Jpn. J. Infect. Dis., 52, 201‑207, 1999

Invited Reyiew

Role of Human Parvovirus B 19 in the Pathogenesis of Rheumatoid Arthritis
Keiko Kumura Ishii*, Yuichi Takahashi, Mitsuo Kaku and Takeshi Sasakil
Department of Molecular Diagnostics and )Department ofRheumatology and Hematology,
Tohoku UniversitySchool of Medicine,
SeilTO‑〝∽Chi 1‑1, Aoba‑ku, Sendai 980‑8574, Japan(Received November 24, 1999)
StJMMARY∴ Rheumatoid arthritis (RA) is a chronic inflammatory dise?se of uAknown origin･ It has been

speculated that infectious agents are responsible for triggenng RA. Persistent infection with human parvovirus●

B 19 and its induction of immunopathology are hypothesized to explain the initiation and perpetuation of thediseaseprocess.

"of the patients with RA, and the detection of humoral or

1. Introduction●

cellular immune responses agalnSt Certain bacteria in patients

Rheumatoid arthritis (RA) is a chromic inflammatory disease
which affects approximately 1 % of the world population･ RA

with RA (14). Cu汀ently, polymerase chain reaction (PCR), a

suitable technique for detecting organisms present at low

is characterized by hyperplastic synovial membranes injoints

concentrations or in a non‑cultivable state, has been used towith pronounced infiltration of macrophages and leukocytes

search for candidate pathogens. This technique, however, hasand progressive destruction of cartilage and bone after inva‑

In the initiation of the pathologlCal process of RA, unknown

yielded negative results for Mycobacteria sp. and variable
results for MycoplasTa Sp･ and Chlamydia sp･ (15)･ Human
T cell lymphotropic vlruS type1 (HTIN‑I) was implicated in

antigen(S),perhaps derived from infectiousagents, is supposed

chronic joint inflammation. Viral mRNA and proteinsWere

sion by inflammatory pannus (I).
●●detected in the synovial cells from patients infected withto be responsible fわr induclng the activation of immune cells

HTLV‑1 (16) and the development of a fbm of arthritis wasin rheumatoid synovium･ Synovial macrophages produce●

slgnificant amounts of cytokines such as tumor necrosis

observed in mice transgenic for the Tax protein of HTLV‑I

factor a (TNFa), interleukin‑1 (IL‑I), IL‑6, granulocyte‑(17). Epstein‑Barr vims (EBV) was also demonstrated tomacrophage colony stimulating factor (GM‑CSF), platelet‑

express EBV‑encoded small RNA (EBER)and latent membrane

derived growth factor (PDGF), IL‑8, and monocyte

protein‑ 1 (LMP‑ 1) in synovial lining cells from patients withchemoattractant protein‑ 1 (MCP‑ 1 ) (2‑5). Tissue‑damaging

RA (18). The expression of viral products in synovial cells

proteases including collagenase (matrix metalloproteinase‑can be a trigger of inflammation.

1 , MMP‑1), gelatinase (MMP‑2), and stromelysin (MMP‑3)

Human parvovirus B I 9 causes arthropathy, which resembles

are also produced by macrophages at the cartilage‑pannus

RA (19, 20). In our study, a typical RA developed in 3 out of
12 patients with parvovims arthritis (21). DNA and a capsid

junction (6‑8). Macrophage‑derived TNFa and IL‑I further
activate the fibroblasts and lead to the release of cytokines,

protein of parvovirus B 19 were detected in the synovialtissue
and bone marrow while arthritis was present. Treatment of

MMPs, and growth factors including fibroblast growth factor(FGF) and vascular endothelial growth factor (VEGF) (9‑ 1 1 ).
Cytokines produced by macrophages and fibroblasts induce

patients with a high dose of immunoglobulin was effective in
+

I

+

I

I

t

+

improvlng their symptoms and reduclng Slgnals of the virus･

angiogenesis (e･g･ , TNFα , IIJ8, FGF, and VEGF), the expression

We further foundthat the target cells of parvovirus B 19 wereof adhesion molecules (e.g., TNFa and IL‑ 1 ),and chemotactic

immune cells in the synovium and bone ma汀OW, B19 in thestimulation to attract circulating cells (e.g., Ⅰし8 and MCP‑ 1 )synovial membrane was infectious, and infection with B 19

( I 2)･ A complex paracrine and autocrine network of cytokines

stimulated the immune cells to produce TNFα and IL6 (22)･

working through the interaction between synovial macro‑

Based on these findings, We will discuss a mechanism thatphages and fibroblasts perpetuates and expands the inflam‑mation, leading to joint destructi'on ( 1 3).

explains how human parvovirus B 19 function in RA patho‑
logy.

The specific antigen(S) that activates･the immune response
in immunogenetically susceptible hosts has not been isolated.

