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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2793-2799
Elevation of the Serum Fas Ligand in Patients With Hemophagocytic
Syndrome and Diamond-Blackfan Anemia
By
Daiichiro Hasegawa,
Seiji Kojima,
Eiji Tatsumi,
Akira Hayakawa,
Yoshiyuki Kosaka,
Hajime Nakamura,
Masahiro Sako,
Yuko Osugi,
Shigekazu Nagata, and
Kimihiko Sano
From the Departments of Pediatrics and of Tumor Genetics, Kobe
University School of Medicine, Kobe, Japan; the Division of Hematology
and Oncology, Children's Medical Center, Japanese Red Cross Nagoya
First Hospital, Nagoya, Japan; the Department of Pediatrics, Osaka City
General Hospital, Osaka, Japan; the Department of Pediatrics, Osaka
University Hospital, Osaka, Japan; and the Department of Genetics,
Osaka University Medical School, Osaka, Japan.
 |
ABSTRACT |
Fas ligand (FasL) is a membrane protein that is expressed in
activated T cells and natural killer cells. FasL binds to Fas on target
cells and induces apoptosis. There exists a soluble form of FasL
(sFasL), and sFasL also induces apoptosis of Fas-bearing cells. The
serum sFasL concentrations were reported to be elevated in patients
with large granular lymphocytic leukemia and natural killer cell
lymphoma. In this study, we have measured serum sFasL concentrations in
other hematological disorders, including severe aplastic anemia (SAA),
hemophagocytic lymphohistiocytosis (HLH), and Diamond-Blackfan anemia
(DBA). The serum sFasL concentration of age-matched healthy controls
was 0.16 ± 0.11 ng/mL (mean ± SD, n = 22). The serum sFasL levels
in the patients with HLH and DBA were 3.75 ± 3.82 (n = 19;
P < .0001, HLH v control) and 2.76 ± 2.43 ng/mL (n
= 6; P = .012, DBA v control), respectively. Serum interferon- concentration was elevated in the patients with HLH (1.61 ± 2.62 ng/mL) but not in those with DBA (below the detectable level). These results suggest that the Fas-FasL system plays a role, at
least in part, in the pathophysiology of HLH and DBA.
| |
INTRODUCTION |
Fas (ALSO KNOWN AS APO-1 or CD95) is a
member of the tumor necrosis factor (TNF) receptor/nerve growth factor
receptor family and transduces an apoptotic signal by activating a
cascade of interleukin-1 -converting enzyme (ICE)-like cysteine
proteases (caspases).1 Fas is constitutively expressed in a
variety of tissues, including thymus, liver, heart, and kidney. Fas is
barely detectable in bone marrow CD34+ cells isolated from
healthy volunteers. Treatment of these cells with interferon-
(IFN-) or TNF- increases the expression of Fas and these cells
become susceptible to anti-Fas antibody-induced apoptosis.2,3 The ligand for Fas (FasL) is a type II
membrane protein that is expressed in the cells having cytotoxic
activity, including activated T cells and natural killer (NK) cells,
and in the cells in immune-privileged sites such as the testes, the brain, and the anterior chamber of the eye.4,5 Mice
carrying an abnormality in either the Fas (lpr) or FasL
(gld) gene show marked lymphoadenopathy and autoimmune
disease.6,7 Moreover, an abnormality of the Fas gene was
shown in human children suffering from autoimmune lymphoproliferative
syndrome.8,9 These results indicate that the Fas/FasL
system plays an important role in the clonal selection of T cells. The
role of the Fas/FasL system has also been implicated in cell-mediated
cytotoxicity during virus infections, autoimmune diseases, and tumor
immunity.1 It has been recently reported that the Fas/FasL
system is involved in the pathogenesis of Hashimoto's thyroiditis and
hepatitis.10,11
Cleavage of membrane-bound FasL by a metalloproteinase-like enzyme
results in the formation of soluble FasL (sFasL).12 sFasL binds to Fas antigen and transduces an apoptotic signal in Fas-bearing cells.13,14 Therefore, cytotoxic cells can kill the target cells either via direct contact or by secreting sFasL. Tanaka et
al12 reported that serum sFasL concentrations are elevated in the patients with large granular lymphocytic (LGL) leukemia and NK
lymphoma. They suggested that neutropenia and liver dysfunction, both
of which are common complications of these diseases, can be attributed
to the elevated levels of sFasL.
