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: 10370244
• 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/10370244
• 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; Lead; Lymphoid; Messenger RNA; Mucous Membrane; Mutation; Nuclear; Patients; Pattern; Persons; Pneumococcal Pneumonia; Pneumococcal conjugate vaccine; Pneumococcal vaccine; Pneumonia; Polysaccharides; Polyvalent pneumococcal vaccine; Population; Process; Production; Proteins; Recruitment Activity; 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; antigen antibody binding; antigen binding; capsule; differential expression; experimental study; fighting; improved; mortality; novel; novel therapeutics; protein expression; 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。肺炎的发病率， 透析患者正在增加，导致死亡率比肺炎高14-16倍， 一般人口。关于肺炎球菌疫苗接种的免疫应答， CKD和ESRD。初步数据表明，抗体的产生和持续时间，以应对肺炎球菌 在CKD和ESRD中，疫苗的接种率降低。抗体产生减少的原因和反应持续时间 肺炎球菌疫苗是未知的。 CKD和ESRD可能直接损害B细胞，并降低T滤泡辅助细胞（TFH） 支持有效B细胞选择和分化。生产高特异性、亲和力和， 因此，功能来源于编码免疫球蛋白的免疫球蛋白基因中突变的频率和模式。 抗体的抗原结合可变区（VH），以响应感染或疫苗。制定有效 抗体需要通过体细胞超突变（SHM）在VH基因中发生一系列突变，并且效应子中的变化 通过类别转换重组将IgM恒定区转化为IgG或伊加。这两个过程都需要DNA编辑 淋巴生发中心（GC）B细胞中的酶AID（活化诱导的胞苷脱氨酶）。效果 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， 成人CKD，并确定： a）CKD是否损害鼻粘膜和血液中具有PCV-13的PPS特异性伊加和IgG的水平，和 特异性IgG 1/2和IgA 1/2的差异表达; B）PPS特异性粘膜（鼻咽） 并且系统性伊加和IgG被CKD损害。 c）如果PPS特异性IgG 1/2（和IgA 1/2）显示差异i）血液中PCV-13与CKD的产生， 鼻咽粘膜ii）杀死S.肺炎。 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应答受损相关。 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感染后第7天各组特异性IgG抗体分泌细胞; B）测定TFH细胞募集和活性，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）确定慢性炎症的贡献（例如，IL-6、TNF-α）对TFH和AID反应的影响， PCV-13后的胶囊特异性抗体水平、亲合力、功能。