2. Parvovirus BID and rheumatoid arthritis

Bacteria and viruses have been suggested as pathogens that

initiate RA･ The involvement of bacteria in the etiology of

Parvovims B19 is a small virus, classified in the genus,

RA was based on findings including the emcacy of some

Erythrovirus in the Parvoviridae family. The genome of

antimicrobial agents in RA, alterations in the interstitialfloraparvovirus B19 is about 5･6 kb of single‑stranded DNA･
Parvovirus B 19 encodes non‑structural protein NSl , capsid*Corresponding author: Tel: +81 ‑22‑717‑7373, Fax: +81 ‑221717‑

proteins VPl and VP2, and other small proteins･ All the tran‑●

scripts are transcribed from the unlque promoter P6･7390, E‑mail: ishii‑k@mail･cc･tohoku.ac.Jp

Parvovims B19 is the only paⅣovirus known to be path0‑

genic in humans･ The virus was first found in serum fromasymptomatic blood donors. B19 is now known to cause a

ThisarticleisanInvitedReviewbasedonalecturepresentedatthe
9thSymposlumOftheNationalInstituteoflnfectiousDiseases,

wide variety of clinical symptoms, including erythema

Tokyo,21May1999.

infectiosum in children (23), arthralgia/arthritis in adults201

(19,24), transient aplastic crisis in persons with underlying

parvovirus B 19 in the pathogenesis of RA･hemolysis (reviewed in 25), nonimmune hydrops fetalis byinfection in utero (26), and pure red cell aplasia in

3. Prospective studies of patientswith parvovirus BID

immunocPmpromised patients (27)･

ar thritis

ParvovlruS B 19 arthropathy is transient in most cases but●

In order to elucidate whether RA is trlggered by infection

occasionally becomes chronic. Some cases have arthropathy

that is clinically indistinguishable from RA and fulfills thewith parvovirus B 19, prospective studies have been conducted･

diagnostic criteria for definite RA (19,20). RA is defined by

Tyndall et al. demonstrated a case of erosive polyarthritis

the prese.nee of 4 0r more of the following criteria: 1) moming

which developed after musculoskeletal disease associatedstiffness ln and aroundjoints lasting at least I h before maximal

with definite parvovirus infection (34). Gran et all reported

improvement; 2) soft tissue swelling of 3 0r morejoint areasthat among 7 patients with RA, a patient positive fわr anti‑

as observed by a physician; 3) swelling of the proximal

B 19 1gM antibody showed radiologlCal signs of bone destmc‑

interphalangeal, metacarpophalangeal, or wrist joints; 4)tion (35). Nikkariet al. presented the case of a patient with●symmetric swelling; 5) rheumatoid nodules; 6) the presence

rheumatoid nodules a且d bone erosions as well as rheumatoidof rheumatoid factor; and 7) radiographic erosions and/or

factor. Among 61 patients with early RA, this patient was theperiarticular osteopenia in hand and/or wrist joints (28).

only one positive fわr parvovirus B19 DNA in the synovial●

Followlng ParVOVirus B I 9 infection, rheumatoid factor at low‑tissue(36).

"

to‑moderate titer was detected in some cases (19,29‑33) andWe examined 67 patients with acute inflammatory polyarthri‑

the development of rheumatoid nodules and/Or bone erosions

tis for parvovirus B19 infection (21)･ Twelve patients were

was also observed (34‑36). Therefore, the etiologic role ofpositive fわr anti‑B19 IgM antibody at the onset of a仙ritis･

parvovirusB 19 in RA has been a subject of great interest. In

Joint pain remained in one third (4/1 2) ofanti‑B 19 IgM‑positive

early studies, anti‑B 19 antibodies were used to demonstratepatients at 6 months after onset, Compared with a rapid

parvovirus B19 infection in patients with RA. PCR has

decrease in anti‑B 19 IgM一megative patients (2/52)･ Three out

recently txBen applied to demonstrate the presence of parvovirus

of four rheumatoid factor‑positive patients fulfilled the criteria

B19 DNA in blood and synovial materials. However, thefor definite RA. Active polyarthritis had developed in theirfingers, wrists and elbows along with the development of

results obtained so far are controv.ersial (3 I ,37‑40)･ Since theIncidence of exposure to parvovlruS increases rapidly withrheumatoid nodules and destmctive changes in thejoints. The
clinical course of one of the patients is shown in Figure l･age, carefully selected control samples are required (41).

Recent studies have shown that parvovirus B19 DNA can

The presence of parvovims B19 genome DNA in these

persist in the synovial membranes not only in patients withchronic arthropathy but also in healthy immunocompetentpatients was examined by a method of nested PCR amplify‑

ing a region of NSl (21). Parvovirus B19 DNA was detectedindividuals (42,43). The presence of microbial DNA in thein the peripheral blood cells during the first 4 months, but

synovium, however, cannot be taken as proof of the causation

only in the synovial tissue and bone marrow after 2 years･of arthritis. Meta血lic prducts of paⅣovirus B 19 such as viral

No DNA of EBV or cytomegalovims was detected in themRNA and proteins, and a B 19‑specific immune response orsame samples･ Persistent parvovirus B19 infection in the

inflammation should be detected to demonstrate the role ofsynovium and bone ma汀OW Was eVidenced through detection

ccLinui,cSaj

Fig. l･ Clinicd course of a male patient with rheumatoid arthritis (RA)･ MTX, methotrexate; RF, rheumatoid factor; ERS,
erythr∝yte sedimentation rate.

