Y. Ukeba-Terashita et al. / Open Journal of Pediatrics, 2011, 1, 30-33
32
The dominant population of EBV-infected cells is re-
ported to be CD8+ T cells in EBV-HLH, whereas the
ma jor target s of EBV in CAEBV are CD4+ T cells or NK
cells [5-7]. EBV-infected CD8+Tcells are activated and
produce cytokines such as IFN-γ, TNF-α and inter-
leukin-6, which activate macrophages and endothelial
cells resulting in hemophagocytosis, DIC, and multi-
organ failure [1,5,12]. NK cells, as well as EBV-specific
cytotoxic T cells (CTL), play a critical role in the elimi-
nation of EBV-infected cells [1]. This is supported by the
fact that the functional defects in cytotoxic activity of
CTL and NK cells such as X-linked lymphoproliferative
syndrome and FHL predispose for EBV-HLH [1]. In
acute IM the number of NK cells, although it usually
increases, is inversely correlated with the severity of the
disease [13]. Thus, the numerical defect of NK cells as
observed in our case could cause the development of
EBV-HLH or severe IM. Our case showed subsequent
recovery of both NK activity and the number of CD16+ ,
56+ or 57+cells as well as decline in CD8+HLA-DR+
cells, which was associated with clinical improvement.
Furthermore, no mutation was detected in causative
genes of XLP such as SH2DA or XIAP gene. Thus, al-
though mutations of other FHL-related genes have not
been tested, the numerical and functional abnormality
was unlikely to be intrinsic to his NK cells. Of note was
the finding that high lev els of EBV-DNA was detected in
CD16+ and 56+ cells, in addition to T and B cells, despite
the decreased number of the subsets in our case. Al-
though other methods such as in situ hybridization and
immunohistochemistry were not performed, a high level
of infection in CD 16+ and 56+ cells was confirmed by
serial examination for several months. The copy number
of EBV-DNA in PBMC of our case was comparable to
that in previously reported cases of EBV-HLH, CAEBV
and post-transplantational lymphoproliferative disorder
[14]. Although EBV-HLH has a tendency to have larger
viral burdens than acute phase of IM, it is difficult to
differentiate between these two diseases simply by viral
load in whole PBMC [15]. The copy number of EBV-
DNA gradually declined in all of the subsets and was
finally detectable in B cells only at a latency level one
year after the onset of the disease. These findings are in
contrast to NK cell-type CAEBV or NK cell lymphoma
which shows a clonal expansion of EBV-infected NK
cells [5]. It is known that EBV is able to infect NK cells
at an early stage of IM, although the precise mechanisms
of infection remain unclear [16]. As well, EBV genome
is also detected in bo th NK and B cells under some con-
ditions such as EBV-HLH but usually at a lower level
than CD8+ T cells [6]. Isobe et al have reported that in
vitro infection of EBV induces apoptosis of NK cells
[17]. Thus, it is possible that the infection by EBV in-
duced apoptosis of NK cells in vivo and allowed un-
regulated activation of EBV-infected CD8+T cells. De-
creased number of peripheral B cells in association with
HLH as observed in our case has also been reported [18].
Imashuku et al have demonstrated depletion of B cells in
the spleen of the patients with HLH and suggested in-
volvement of cytokines produced by activated T or NK
cells and/or Fas-FasL-mediated apoptosis [18].
Although our case showed both clinical and labora-
tory improvement before the commencement of HD-
IVIG therapy suggesting self-limiting nature, it is possi-
ble that the therapy accelerated the improvement by its
anti-inflammatory mechanism [19]. Further studies are
required to clarify the mechanisms of the decrease in the
number of peripheral NK cells in EBV-HLH without un-
derlying primary immunodeficiencies or FHL.
In conclusion, EBV infected various subsets of PBMC
including NK cells in a case of HLH associated with a
primary infection of EBV. EBV genome gradually de-
clined in association with his clinical improvement and
was finally detectable in only B cells at a latency level.
Transient decrease in NK cells could be involved in the
development of EBV-HLH in our case.
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