Abstract
BackgroundGerminal center derived memory B cells and plasma cells constitute, in health and during EBV reactivation, the largest functional EBV reservoir. Hence, by reducing germinal center derived formation of memory B cells and plasma cells, EBV loads may be reduced. Animal and in-vitro models have shown that IL-21 can support memory B and plasma cell formation and thereby potentially contribute to EBV persistence. However, IL-21 also displays anti-viral effects, as mice models have shown that CD4+ T cell produced IL-21 is critical for the differentiation, function and survival of anti-viral CD8+ T cells able to contain chronic virus infections.Case presentationWe present immunological work-up (flow-cytometry, ELISA and genetics) related to a patient suffering from a condition resembling B cell chronic active EBV infection, albeit with moderately elevated EBV copy numbers. No mutations in genes associated with EBV disease, common variable immunodeficiency or pertaining to the IL-21 signaling pathway (including hypermorphic IL-21 mutations) were found. Increased (> 5-fold increase 7 days post-vaccination) CD4+ T cell produced (p < 0.01) and extracellular IL-21 levels characterized our patient and coexisted with: CD8+ lymphopenia, B lymphopenia, hypogammaglobulinemia, compromised memory B cell differentiation, absent induction of B-cell lymphoma 6 protein (Bcl-6) dependent peripheral follicular helper T cells (pTFH, p = 0.01), reduced frequencies of peripheral CD4+ Bcl-6+ T cells (p = 0.05), compromised plasmablast differentiation (reduced protein vaccine responses (p < 0.001) as well as reduced Treg frequencies. Supporting IL-21 mediated suppression of pTFH formation, pTFH and CD4+ IL-21+ frequencies were strongly inversely correlated, prior to and after vaccination, in the patient and in controls, Spearman’s rho: − 0.86, p < 0.001.ConclusionsTo the best of our knowledge, this is the first report of elevated CD4+ IL-21+ T cell frequencies in human EBV disease. IL-21 overproduction may, apart from driving T cell mediated anti-EBV responses, disrupt germinal center derived memory B cell and plasma cell formation, and thereby contribute to EBV disease control.
Highlights
Germinal center derived memory B cells and plasma cells constitute, in health and during Epstein-Barr virus (EBV) reactivation, the largest functional EBV reservoir
We have described the immunological effects associated with an elevated CD4+ IL21+ profile in an elderly lady suffering from chronic EBV infection where some of the clinical and immunological findings resembled those of B cell chronic active EBV disease (B cell CAEBV) [10]
T- and natural killer (NK)- cell tropic EBV infections are rare entities primarily reported among East Asians
Summary
Epstein-Barr virus (EBV) infects 90–95% of adults worldwide. In health and in EBV lymphoproliferative disorders, memory B cells and plasma cells, collectively, constitute the largest functional EBV reservoir [1, 2]. Three weeks post-vaccination, our patient’s PCV titers were significantly diminished compared to age and gender matched controls (Table 1) and only the patient failed to generate protective antibody levels to some PCV serotypes: 4, 5, 6B and 18C (data not shown). The patient, in contrast to three controls, responded with a 5-fold increase in CD4+ IL-21+ frequencies but with no induction of CD4+ CD45RA− CXCR5+ CCR7low PD-1high (peripheral) T follicular helper cells ((p)TFH) (Fig. 3). Peripheral TFH and CD4+ IL-21+ frequencies were negatively correlated among vaccinated subjects (pre-, 7 and 21 days postvaccination for the patient + 4 controls = 15 time points, Spearman’s rho: − 0.86, p < 0.001, Fig. 4). Frequencies of CCR7low and PD-1high expression among patient c and controls d CD4+ CD45RA− CXCR5+ T cells are shown (patient vs controls (all time points), p = 0.01, Mann-Whitney U test). CD8+ T cell concentrations, positive IgG anti-EBNA but no detectable EBV copies in his blood (data not shown)
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