In this study, we have measured serum sFasL concentrations in the
patients with hematological disorders in which immunological mechanisms
are suspected to play a role in the pathophysiology, including severe
aplastic anemia (SAA), hemophagocytic lymphohistiocytosis (HLH), and
Diamond-Blackfan anemia (DBA), to clarify the role of the Fas/FasL
system in these disorders.
| |
MATERIALS AND METHODS |
Patients.
Eleven patients with SAA, 6 patients with DBA, 19 patients with HLH,
and 5 patients with infectious mononucleosis (IM) were studied. The
diagnosis of HLH was based on clinical findings (fever and
hepatosplenomegaly), laboratory findings (cytopenia affecting at least
2 lineages in the peripheral blood, hypertriglyceridemia, and/or hypofibrinogenemia), and histopathologic findings
(hemophagocytosis in the bone marrow, spleen, or lymph nodes without
evidence of malignancy).15 The diagnosis of familial
hemophagocytic lymphoproliferative syndrome (FHL) was made with a
positive family history. SAA was defined as pancytopenia with at least
two of the following abnormalities: an absolute neutrophil count of
less than 500/µL, a platelet count of less than
20,000/µL, and a reticulocyte count of less than 60,000/µL, in
association with a bone marrow cellularity of less than 30%. Patients
were diagnosed as having posthepatitis aplastic anemia when they
developed the disease within 3 months after documented hepatitis.16 The diagnosis of DBA was based on the
following criteria: (1) normochromic anemia in early infancy, (2)
reticulocytopenia, (3) normocellular bone marrow with selective
deficiency of red blood cell precursors, (4) normal or slightly
decreased leukocyte counts, and (5) normal or often increased platelet
counts.17
Serological diagnosis of primary Epstein-Barr virus (EBV) infection was
made by the detection of either an increase in EBV viral capsid antigen
(VCA)-specific IgG antibody in the absence of antibody against EBV
nuclear antigen or an increase in VCA-specific IgM antibody titers.
Detection of the EBV genome in the patients' peripheral blood was
performed with the polymerase chain reaction as described by Saito et
al.18
Enzyme-linked immunosorbent assay (ELISA) for sFasL and IFN-.
The serum sFasL levels of age-matched healthy controls and patients
with hematological disorders were measured with ELISA essentially as
described by Tanaka et al12 using monoclonal anti-FasL
antibodies and recombinant human FasL. The limit of detection was 5 pg/mL. The serum IFN- level was determined with a commercially
available kit obtained from Diaclone Research (Besançon, France).
The limit of detection was 5 pg/mL.
Statistical analysis.
The differences in the sFasL levels among controls and SAA, HLH, DBA,
and IM patients were analyzed with Mann-Whitney's U-test using the
computer program DAStat (developed by O. Nagata), whereas that in the
sFasL levels between the active phase and remission phase of HLH
patients were analyzed with Students' t-test. The values below
detectable level in the sFasL level were treated as 5 pg/mL in the
statistical analysis. The differences in the IFN- level among
controls and HLH, DBA, IM, and AA patients were also analyzed with
Mann-Whitney's U-test. The values below detectable level in the
IFN- level were treated as 5 pg/mL in the statistical analysis. The
difference was considered to be significant when the P value
was less than .05.
Flow cytometric analysis.
Quantitative analysis of fluorescence was performed using a Coulter
Epics Flow Cytometry System (Coulter, Hialeah, FL).
