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Increased interleukin-18 expression in bone marrow of a patient with systemic juvenile idiopathic arthritis and unrecognized macrophage-activation syndrome.

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ARTHRITIS & RHEUMATISM
Vol. 50, No. 6, June 2004, pp 1935–1938
DOI 10.1002/art.20268
© 2004, American College of Rheumatology
Increased Interleukin-18 Expression in Bone Marrow of a
Patient With Systemic Juvenile Idiopathic Arthritis and
Unrecognized Macrophage-Activation Syndrome
Nobuaki Maeno, Syuji Takei, Hiroyuki Imanaka, Kimie Yamamoto, Kazumi Kuriwaki,
Yoshifumi Kawano, and Hiroshi Oda
crucial. Previous studies have demonstrated that the
aberrant induction of proinflammatory cytokines such as
interleukin-6 (IL-6), IL-1␤, and tumor necrosis factor ␣
(TNF␣) may be involved in the pathogenesis of systemic
JIA (1). However, it has not yet been elucidated which
mediators are the key ones, nor has the origin of
increased cytokines in systemic JIA been determined.
Recently, we and other researchers reported
highly elevated serum levels of IL-18 (⬎10,000 pg/ml) in
patients with systemic JIA or adult-onset Still’s disease
(AOSD), which is pathogenetically identical to systemic
JIA (2–4). IL-18 strongly stimulates T lymphocytes,
natural killer (NK) cells, and macrophages to produce
proinflammatory cytokines (5,6) and is therefore
thought to be closely related to the pathogenesis of
systemic JIA and AOSD. The cellular source of increased IL-18 synthesis in systemic JIA is unclear,
although circulating or tissue monocyte/macrophages
seem the most likely candidates in AOSD (3). In the
present study, we investigated the source of increased
IL-18 synthesis in a patient with systemic JIA.
The aberrant induction of proinflammatory cytokines is considered to be crucial in the pathogenesis of
systemic juvenile idiopathic arthritis and adult-onset
Still’s disease. Interleukin-18 (IL-18) in particular has
been reported to be a candidate for the key cytokine in
both diseases; however, the origin of IL-18 is unclear. To
clarify the origin, we investigated specimens from various organs obtained during autopsy of a child with
systemic JIA and macrophage activation syndrome,
using immunohistochemical staining. Our results
showed a high number of cells expressing IL-18 in the
bone marrow but not in the other organs. This finding
suggests that bone marrow is the origin of increased
serum IL-18 and raises the possibility that other proinflammatory cytokines are also induced by IL-18 in bone
marrow in this disease. Bone marrow may be an essential organ in the pathogenesis of systemic JIA.
Systemic juvenile idiopathic arthritis (JIA), also
known as Still’s disease, is one of the most common
systemic and chronic inflammatory diseases in childhood
and is characterized by chronic arthritis associated with
a high spiking fever, a salmon-pink evanescent rash,
hepatosplenomegaly, lymphadenopathy, and serositis.
The precise etiology of systemic JIA remains unclear,
although the activation of macrophages is thought to be
CASE REPORT
The patient, a 20-month-old girl, was admitted to
the county hospital because of a 2-week history of high
spiking fever, rash, and tender arthritis of the extremities. Evaluation for bacterial and viral infections, including cytomegalovirus and Epstein-Barr virus, yielded
negative results, and a bone marrow aspirate obtained at
that time showed normal myelographic results. The
patient was treated with intravenous antibiotics and
aspirin for 1 week. However, her condition did not
improve, and she was transferred to our hospital. Upon
admission to our hospital, laboratory tests gave the
following results: white blood cell (WBC) count 15,500/
␮l, hemoglobin concentration 10.0 gm/dl, platelet count
Supported in part by grant-in-aid 13670278 from the Ministry
of Education, Culture, Sports, Science, and Technology of Japan.
Nobuaki Maeno, MD, Syuji Takei, MD, Hiroyuki Imanaka,
MD, Kimie Yamamoto, MD, Kazumi Kuriwaki, MD, Yoshifumi
Kawano, MD, Hiroshi Oda, MD: Kagoshima University Graduate
School of Medical and Dental Sciences, Kagoshima, Japan.
Address correspondence and reprint requests to Nobuaki
Maeno, MD, Department of Infection and Immunity, Kagoshima
University Graduate School of Medical and Dental Sciences, 8-35-1
Sakuragaoka, Kagoshima 890-8520, Japan. E-mail: maeno@m3.
kufm.kagoshima-u.ac.jp.
