Impaired B Cell and Vaccine Responses with Advance Renal Disease

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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.