Phycoerythrin (PE)-conjugated mouse anti-Fas monoclonal antibody (clone
UB2; MBL, Nagoya, Japan) and fluorescein isothiocyanate
(FITC)-conjugated mouse anti-glycophorin A (GPA) monoclonal antibody
(clone D2.10; MBL) were used to determine the Fas expression on bone
marrow erythroid lineage cells. Appropriate isotypic controls were used in all of the experiments.
| |
RESULTS |
We have measured serum sFasL concentrations in a total of 41 patients
with hematological disorders, including 11 SAA, 19 HLH, 6 DBA, and 5 IM
patients and 22 age-matched healthy controls. The values in each group
were plotted and shown in Fig 1. The serum
samples from SAA, HLH, DBA, and IM patients were taken upon diagnosis
and kept at  80°C until analysis. The serum sFasL
concentration in healthy controls was 0.16 ± 0.11 ng/mL (mean ± SD; range, <0.005 to 0.37 ng/mL). We tentatively set the upper normal
limit of serum sFasL at 0.5 ng/mL. IM patients showed a moderate
increase in their serum sFasL levels (1.39 ± 0.56 ng/mL; mean ± SD). These IM patients showed mild liver dysfunction with a moderate
increase in serum aminotransferases and leukocytosis with atypical
lymphocytes. None of the IM patients analyzed showed anemia or
thrombocytopenia.
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| Fig 1.
The serum sFasL concentrations in patients with
hematologic disorders. Sera from patients and age-matched healthy
controls were assayed by ELISA for sFasL as described
before.12 The mean values are shown by horizontal bars.
( ) Familial cases of HLH (FHL). Statistical analysis was performed
as described in the Materials and Methods and the P value is
presented.
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The serum sFasL concentration exceeded 0.5 ng/mL in 15 of 19 HLH
patients. The mean ± SD value was 3.75 ± 3.82 ng/mL (range, <0.005 to 12.25 ng/mL), and this was significantly higher than the
controls (P < .0001). The clinical profiles of the HLH
patients are shown in Table 1. Three
patients underwent bone marrow transplantation and 2 patients died. The
other patients were treated with steroids with or without other
immunosuppressive and cytotoxic agents, including cyclosporin A, FK506,
OKT3, and etoposide; 4 of these patients died from the disease.
The serum sFasL levels exceeded 0.5 ng/mL in 5 of the 6 DBA patients.
Three patients were steroid-dependent and the others were
transfusion-dependent. The serum sFasL concentration was 2.75 ± 2.42 ng/mL (mean ± SD; range, 0.23 to 6.78 ng/mL). There was a
significant difference between the controls and DBA patients (P = .0012).
We have measured the serum sFasL concentrations in 11 SAA patients,
including 3 with posthepatitis SAA. Although the involvement of
CTL has been implicated in SAA,19 none of the
patients analyzed exceeded 0.5 ng/mL. The mean ± SD was 0.15 ± 0.14 ng/mL. There was no significant difference between the controls
and SAA patients (P = .41).
Administration of agonistic anti-Fas antibodies to mice causes liver
damages in vivo.20 The same antibodies decrease
hematopoietic colony formation2,3 and induce apoptosis in a
variety of cell types, including hepatocytes and leukemic cells in
vitro. Therefore, it is conceivable that a high level of sFasL produced by circulating and/or tissue-infiltrating cytotoxic cells
causes cell damage in patients with HLH or DBA. However, DBA patients do not show liver dysfunction and pancytopenia, both of which are
commonly observed in HLH. Therefore, the elevation of serum sFasL per
se may not be enough to cause cell damage in the liver and bone marrow.