Submitted for publication June 4, 2003; accepted in revised
form February 4, 2004.
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408,000/␮l, serum glutamic oxaloacetic transaminase
(SGOT) level 57 units/liter (normal ⬍40), serum glutamic pyruvic transaminase (SGPT) level 37 units/liter
(normal ⬍35), lactate dehydrogenase (LDH) concentration 995 units/liter (normal ⬍400), erythrocyte sedimentation rate 108 mm/hour, and serum C-reactive protein
level 20.4 mg/dl (normal ⬍0.5). Systemic JIA was diagnosed, and the dosage of aspirin was increased to 40
mg/kg/day.
Despite this week-long therapy, the patient’s
condition continued to deteriorate, and liver dysfunction
and pancytopenia developed. A peripheral smear
showed no abnormalities. Aspirin was then discontinued, and a course of parenteral steroids was instituted.
However, 1 week later, her transaminase and LDH
levels had further increased (SGOT 526 units/liter,
SGPT 202 units/liter, and LDH 7,891 units/liter). In
addition, the pancytopenia and coagulation disturbance
had progressed (WBC count 2,900/␮l, hemoglobin concentration 7.9 gm/dl, platelet count 38,000/␮l, fibrinogen
level 109 mg/dl, and fibrinogen–fibrin degradation product 27.4 ␮g/ml [normal ⬍1.0 ␮g/ml]). The next day,
before cyclosporin A treatment was initiated, the patient
died of a pulmonary hemorrhage. At that time, her
serum levels of ferritin and proinflammatory cytokines
were extremely elevated, as follows: ferritin 12,178 ng/
ml, interferon-␥ (IFN␥) 4,900 pg/ml, TNF␣ 82.3 pg/ml,
IL-6 83.3 pg/ml, monocyte colony-stimulating factor
627 pg/ml, and IL-18 210,288 pg/ml (IL-18 enzymelinked immunoassay kit; MBL, Nagoya, Japan).
A postmortem examination, conducted with informed consent from the patient’s parents, revealed
hemophagocytosis in the bone marrow. These findings
indicated macrophage activation syndrome (MAS), one
of the most common and severe complications of systemic JIA (7). The pulmonary hemorrhage observed in
this patient might be attributable to the hemorrhagic
diathesis mediated by MAS; such a finding is reportedly
a characteristic of MAS (7).
In order to investigate the origin of the highly
increased level of IL-18, we used immunohistochemical
staining with a monoclonal antibody to IL-18 (clone
25-2G; MBL) or CD68 (clone KP1; Dako, Kyoto, Japan)
to examine specimens of the liver, spleen, axillary lymph
nodes, lung, and bone marrow obtained from this patient. Autopsy specimens from a 22-month-old boy who
had died of gastrointestinal bleeding were also studied
as a control after informed consent was obtained. The
bone marrow specimens from the patient with systemic
JIA, compared with those from the control subject
(Figure 1A), demonstrated prominent infiltrates of
MAENO ET AL
Figure 1. Immunohistochemical staining of bone marrow with antiCD68 monoclonal antibody or anti–interleukin-18 (anti–IL-18) monoclonal antibody. Bone marrow specimens from the control subject
were stained with anti-CD68 (A) and anti–IL-18 (B), as were the
specimens from the patient with systemic juvenile idiopathic arthritis
(C and D and E and F, respectively). The specimens from the
patient were also subject to control staining by replacing the primary
antibody with an isotype-matched control reagent (mouse IgG1) (G),
and by neutralizing (NT) the anti–IL-18 antibody with recombinant
IL-18 protein (H). Brown color indicates positivity. (Original magnification ⫻ 100 in A, B, C, E, G, and H; ⫻ 400 in D and F; ⫻ 1,000 in
insets.)
ELEVATED IL-18 IN A PATIENT WITH SYSTEMIC JIA
Figure 2. Immunohistochemical staining of liver specimens with antiCD68 monoclonal antibody or anti–interleukin-18 (anti–IL-18) monoclonal antibody. Liver specimens from the control subject were stained
with anti-CD68 (A) and anti–IL-18 (B), as were those from the patient
with systemic juvenile idiopathic arthritis (C and D). (Original magnification ⫻ 100.)
macrophages stained with CD68, and some macrophages showed hemophagocytosis (Figures 1C and D).
