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死亡的第二大原因。肺炎事件 透析患者正在增加，导致死亡率比肺炎高14-16倍 一般人口。关于对患者肺炎球菌疫苗接种的免疫响应的知之甚少 CKD和ESRD。初步数据表明抗体产生和持续时间响应肺炎 CKD和ESRD中的疫苗减少。抗体产生和持续时间减少的原因 肺炎球菌疫苗尚不清楚。 CKD和ESRD可能会直接损害B细胞，并降低T滤泡辅助器（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，以及 因此，功能源自免疫球蛋白基因中突变的频率和模式，该基因编码 抗体的抗原结合变量区域（VH）响应感染或疫苗。开发有效 抗体需要通过体细胞超突变（SHM）在VH基因中的串行突变和效应子的变化 通过类开关重组从IgM到IgG或IgA的恒定区域。这两个过程都需要DNA编辑 淋巴样生发中心（GC）中B细胞中的酶AID（激活诱导的胞苷脱氨酶）。效果 CKD在B细胞成熟，SHM，类开关重组和AID上的of尚不清楚。 我们将表征粘膜（鼻咽）和全身B细胞以及对PCV-13的抗体反应 患有CKD的成年人并确定： a）CKD是否会损害鼻粘膜和PCV-13血液中PPS特异性IgA和IgG的水平，以及 特定IgG1/2和IgA1/2的差异表达； b）PPS特异性粘膜（鼻咽）的质量（亲和力）和功能（脑吞噬）是否是否存在 CKD损害了系统的IgA和IgG。 c）如果PPS特异性IgG1/2（和IgA1/2）显示差异i）i）用PCV-13生产，血液中的CKD和 鼻咽粘膜。 ii）杀死肺炎链球菌。 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 PCV-13疫苗接种后与TFH的受损和辅助反应相关。 a）表征肺炎球囊囊中的频率，多样性，聚类和VH基因突变频率 PCV-13后第7天，每组的特定IgG抗体分泌细胞； b）确定TFH细胞募集和活性，I）在刺激前和刺激后的辅助表达 mRNA用于辅助和II）细胞内辅助蛋白表达。 c）确定CKD中慢性感染（例如，IL-6，TNF-α）在TFH和AID反应中的贡献 PCV-13后胶囊特异性抗体水平，亲和力。