody production and duration in response to pneumococcal vaccines is unknown. CKD and ESRD may impair B cells directly and reduce the ability of T follicular helper (TFH) cells to support effective B cell selection and differentiation. Production of antibodies of high specificity, affinity, and, thus, function is derived from the frequency and pattern of mutation in immunoglobulin genes that encode the antibody’s antigen-binding variable region (VH) in response to infection or vaccine. Development of effective antibodies requires serial mutations in VH genes by somatic hypermutation (SHM) and changes in the effector constant region from IgM to IgG or IgA by class switch recombination. Both processes require the DNA editing enzyme AID (activation-induced cytidine deaminase) in B cells in lymphoid germinal centers (GC). The effect of CKD on B cell maturation, SHM, class switch recombination and AID is unknown. We will characterize mucosal (nasopharyngeal) and systemic B cell and antibody responses to PCV-13 among adults with CKD and determine: a) Whether CKD impairs levels of PPS-specific IgA and IgG in nasal mucosa and in blood with PCV-13, and differential expression of specific IgG1/2 and IgA1/2; b) Whether the quality (avidity) and function (opsonophagocytosis) of PPS-specific mucosal (nasopharyngeal) and systemic IgA and IgG are compromised by CKD. c) If PPS-specific IgG1/2 (and IgA1/2) show differential i) production with PCV-13 with CKD in blood and nasopharyngeal mucosa. ii) killing of S. pneumoniae. We will determine whether CKD impacts the mutation frequency of VH genes in PPS-specific B cells in association with impaired TFH and AID responses after PCV-13 vaccination. a) Characterize the frequency, diversity, clustering and VH gene mutation frequency in pneumococcal capsule- specific IgG antibody-secreting cells in each group on day 7 after PCV-13; b) Determine TFH cell recruitment and activity, expression of AID in B cell subsets pre- and post-stimulation by i) mRNA for AID and ii) intracellular AID protein expression. c) Determine the contribution of chronic inflammation (eg., IL-6, TNF-α) in CKD on TFH and AID responses and capsule-specific antibody levels, avidity, function after PCV-13.

细菌感染是 ESRD 中肺炎的第二大死亡原因。 透析患者不断增加，死亡率比肺炎高 14-16 倍 一般人群对肺炎球菌疫苗接种的免疫反应知之甚少。 CKD 和 ESRD 的初步数据表明，抗体的产生和持续时间对肺炎球菌有反应。 CKD 和 ESRD 中抗体产生的原因和反应持续时间减少。 肺炎球菌疫苗尚不清楚。 CKD 和 ESRD 可能直接损害 B 细胞并降低滤泡辅助 T (TFH) 细胞的能力 支持有效的 B 细胞选择和分化，产生高特异性、亲和力的抗体， 因此，功能源自编码免疫球蛋白基因的突变频率和模式。 抗体的抗原结合可变区（VH）响应感染或疫苗的有效性。 抗体需要通过体细胞超突变（SHM）对 VH 基因进行连续突变以及效应子的变化 通过类别转换重组从 IgM 恒定区到 IgG 或 IgA 这两个过程都需要 DNA 编辑。 淋巴生发中心 (GC) B 细胞中酶 AID（激活诱导胞苷脱氨酶）的作用。 CKD 对 B 细胞成熟、SHM、类别转换重组和 AID 的影响尚不清楚。 我们将描述粘膜（鼻咽）和全身 B 细胞和抗体对 PCV-13 的反应 患有 CKD 的成年人并确定： a) CKD 是否会损害 PCV-13 鼻粘膜和血液中 PPS 特异性 IgA 和 IgG 的水平，以及 特异性IgG1/2和IgA1/2的差异表达； b) PPS特异性粘膜（鼻咽）的质量（亲合力）和功能（调理吞噬作用）是否良好 CKD 会损害全身 IgA 和 IgG。 c) 如果 PPS 特异性 IgG1/2（和 IgA1/2）显示出差异 i) 血液中患有 CKD 的 PCV-13 的产生和 ii) 杀死鼻咽粘膜肺炎链球菌。 我们将确定 CKD 是否影响 PPS 特异性 B 细胞中 VH 基因的突变频率 与 PCV-13 疫苗接种后 TFH 和 AID 反应受损相关。 a) 表征肺炎球菌荚膜中的频率、多样性、聚类和 VH 基因突变频率- PCV-13后第7天各组特异性IgG抗体分泌细胞； b) 确定 TFH 细胞募集和活性，以及​​ i) 刺激前和刺激后 B 细胞亚群中 AID 的表达 AID 的 mRNA 和 ii) 细胞内 AID 蛋白表达。 c) 确定 CKD 中慢性炎症（例如 IL-6、TNF-α）对 TFH 和 AID 反应的贡献， PCV-13 后胶囊特异性抗体水平、亲合力和功能。