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Blood, 15 April 2001, Vol. 97, No. 8, pp. 2526-2527
CORRESPONDENCE
To the editor:
Serum viral interleukin-6 in AIDS-related multicentric
Castleman disease
Viral interleukin-6 (vIL-6) encoded by Kaposi sarcoma
(KS)-associated herpesvirus (KSHV) has been detected in 3 acquired
immunodeficiency syndrome (AIDS)-related disorders: KS, primary
effusion lymphoma, and multicentric Castleman disease
(MCD).1,2 Similar to its human counterpart, vIL-6 supports
the growth and survival of certain mouse and human cell lines in
vitro.1,3 When expressed in mice, recombinant vIL-6
induced marked lymph-node plasmacytosis similar in morphology to the
plasmacytosis noted in the plasma-cell variant of human
MCD.4 MCD is a lymphoproliferative disorder featuring
systemic manifestations of inflammation and B-cell hyperreactivity. Virtually all HIV-positive cases of MCD and nearly 50% of HIV-negative cases are infected with KSHV, and all KSHV-positive MCD tissues were
found to express vIL-6.1 In contrast to localized
Castleman disease that typically remits after surgical removal of the
localized mass, the multicentric form, occurring in a small percentage
of patients, behaves more aggressively and is frequently
fatal.5 Immunohistochemical studies demonstrated abundant
human IL-6 (hIL-6) expression in the germinal centers of MCD lymph
nodes, and there is evidence for a pathogenetic role of hIL-6 in
MCD.1 KSHV vIL-6 is expressed by immunoblastic cells
present among the mantle zone of MCD.1 The expression of
vIL-6 in MCD lesions and the functional similarities of cellular and
vIL-6 raised the possibility that vIL-6 may also play a role in the
pathogenesis of MCD. But the role of vIL-6, if any, in MCD or other
KSHV-associated disorders has not been fully examined. As a step
toward further understanding a potential pathogenetic role of
vIL-6, we measured circulating vIL-6 levels in an HIV-positive patient
at the onset of MCD. A 40-year-old HIV-positive homosexual man presented with a sore
throat, nonproductive cough, night sweats, fever, diarrhea, marked
fatigue, and weight loss in June 1999. The patient had received highly
active antiretroviral therapy (HAART) since July 1996, including lamivudine (3TC; 150 mg × 2/d), stavudine (d4T; 40 mg
× 2/d), and nelfinavir (NFV; 2250 mg × 1/d). HIV-RNA load had been
stable at less than 1200 copies/mL since 1996. CD4+ T-cell
counts had remained over 300 cells/mm3. On physical
examination, the patient had lymphadenopathy, abdominal distention with
hepatosplenomegaly, abdominal tenderness, and skin rash, but no
evidence of KS. Oral administration of prednisone (30 mg/d) was
started, to relieve systemic symptoms. A cervical lymph-node biopsy
displayed the typical features of mixed plasma cell/hyaline vascular
type of MCD:5 concentric layers of small lymphocytes
surrounding the germinal centers and plasma cell infiltration in the
interfollicular areas (Figure 1A-B). KSHV
infection in the patient was confirmed by immunohistochemical detection
of KSHV-latency-associated nuclear antigen (KSHV-LANA) in a
lymph-node biopsy specimen (Figure 1C). A vIL-6-specific monoclonal
antibody6 detected vIL-6 expression in the same specimen by
immunohistochemistry (Figure 1D). The KSHV-LANA-positive and
vIL-6-positive cells, similar in frequency, localized predominantly to
the mantle zone of the lymph node. By contrast, expression of hIL-6,
which has previously been detected in the germinal centers of certain
MCD cases, was not detectable by immunohistochemistry in this lymph node (data not shown). Due to a dramatic improvement of systemic symptoms, prednisone was tapered after 10 days, and administration of
the antiherpesvirus agent foscarnet (7g × 2/day) started, followed by
splenectomy in September 1999. Fifteen months later, the patient continued to be well, in remission, on occasional maintenance chemotherapy.
