Evidence of perturbed germinal center dynamics, but preserved antibody diversity, in end-stage renal disease

INTRODUCTION: End-stage renal disease (ESRD) is associated with increased infectious susceptibility and with reduced vaccine responses consistent with compromised humoral immunity. Whether the compromised humoral immunity is due to reduced antibody diversity (reduced somatic hypermutation [SHM]) or altered germinal center (GC) dynamics is not known. The GC-derived chemokine CXCL13 as well as peripheral T follicular helper cells (pTFH) reflect GC dynamics, but have, similar to SHM, never been characterized in relation to ESRD.

METHODS: Serum CXCL 13 was determined by ELISA. PTFH were flow-cytometrically defined as CD4+ CD45RA- CCR7+ CXCR5+ lymphocytes. Apoptotic lymphocyte subsets were in addition annexin V+. SHM was determined, by next-generation sequencing and bioinformatics, as nucleotide mutations within the IgG VH (comprising the important antigen-binding domains of IgG, CDR1, and CDR2).

RESULTS: Elevated CXCL13 levels characterized ESRD (n = 19; [median] 90 pg/ml, P < 0.01) (controls, n = 18; 62 pg/ml). ESRD pTFH frequencies (n = 19; 11.6% [of CD4+ memory T cells], P < 0.02*, *Bonferroni corrected) (controls, n = 22; 14.9%) and concentrations (n = 19; 0.03 × 109/L, P < 0.02*) (controls, n = 22; 0.07 × 109/L) were reduced. ESRD pTFH were more apoptotic (n = 9; 25.7%, P = 0.04*) (controls, n = 10; 15.9%). SHM did not discriminate between ESRD (n = 10; 7.4%, P = 0.21) and controls (n = 10; 8.4%).

CONCLUSIONS: Elevated CXCL13 levels, reduced pTFH levels, and increased pTFH apoptosis suggest that perturbed GC dynamics, and not reduced antibody diversity, underlie the diminished vaccine responses and the compromised humoral immunity in ESRD. However, largely preserved SHM provides a rationale for pursuing vaccination in relation to ESRD.