Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4391-4393
CORRESPONDENCE
Multiple Myeloma and HHV8 Infection
 |
LETTER |
To the Editor:
In a recent issue of BLOOD Said et al1 reported the
presence of human herpesvirus 8 (HHV8) DNA in bone marrow stromal
dendritic cells of patients with multiple myeloma and acquired
immunodeficiency syndrome patients with plasmocytosis. Using polymerase
chain reaction (PCR) and in situ hybridization, the authors corroborate
their previous report indicating the presence of HHV8 in stromal cell cultures of patients with multiple myeloma and monoclonal gammopathy of
unknown significance (MGUS).2
We recently conducted a similar study analyzing bone marrow biopsies of
patients with multiple myeloma using a highly sensitive nested PCR
assay with oligonucleotide primers derived from the open
reading frame 26.3 HHV8 DNA was detected in only 1 (5.9%) of 17 biopsies tested, although the presence of appropriate DNA was
confirmed by amplifying the human 
-globin control gene in all
samples (Table 1). We further analyzed sera
of patients with multiple myeloma and MGUS using an enzyme-linked
immunosorbent assay (ELISA) based on the recombinant HHV8 protein 65.2 (kindly provided by T.F. Schulz, Liverpool).4 Anti-HHV8
antibodies were present in 15 (88.2%) of 17 of patients with Kaposi's
sarcoma but was absent in 19 sera of patients with multiple myeloma and detected in only 1 (5.6%) of 18 patients with MGUS (Table 1).
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Table 1.
Presence of HHV8 in Patients With Multiple Myeloma and
MGUS Analyzed by PCR in Bone Marrow Biopsies and by Serology
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Our results are in contrast to the data reported by Said et al. We have
previously shown that the PCR assay used in this study can detect
HHV8 DNA in all samples of formalin-fixed, paraffin-embedded Kaposi's
sarcoma tissue.3 However, in our myeloma samples, a
sampling error cannot be completely excluded because the presence of
HHV8 has been reported to be restricted to the stromal cells but absent
in tumor cells.2 The absence of antibodies to HHV8 in all
patients with multiple myeloma and in most patients with MGUS is,
however, surprising. Indeed, a "serological footprint" of a
previous HHV8 infection was found in 80% to 90% of patients with
Kaposi's sarcoma and a similar "footprint" would be expected in
multiple myeloma patients. Others have also reported a lack of
anti-HHV8 antibodies in a significant proportion of patients with
multiple myeloma.5,6 Epidemiological differences may result
in these discrepancies. However, because only a single HHV8 antigen has
been used in our ELISA, one can speculate that a different mode of
infection and pathogenesis may be involved in the development of
Kaposi's sarcoma and multiple myeloma, associated with a distinct
immune response. Further data are urgently needed to define the role of
HHV8 infection in patients with multiple myeloma and
MGUS.
Gieri Cathomas
Aline Stalder
Michael O. Kurrer
Department of Pathology
University Hospital
Zürich
Zürich, Switzerland
Nicolas Regamey
Peter Erb
Institute for Medical
Microbiology
University of Basel
Basel, Switzerland
Helen
I. Joller-Jemelka
Department of Clinical Immunology
University
Hospital Zürich
Zürich, Switzerland
| |
REFERENCES |
1.
Said JW,
Rettig MR,
Heppner K,
Vescio RA,
Schiller G,
Ma HJ,
Belson D,
Savage A,
Shintaku IP,
Koeffler HP,
Asou H,
Pinkus G,
Pinkus J,
Schrag M,
Green E,
Berenson JR:
Localization of Kaposi's sarcoma-associated herpesvirus in bone marrow biopsy samples from patients with multiple myeloma.
Blood
90:4278,
1997[Abstract/Free Full Text]
2.
Retting MB,
Ma HJ,
Vesico RA,
Pold M,
Schiller G,
Belson D,
Savage A,
Nishikubo C,
Wu C,
Fraser J,
Said JW,
Berenson JR:
Kaposi's sarcoma-associated herpesviurs infection in bone marrow dendritic cells from multiple myeloma patients.
Science
276:1851,
1997[Abstract/Free Full Text]
3.
Cathomas G,
McGandy CE,
Terracciano LM,
Itin PH,
DeRosa G,
Gudat F:
Detection of herpesvirus-like DNA by nested polymerase chain reaction in archival skin biopsies of various forms of Kaposi's sarcoma.
J Clin Pathol
49:631,
1996[Abstract/Free Full Text]
4.
Simpson GR,
Schulz TF,
Whitby D,
Cook PM,
Boshoff C,
Rainbow L,
Howard MR,
Gao S-J,
Bohenzky RA,
Simmonds P,
Lee C,
deRuiter A,
Hatzakis A,
Tedder RS,
Weller IVD,
Weiss RA,
Moore PS:
Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen.
Lancet
348:1133,
1996[Medline]
[Order article via Infotrieve]
5.
MacKenzie J,
Sheldon J,
Morgan G,
Cook G,
Schulz TT,
Jarrett RF:
HHV-8 and multiple myeloma in the UK.
Lancet
350:1144,
1997[Medline]
[Order article via Infotrieve]
6.
Marcelion A-G,
Dupin N,
Bouscary D,
Bossi P,
Cacoub P,
Ravaud P,
Calvez V:
HHV-8 and multiple myeloma in France.