Furthermore, it is noteworthy that strong IL-18 staining
was observed in these bone marrow cells (Figures 1E
and F). In contrast, few cells expressing IL-18 were
observed in the bone marrow from a control subject
(Figure 1B). The infiltration of CD68-positive cells in
the patient’s liver was not so significant and was localized around the portal tract, while CD68-positive
Kupffer cells were widely seen in sinusoids in the control
subject (Figures 2A and C). IL-18 was expressed in the
liver cells of neither the patient with systemic JIA nor
the control subject (Figures 2B and D). In addition, no
cells with significant IL-18 staining were observed in the
spleen, lung, or lymph nodes of the patient with systemic
JIA (data not shown).
DISCUSSION
Our results suggest that highly elevated serum
IL-18 levels originate in bone marrow, raising the possibility that bone marrow contains abundant proinflammatory cytokines induced by IL-18 in this disease. This
1937
hypothesis may be supported by reports that several
kinds of viruses, such as varicella virus, measles virus, or
parvovirus B19, can induce bone marrow suppression
that may lead to transient clinical remission in children
with intractable systemic JIA (8,9). Furthermore,
Schnedl et al reported that diffuse bone marrow edema
was characteristically detected by magnetic resonance
imaging and biopsies in patients with AOSD, and that
this might be the result of increased permeability of the
capillary endothelium in the bone marrow mediated by
inflammatory cytokines (10). In addition, quantitative
and qualitative abnormalities in bone marrow cells were
demonstrated in patients with JIA, and these changes
were considered to be consequences of the inflammatory milieu, including cytokines (11). Likewise, the etiologic association between bone marrow cells and rheumatoid arthritis (RA) in adults has been discussed.
Remarkable elevations of IL-6, IL-8, and TNF␣ in bone
marrow were reported in patients with RA (12,13).
Another study demonstrated that nurse-like cells from
the bone marrow of patients with severe RA have
unique characteristics and may play an important role in
the pathogenesis of RA (14). The immunologic role of
bone marrow cells in the pathogenesis of systemic JIA
needs to be elucidated by further studies.
In this study, the significant expression of IL-18
was observed only in bone marrow and not in other
organs. We at first supposed that the liver, especially its
Kupffer cells, might be the source of the high elevation
of IL-18, because Kupffer cells have been shown to
produce IL-18 in a mouse model of endotoxin shock (5)
and in children with biliary atresia (15). In our patient,
however, immunohistochemical staining revealed few
infiltrated Kupffer cells and no expression of IL-18 in
the liver tissue. Therefore, the origin of IL-18 might
differ among diseases. Accordingly, the expression of
other cytokines, including IL-6, TNF␣, and IFN␥, in
liver and bone marrow should be also studied. We
cannot exclude the possibility that our findings are a
distinctive feature of MAS. However, considering that
highly elevated serum IL-18 levels were detected in
almost all patients with systemic JIA/AOSD regardless
of the presence of MAS (2–4), our results may be
commonly observed in patients with systemic JIA or
AOSD.
It was recently reported that depressed NK cell
functions might account for inadequate control of T cell
and macrophage activation in patients with systemic JIA
complicated by MAS (16), because NK cells and the
perforin-based systems are normally involved in the
down-regulation of cellular immune responses (17).
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MAENO ET AL
Considering that NK cells are strongly stimulated by
IL-18, the relationship between the highly elevated
IL-18 level and the NK cell dysfunction in patients with
systemic JIA is interesting and should be investigated. If
NK cells produce no negative feedback despite highly
elevated IL-18 levels, the sustained macrophage activation will result in further production of high levels of
proinflammatory cytokines. In addition, autologous
stem cell transplantation for severe systemic JIA was
recently shown to restore the reduced perforin expression in CD8 T cells and NK cells (18) and to induce a
significant and drug-free remission of the disease
(19,20). Bone marrow ablation and subsequent reconstitution may remove the activated cells and then allow
regrowth of the normal cell population. Therefore,
strategies that target activated bone marrow cells, including anti–IL-18 therapy, may lead to a more satisfactory treatment for systemic JIA.
In conclusion, we demonstrated that bone marrow was the probable source of highly elevated IL-18
levels in a patient with systemic JIA. Further investigations are needed to determine the role of “bone marrow
IL-18” in the pathogenesis of systemic JIA or AOSD.
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expressions, patients, syndrome, systemic, activation, bones, idiopathic, increase, marrow, macrophage, arthritis, unrecognized, interleukin, juvenile
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