It is known that IFN- upregulates the Fas expression and makes
target cells susceptible to Fas-mediated apoptosis in a variety of cell
types.21,22 High serum levels of IFN- are reported to be
a common feature in HLH patients.23 We then measured the
serum IFN- concentrations in our HLH and DBA patients. As shown in
Fig 2, most of the HLH patients showed high
serum IFN- levels (mean ± SD; 1.61 ± 2.62 ng/mL), whereas
those in all of the DBA patients were below the detectable level. IM
patients showed a moderate increase in their serum IFN-
concentrations. These results raise the possibility that IFN-
upregulates Fas in the target cells in HLH and makes them susceptible
to FasL-mediated cell death.
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| Fig 2.
The serum IFN- concentrations in patients with
hematologic disorders. The mean values are shown by horizontal bars.
() FHL cases. Statistical analysis was performed as described in the Materials and Methods and the P value is presented.
|
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A typical example of the changes in the serum sFasL and IFN- levels
and the clinical course of one HLH patient is shown in Fig 3. The peak of serum sFasL and IFN-
levels paralleled with the degree of leukocytopenia and preceded the
peak of the serum lactate dehydrogenase (LDH) level in this patient.
These values decreased after chemotherapy with steroids and etoposide.
This patient underwent syngeneic bone marrow transplantation using an
identical twin sister as the donor. She is alive and has been well for
9 months after the bone marrow transplantation. We have compared the
serum sFasL levels during the acute phase and remission state in 9 HLH
patients who showed elevated serum sFasL levels during the acute phase.
As shown Fig 4, the serum sFasL level decreased with remission in all of the patients analyzed.
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| Fig 3.
The clinical course and serum sFasL and IFN-
concentrations in an HLH patient. -glb, -globulin; PSL,
prednisolone; mPSL, methylprednisolone; CyA, cyclosporine A. ( ) WBC;
() LDH; ( ) sFasL; ( ) IFN-.
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| Fig 4.
The serum sFasL concentrations during active phase and
remission state in 9 HLH patients. () FHL cases.
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The serum sFasL level was high in most of the DBA patients (Fig 1).
Given that cytotoxic cells are involved in the DBA, these cells might
recognize some foreign or self antigen on the cell surface of erythroid
progenitors and cause apoptosis via the Fas/FasL and/or
perforin/granzyme pathways. We have examined the bone marrow cells
obtained from 2 DBA patients and 4 healthy volunteers for the
expression of the Fas antigen on the erythroid lineage
(GPA+) cells. Representative results of the flow cytometry
analysis are shown in Fig 5. In the bone
marrow cells obtained from the DBA patients, 63% and 79% of
GPA+ cells were Fas+ (Fig 5A). The expression
of Fas antigen on erythroid lineage cells is not restricted to DBA
patients. In bone marrow cells obtained from healthy volunteers, 87%,
46%, 54%, and 65% of GPA+ cells were Fas+
(Fig 5B).
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| Fig 5.
Expression of the Fas antigen in erythroid lineage cells
in bone marrow. Bone marrow cells obtained from a DBA patient (A) and a
healthy volunteer (B) were stained with the FITC-conjugated anti-GPA
and PE-conjugated anti-Fas antibodies. The panel shows the fluorescence
intensity of GPA (x-axis) and Fas (y-axis).
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| |
DISCUSSION |
FasL is a 40-kD glycoprotein that is expressed on the cell membrane of
cytotoxic cells, including CD4+ and CD8+ T
cells and NK cells.4 FasL is cleaved by a
metalloproteinase-like enzyme to release a 26-kD glycoprotein,
sFasL.12 Therefore, serum sFasL levels can be a marker for
activation of cytotoxic cells in a variety of human diseases. A
moderate increase in serum sFasL was observed in IM patients (Fig 1).
These results might reflect the facts that CD8+ T cells are
activated in IM and that these cells play a major role in host defense
against EBV.24
HLH is a term applied to a life-threatening disease characterized by a
generalized histiocytic proliferation with marked
hemophagocytosis.25 HLH occurs in several disorders,
including an autosomal recessive inherited disease called FHL and
virus- or infection-associated hemophagocytic syndrome (VAHS or IAHS).