Lancet
350:1144,
1997
| |
RESPONSE |
Cathomas et al1 report detecting human herpesvirus 8 (HHV-8) using a polymerase chain reaction (PCR)-based assay with open reading frame (ORF) 26 primers in only one of 17 bone marrow biopsies obtained from myeloma patients. In addition, there was a
lack of serological response to HHV-8 using an enzyme-linked
immunosorbent assay technique. These data contrast with our recent
report showing HHV-8 in most bone marrow biopsies obtained from myeloma
patients using both PCR-based and in situ hybridization
techniques.2 Recently our findings have been confirmed by
Broussett et al3 who found this virus in 18 of 20 paraffin-embedded bone marrow biopsies from myeloma patients, whereas
bone marrow biopsies from patients with lymphoma (n = 15) or reactive
processes (n = 5) did not show viral presence.3 Because
these patients were from France, epidemilogical differences are
unlikely to explain the lack of HHV-8 in the Swiss study.
We have sequenced the KS330233 fragment amplified from
myeloma bone marrow DNA and noted significant interpatient
variation.4 However, samples obtained from several
different tissue sources within the same patient (bone marrow biopsy,
dendritic cells derived from long-term culture of bone marrow aspirate,
and peripheral blood enriched for dendritic cells) showed differences
of 0 to 1 base pair. Sequencing of other KSHV ORFs (65 and 72) in
myeloma patients also showed differences between patients. These
findings make PCR contamination unlikely as an explanation for our
results. Interestingly, viral sequences show much more homology between different myeloma patients than when these sequences are compared with
HHV-8 from Kaposi's sarcoma. Because the authors used a unique set of
primers for initial amplification of the KS330233
fragment,5 this primer pair may be less specific for viral
sequences derived from myeloma patients.
Similar sequence variation may also explain the serological findings.
Some of these sequence differences lead to changes in amino acids and
frameshifts which will result in alterations of the virally encoded
protein products. These findings may explain the lack of a serological
response in myeloma patients1,6,7 who may contain variants
of HHV encoding viral proteins with different structures. Use of a
single HHV-8 antigen may therefore be problematic, as the authors point
out. In fact, Alsina et al8 have recently reported a
serological response in most myeloma patients using antibodies derived
against a different viral antigen. Furthermore, lack of detectable
antibody may result from the markedly decreased humoral response in
these patients. As a result, although a serological response to HHV-8
may exist in myeloma patients, it may be weak and therefore
undetectable using these HHV-8 serological assays. Finally, HHV-8
localization within the bone marrow-based dendritic cells may prevent
the maturation of an antigenic response due to B-cell tolerance of
antigens presented in the bone marrow.9
Thus, our recent report2 with these additional findings and
the reports from Broussett et al3 and Alsina et
al8 make it likely that HHV-8 is frequently present in the
bone marrow of myeloma patients. Its possible role in the pathogenesis
of this B-cell malignancy remains to be elucidated.
Jonathan
W. Said
Karen Heppner
I. Peter Shintaku
Matthew Schrage
Eric Green
Department of Pathology
UCLA Center for the Health
Sciences
UCLA School of Medicine
Los Angeles, CA
Matthew R. Rettig
Robert A. Vescio
Gary Schiller
Hong J. Ma
Daniel Belson
Alison Savage
James R. Berenson
Department of
Medicine
Division of Hematology/Oncology
Veterans Affairs West Los
Angeles Medical Center
Los Angeles, CA
H. Phillip
Koeffler
Hiroya Asou
Cedars Sinai Medical Center
Los Angeles,
CA
Geraldine Pinkus
Jack Pinkus
Brigham and Woman's
Hospital
Harvard Medical School
Boston, MA
| |
REFERENCES |
1.
Cathomas G,
Regamey N,
Stalder A,
Kurrer MO,
Joller-Jemelka HI,
Erb P:
Multiple myeloma and HHV-8 infection.
Blood
91:4391,
1998[Free Full Text]
2.
Said JW,
Rettig MR,
Heppner K,
Vescio RA,
Schiller G,
Ma HJ,
Belson D,
Savage A,
Shintaku IP,
Koeffler HP,
Asou H,
Pinkus G,
Pinkus J,
Schrag M,
Green E,
Berenson JR:
Localization of Kaposi's sarcoma-associated herpesvirus in bone marrow biopsy samples from patients with multiple myeloma.
Blood
90:4278,
1997
3.
Broussett P,
Meggetto F,
Attal M,
Delsol G:
Kasposi's sarcoma-associated herpesvirus infection and multiple myeloma.
Science
278:1972,
1997
4. (suppl 1)
Rettig M,
Vescio R,
Ma H,
Schiller G,
Savage A,
Berenson J:
Sequence variability of HHV-8 from the dendritic cells of multiple myeloma patients.
Blood
90:86a,
1997
5.
Cathomas G,
McGandy CE,
Terracciano LM,
Itin PH,
De Rosa G,
Gudat F:
Detection of herpesvirus-like DNA by nested PCR on archival skin biopsy specimens of various forms of Kaposi sarcoma.
J Clin Pathol
49:631,
1996
6.
MacKenzie J,
Sheldon J,
Morgan G,
Cook G,
Schulz TT,
Jarrett RF:
HHV-8 and multiple myeloma in the UK.
Lancet
350:1144,
1997
7.
Marcelion A-G,
Dupin N,
Bouscary D,
Bossi P,
Cacoub P,
Ravaud P,
Calvez V:
HHV-8 and multiple myeloma in France.
Lancet
350:1144,
1997
8. (suppl 1)
Alsina M,
Gao SJ,
Montalvo EA,
Leach CT,
Roodman GD,
Jenson HB:
Increased prevalence of antibodies to Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in patients with multiple myeloma.
Blood
90:87a,
1997
9.
Chen C,
Nagy Z,
Radic MZ,
Hardy RR,
Huszar D,
Camper SA,
Weigert M:
The site and stage of anti-DNA B-cell deletion.
Nature
373:252,
1995[Medline]
[Order article via Infotrieve]
