title: Evidence of perturbed germinal center dynamics, but preserved antibody diversity, in end-stage renal disease.
abstract: 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.
  
  
  
  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 theIgG VH(comprising the important antigen-binding domains of IgG,CDR1, andCDR2).
  
  
  
  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%).
  
  
  
  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.
authors.affiliation: Department of Clinical Immunology Odense University Hospital Odense Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Assing
authors.affiliation: Department of Clinical Immunology Odense University Hospital Odense Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Nielsen
authors.affiliation: Department of Clinical Immunology Odense University Hospital Odense Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Jakobsen
authors.affiliation: Clinical Research UnitDepartment of NephrologyOdense University HospitalOdenseDenmark; Institute of Clinical ResearchUniversity of Southern DenmarkOdenseDenmark.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Scholze
authors.affiliation: Department of Clinical Biochemistry Odense University Hospital Odense Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Nybo
authors.affiliation: Department of Nephrology Odense University Hospital Odense Denmark.
authors.forename: Grete
authors.initials: G
authors.lastname: Soerensen
authors.affiliation: Department of Clinical Immunology Odense University Hospital Odense Denmark.
authors.forename: Sussie
authors.initials: S
authors.lastname: Mortensen
authors.affiliation: Department of Clinical Immunology Odense University Hospital Odense Denmark.
authors.forename: Knud
authors.initials: K
authors.lastname: Vejen
authors.affiliation: Department of Clinical Immunology Odense University Hospital Odense Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Barington
authors.affiliation: Department of Nephrology Odense University Hospital Odense Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Bistrup
mesh_terms: D000916:Antibody Diversity; D015496:CD4-Positive T-Lymphocytes; D054382:Chemokine CXCL13 / Q000378:metabolism*; D018858:Germinal Center; D006801:Humans; D007676:Kidney Failure, Chronic / Q000276:immunology*; D054380:Receptors, CXCR5; D016176:T-Lymphocyte Subsets; D006377:T-Lymphocytes, Helper-Inducer
chemical_list: D054382:Chemokine CXCL13; D054380:Receptors, CXCR5
keywords: CXCL13; end‐stage renal disease; peripheral T follicular helper cells