The distinction between FHL and VAHS/IAHS is not always easy without a
positive family history, because some FHL cases seem to be triggered by
an infection of viral nature. Therefore, the Histiocyte Society has
proposed to call these disorders HLH.15 The patients have
intermittent fever, lymph node enlargement, and
hepatosplenomegaly.26 The most common virus implicated in
this syndrome is EBV. IM is a benign, self-limiting disease associated
with a primary EBV infection. Most of the IM patients show
lymphocytosis with atypical lymphocytes, liver enzyme abnormalities,
neutropenia, and mild thrombocytopenia. In rare cases, patients develop
severe or fatal IM with clinical characteristics that resemble those of
HLH. Laboratory studies of HLH patients demonstrate severe cytopenia
and abnormal liver function tests with elevated levels of serum
transaminases and LDH. Most of the patients show elevated serum levels
of soluble interleukin-2 (IL-2) receptor and cytokines, including
IFN- and TNF-, suggesting that the pathogenesis of this syndrome
is attributable to cytotoxic damage mediated by abnormally activated T
and/or NK cells.23 However, the precise mechanism
causing this syndrome is not known. The serum sFasL concentration is
elevated in most of the HLH patients and its level is closely related
to the disease status (Figs 1, 3, and 4). These results indicate that
cytotoxic cells are activated in HLH. It is well established that sFasL or agonistic anti-Fas antibody causes apoptosis of Fas-bearing cells,
including hepatocytes, both in vivo and in vitro.11,14,27 As little as 1 ng/mL of sFasL kills 90% of a mouse T-cell line expressing Fas in 15 hours and 3.2 ng/mL of sFasL kills 40% of a mouse
fibroblast cell line expressing Fas in 7 hours.13 The mean
serum sFasL concentration in HLH patients was 3.75 ng/mL (Fig 1), and 2 patients exceeded 10 ng/mL. These values were high enough to cause cell
damage to these cells in vitro. Hepatocytes naturally express Fas and
can be a target for FasL-triggered cell death. However, Fas surface
expression does not necessarily render cells susceptible to Fas
ligand-induced cell death.1 Tanaka et al14
showed that injection of recombinant sFasL alone does not kill the
mice. Simultaneous administration of killed bacteria, Propionibacterium acnes, renders them susceptible to sFasL, and the treated mice die of hepatic failure within 24 hours after intravenous injection of 30 µg of sFasL. Because the administration of killed P acnes stimulates the production of a variety of
cytokines, including IFN-, TNF, and IL-1, it is conceivable that
these cytokines make the animals sensitive to sFasL. Tamura et
al28 reported that IFN- upregulates the ICE gene in the
U937 monocytic cell line. Because both IFN- and sFasL are elevated
in HLH patients (Figs 1 and 2), these cytokines may act together to
cause hepatic damage in these patients.
IFN- is a potent inhibitor of myeloid colony formation in
vitro.29 On the other hand, IFN- has been used to treat
chronic granulomatous disease patients without serious side
effects.30 Transgenic mice expressing high levels of
IFN- in their bone marrow did not show decreased hematopoiesis
despite the decreased number of hematopoietic progenitor
cells.31 Therefore, IFN- alone may not cause
myelosuppression in animals. It has been reported that IFN- induces
Fas receptor expression on CD34+ human bone marrow cells
and agonistic anti-Fas antibody enhances IFN--mediated suppression
of hematopoietic colony formation.2,3 Neutrophils are
highly susceptible to agonistic anti-Fas antibody-mediated apoptosis.32 Therefore, it is possible that sFasL is
involved in the cytopenia observed at least in some of the HLH
patients. However, whether sFasL and IFN- suppress hematopoiesis in
vivo should be studied further.
