Loss of circulating CD27+ memory B cells and CCR4+ T cells occurring in association with elevated EBV loads in XLP patients surviving primary EBV infection

Abstract

Detailed longitudinal studies of patients with X-linked lymphoproliferative disease (XLP) may increase our understanding of the immunologic defects that contribute to the development of lymphoma and hypogammaglobulinemia in XLP. We describe progressive changes observed in immunoglobulin concentrations, lympho-cyte subsets, and Epstein-Barr virus (EBV) loads occurring in a 2-year period in a newly infected, but otherwise healthy, carrier (patient 9). We compare these findings with those observed in the patient's brother, who had hypogammaglobuline-mia and XLP (patient 4). Immunoglobulin G (IgG), IgM, and IgA concentrations increased in patient 9 during acute EBV infection, but thereafter they decreased steadily to concentrations consistent with hypogammaglobulinemia, reaching a plateau 5 months after infection. In both patients, CD19 B-lymphocyte rates remained lower than 3%, with a contraction of the B-cell memory compartment (CD27 CD19 /CD19) to 20% (normal range, 32%-56%). T-lymphocyte subpopulations showed a reduction in CD4 T-cell counts and a permanent CD8 T-cell expansion. Interestingly, CXCR3 memory T H 1 cells were expanded and CCR4 T H 2 lympho-cytes were reduced, suggesting that abnormal skewing of memory T-cell subsets might contribute to reduced antibody synthesis. Despite an expanded number of CD3 CD8 lymphocytes, increased EBV loads occurred in both patients without overt clinical symptoms of mononucleo-sis, lymphoproliferative disease, or lym-phoma.

Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells

“…This parallels the reduced basal levels of some serum Ig isotypes observed in XLP patients prior to EBV infection (46) as well as in uninfected SAP -/-mice (15,17). However, there tended to be a further decrease in the frequency of memory B cells following EBV infection, again mirroring the progressive decline in serum Ig levels in EBV + XLP patients (1,40) and infected SAP -/-mice (17). Our results support a recent study that reported reduced numbers of total memory B cells in 2 related XLP patients during EBV infection (40).…”

“…However, there tended to be a further decrease in the frequency of memory B cells following EBV infection, again mirroring the progressive decline in serum Ig levels in EBV + XLP patients (1,40) and infected SAP -/-mice (17). Our results support a recent study that reported reduced numbers of total memory B cells in 2 related XLP patients during EBV infection (40). However, this study also found reduced numbers of total B cells, in contrast to our data and data published previously (36), suggesting additional factors may affect B cell numbers in this 1 family (40).…”

“…1 and XLP no. Similarly, a recent study reported a reduction in the frequency of CCR4 + Th2-like memory CD4 + cells in 2 XLP patients; however, cytokine production by these cells was not examined (40). A defect in production of cytokines involved in regulating B cell function by human XLP CD4 + T cells could explain the inability of these cells to stimulate Ig production by B cells.…”

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

“…Because of the paucity of germinal center and memory B cells in SAP-deficient mice (29,32,48), both of which are preferential reservoirs of long-term latency (6), we anticipated that maintenance of long-term latency would be defective, as we had previously shown for CD40 Ϫ/Ϫ B cells within CD40 ϩ /CD40 Ϫ chimeric mice (7). However, unexpectedly, the frequencies of latency in CD19 ϩ B cells from SAP-deficient and wild-type mice between 90 and 210 dpi were remarkably comparable, with the SAP-deficient mice showing only modest reductions ranging between 1.4-and 4-fold (circles in Fig.…”

Treatment of primary Epstein-Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell-directed therapy

“…Previous genetic studies revealed that he carried a germ line G383C SH2D1A mutation, which was predicted to lead to the substitution of arginine for serine at codon 28 of SAP. 13 Prior to the current illness, patient no. 1 had been healthy.…”