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| Figure 1.
Microscopic morphology of representative lymph node
sections and immunohistochemical detection of KSHV infection.
(A) Small hyalinized germinal center surrounded by concentric layers of
small lymphocytes (hematoxylin and eosin stain; × 100). (B)
Interfollicular sheets of plasma cells are shown (hematoxylin and eosin
stain; × 1000). (C) KSHV-LANA antigen detection in the lymph node
mantle zone visualized by immunohistochemical staining with monoclonal
antibody (× 200). The inset shows the characteristic speckled nuclear
pattern (× 1000). (D) vIL-6 detection in immunoblastic cells in the
lymph node mantle zone (× 100). The insets show specific cytoplasmic
staining (× 1000).
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Serum vIL-6 was initially detected at 4756 pg/mL (Figure
2). But vIL-6 decreased to undetectable
(less than 300 pg/mL) levels over the next 10 days and subsequently
remained undetectable. By contrast, serum levels of hIL-6 fluctuated at
low levels (range, < 1.0-10.8 pg/mL) throughout this period. The
HIV-RNA load presented marked changes during this period. For
approximately 3 years prior to the onset of MCD, the HIV-RNA load in
this patient had remained at less than 1200 copies/mL. After MCD was
diagnosed, the HIV-RNA load peaked at 146 460 copies/mL, followed by a
rapid decrease to 792 copies/mL on day 21 of treatment (Figure 2). Of
note, the patient continued to receive the same antiretroviral drug
regimen he had received during the previous 3 years. Thus vIL-6 and
HIV-RNA serum levels displayed parallel decreases over a 20-day period of observation following initiation of steroid treatment for MCD (Rho = .9: P = .005, Spearman test).
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| Figure 2.
Detection of vIL-6, hIL-6, and HIV RNA in serial serum
samples from an HIV-positive patient with MCD.
On day 1, prednisone treatment was initiated. vIL-6 levels were
measured by a vIL-6-specific enzyme-linked immunosorbent assay (ELISA)
established in our laboratory.6 hIL-6 was measured by a
commercially available ELISA kit (R&D Systems, Minneapolis, MN) that
does not detect vIL-6.6 The lower limit of ELISAs
sensitivity in serum was calculated to be 300 pg/mL of vIL-6 and 1.0 pg/mL of hIL-6. HIV-RNA load was measured by Amplicor HIV-1 reverse
transcriptase-polymerase chain reaction test (Roche Diagnostic
Systems, Basel, Switzerland), kindly performed by Dr Timothy Alcorn,
Laboratory Corporation of America. 3TC indicates lamivudine; d4T,
stavudine; and NFV, nelfinavir.
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The widespread use of HAART has led to a substantial decrease in the
incidence of KS,7 perhaps due to KS cell growth
stimulation by certain HIV-derived proteins,8 but the
impact of HAART on AIDS-related B-cell disorders is
unclear.7 In this patient, it is unlikely that either the
increase or the decrease in HIV-RNA load is attributable to HAART
because the antiretroviral regimen had not changed. Rather, it is more
likely that factors derived from or induced by MCD lesions, including
vIL-6, may have activated HIV replication in this patient. Although the
pathogenesis of MCD is likely complex, the remarkable association
between circulating vIL-6 levels and MCD status shown here, combined
with previous information on the biologic activities of this virokine,
further support a role of vIL-6 in the pathogenesis of AIDS-MCD.
Yoshiyasu Aoki and Giovanna Tosato
Medicine Branch National Cancer Institute National
Institutes of Health Bethesda, MD
Terry W. Fonville
Department of Medicine St Vincent's Hospital and Medical
Center New York, NY
Stefania Pittaluga
Hematopathology Section National Cancer Institute
National Institutes of Health Bethesda, MD
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