Impaired B Cell and Vaccine Responses with Advance Renal Disease

细菌感染是ESRD的第二大死亡原因。儿童肺炎的发病率 透析患者正在增加，导致的死亡率是肺炎的14-16倍 普通人口。对于肺炎球菌疫苗接种后的免疫应答，我们知之甚少。 CKD和ESRD。初步数据表明，肺炎球菌的抗体产生和持续时间 CKD和ESRD的疫苗接种减少。抗体产生减少和应答持续时间减少的原因 对肺炎球菌疫苗的反应尚不清楚。 CKD和ESRD可能直接损害B细胞，降低T滤泡辅助细胞(TFH)的能力 支持有效的B细胞选择和分化。产生高特异性、高亲和力的抗体， 因此，功能是从编码免疫球蛋白基因突变的频率和模式中得出的。 抗体对感染或疫苗的抗原结合可变区(VH)。开发有效的 抗体需要通过体细胞高度突变(SHM)和效应器的改变而导致VH基因的一系列突变 通过类开关重组，使Ig M向Ig G或Ig A恒定区。这两个过程都需要DNA编辑 淋巴生发中心(GC)B细胞的激活诱导型胞苷脱氨酶(AID)。其效果 CKD在B细胞成熟、SHM、类开关重组和AID中的作用尚不清楚。 我们将表征黏膜(鼻咽)和系统B细胞以及对PCV-13的抗体反应 患有慢性肾脏病的成年人，并确定： A)慢性肾脏病是否损害鼻黏膜和血液中PCV-13的PPS特异性IgA和Ig G水平，以及 特异性IgG1/2和IgA1/2的差异表达； B)PPS特异性粘膜(鼻咽部)的质量(亲和力)和功能(吞噬细胞功能) CKD损害了系统的免疫球蛋白A和免疫球蛋白G。 C)如果PPS特异性IgG1/2(和IgA1/2)与血液中患有CKD的PCV-13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TFH和AID反应受损的关系 A)确定肺炎球菌胶囊的频率、多样性、聚集性和VH基因突变频率- PCV-13感染后第7天各组特异性抗体分泌细胞； B)测定I刺激前后TFH细胞的募集和活性，B细胞亚群中AID的表达 AID和II)细胞内AID蛋白的表达。 C)确定慢性肾脏病慢性炎症(如IL-6、肿瘤坏死因子-α)对TFH和AID反应的贡献以及 胶囊特异性抗体水平、亲和力、PCV-13后功能。

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.