Immunosuppressive therapy consisting of antilymphocyte globulin and
cyclosporin A is effective in the majority of patients with
SAA,33 suggesting that T-cell-mediated cytotoxicity is involved in the pathogenesis of SAA. The bone marrow cells obtained from the patients with SAA show markedly increased percentages of
Fas-expressing CD34+ cells, which correlated with their
increased sensitivity to anti-Fas antibody-mediated inhibition of
colony formation in culture.19 Aberrant IFN- gene
expression and elevated numbers of activated suppressor T cells are
present in the bone marrow of the SAA patients.34,35 These
results suggest that Fas-mediated cell death plays a role in the
pathogenesis of SAA. However, our results showed that serum sFasL is
not elevated in SAA patients, including primary and posthepatitis diseases (Fig 1). These results do not exclude the possibility that
FasL-expressing cytotoxic cells are present in the patients' bone
marrow and play a role in the pathogenesis of SAA. However, if
FasL-expressing cytotoxic cells actively cause the apoptosis of
CD34+ cells, Fas+-CD34+ cells might
not be able to survive in the bone marrow. The presence of
Fas+-CD34+ cells might reflect the high IFN-
levels in the patients' bone marrow and does not necessarily indicate
that Fas-mediated cell death occurs in SAA. Nakao et al36
established a CD4+-CTL clone from an SAA patient. The
cytolytic activity of this clone is EGTA-sensitive, indicating that
this clone uses perforin/granzyme pathway to kill the target
cells.37 The involvement of the Fas/FasL system in SAA
should be re-evaluated in future studies.
DBA is a severe congenital abnormality of erythropoiesis developing
early in childhood. The bone marrows of affected individuals have
markedly reduced or absent red blood cell precursors with normal marrow
cellularity and preservation of other hematopoietic cell lineages.
Although congenital genetic abnormalities have been suspected in this
disorder, the analysis of erythropoietin,17 erythropoietin
receptor,38 c-kit, and c-kit ligand39,40 genes has failed to detect any abnormalities in DBA patients. Some of DBA
patients respond to corticosteroids, suggesting that an immunological abnormality underlies this disease. However, no clear explanation has
been given for its defective erythropoiesis. We showed here that the
serum sFasL concentration is high in most of the DBA patients (Fig 1),
indicating that activation of cytotoxic cells occurs in DBA. The origin
of increased serum sFasL is not clear at present. Lymphocyte-mediated
inhibition of erythroid colony formation was implicated in some DBA
cases.41,42 Therefore, it might be possible that certain
subsets of lymphocytes overproduce sFasL in DBA patients. This should
be clarified in future study. We have clearly shown that erythroid
lineage (GPA+) cells in BM express Fas antigen (Fig 5).
Bouscary et al43 examined Fas expression on BM cells
obtained from normal subjects and myelodysplastic syndrome patients.
They reported that GPA+ cells did not express Fas antigen
to a detectable extent by their FACS analysis using FITC-labeled UB2
anti-Fas MoAb. The exact reason for the discrepancy between our results
(Fig 5) and theirs is not certain. However, it could be due to a
different labeling of the UB2 MoAb. We used PE-labeled UB2, which might
give brighter fluorescence than the FITC-labeled one. Based on our
findings shown in Fig 5, it is possible that erythroid lineage cells
are killed by cytotoxic cells via the Fas-mediated pathway in certain conditions. However, an analysis of large samples is required to
establish the role of the Fas/FasL system in DBA.
| |
FOOTNOTES |
Submitted August 12, 1997;
accepted December 7, 1997.
Supported in part by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports, and Culture (1996-1997), a
grant from The Ryoichi Naito Foundation for Medical Research (1996),
and a grant from The Shinryoku Foundation (1997).
Address reprint requests to Kimihiko Sano, MD, PhD, Department of
Pediatrics, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650, Japan.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Dr Osamu Mabuchi (Department of Hemato-Oncology,
Hyogo Prefecture Children's Hospital, Hyogo, Japan) and Dr Masuji
Yamamoto (Department of Pediatrics, Hyogo Medical College, Hyogo,
Japan) for providing us with the serum samples of DBA patients.
| |
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Abstract
Introduction
Abstract