202

of signals for VPl mRNA and VPl antlgen uSlng techniquesthat persistent infection with B19 is responsible for theof in situ hybridization (ISH) with labeled probes and immuno‑

pr∝ess of RA･ We further examined the synovium of patients

fluorescence using anti‑VPl monoclonal antibody (PAR3)

withRA at an active stage for the presence of genome DNA,(22), respectively. The persistent presence for months or evenNSl mRNA, and the VPl antigen of paⅣovirus B19 (22)●

(Table). Parvovirus B19 DN4 was found by nested PCR in

years of paⅣovirus B 19 DNA in the synovial membrane andthe synovial tissue from 77% of patients with RA, from 15%
of patients with osteoarthritis (OA), and from 16% of patientsbone marrow has also been reported for chronic arthritis (38,44‑48).

The effects of anti‑rheumatic drugs were transient, andwith trauma. The detection of parvovirus B19 DNA in thecomplete r.emission was not observed (2 I )･ Since thepersistence

synovial membrane of immun∝ompetent healthy individualsof parvovlrusB19 infection in the synovial tissue and bone

is consistent with recent reports (42, 43). NSl mRNA by ISH

marrow was considered to be a cause of chronic arthropathy,

were positive in 73% of the synovial tissue sections froma high dose of immunoglobulin therapy was pe血rmed at 5patients with RA but negative in all from patients with OA

or 6 years after the onset of polyarthritis. Joint palm, swelling,

and trauma･ Similarly,三mmunohistochemical staining withand the values of C‑reactive protein were improved. Parvovirus

the antibody PAR3 detected VPl antigen in the samples from
80% of patients with RA but not in those of patients with OA●

B19 DNA in the bone marrow turned out to be almost
undetectable by PCR and the number of VPl‑positive cells

and trauma･ The parvovirus B 19 genome occasionally exists
tl

decreased･ The ass∝iation between clinical improvement andeven in the non‑RA synovium, but the persistent expression

decrease in viral expression supports a link between chronicof parvovirus B 19 genes seems to be required for the develop‑

inflammation and parvovirus B 19 infection, as indicated in a
Table. Detection of genome DNA, NSl mRNA, and VPl antigen ofpatient who recovered from parvovirus B 1 9‑associated pure
red cell aplasia after immunoglobulin therapy (49).

parvovims B 19 in the synovium

Disease genome DNA NS 1 mRNA VPl antigen

4. Parvovirus BID in synovial tissue of rheumatoidRAar thritis

OA
TraumaThe investlgation of patients with RA that developed after

RA: rheumatoid arthritis, OA: osteoarthritis

parvovirus B 19‑associated acute polyarthritis (21) suggests

eel

la

JL‑6 (q/ml)

Ab
0

TNFa (pglmJ)
200

100

0

1000

2000

RA‑SVCOA‑告vcB‖C
RA･SVC + B‖C

1F5

RA･SVC ■ BMC

PA F13Ton8H

FtA･SVC +Tonsil lps
FtA･SVC +Tonsil PAR3
0A･SVC+ TonSiJ

1FS

OA･SVC + Tonsil PAF13

RA‑告vcOA‑SVCUO37

FtA‑SVC + U937
FtA‑SVC + U937

1F5

FtA‑SVC + U937

PA R3

0A･SVC + U937
0A･SVC + U937

1F5

0A･SVC + U937

PA R3

THP･1
RA‑告vc ■ THPI
RA‑SVC ■ THPI

1F5

RA‑SVC + THPIPAR3OA･SVC + THPIOA･SVC + THPI

1F5OA一SVC + THPl

PA R3
25

SO

lL6 (qlml)

TNFα (開仙)100

Fig･ 2･ The effect of parvovirus B 19 infection on the production of IL‑6 and TNFa in a coculture system･ B 19‑negative bonemarrow cells (BMC), tonsil cells Cronsil), U937 cells,弧d THP‑1 cells Tere cultured withsynovial cells (SVC) frompatients with rheumatoid arthritis (RA) or osteoarthritis (OA) for 3 days ln a double‑chamber system･ Inhibition of the
production of IL‑6 and TNFa was examined by adding anti‑VPl antibody FAR3 in the coculture medium･ An antibody
lF5 was used as a controlantibody･ The concentradons of IL‑6 and TNFα in the culture medium were measured by ELISA(Medgemix FleuruS, FleuruS, Belgium)･ ***, P<0･Ol ; **, P<0･02･203

ment of RA.

5. A possible mechanism for the development of rheu･●

VPl‑positive slgnals in RA synovial tissue were fわund in

matoid arthritis

the lymphoid follicle, germinal center,perivasucular lymphoI
cytes, and sublining macrophages, but not in the synovial

Persistent infection withaninfectious agentand its induction

lining cells, neutrophils, or vessels. Immunohistochemicalof immune‑mediated innammatory responses may be essential

staining uslng a COmbination of antibodies agalnSt VPl and aforthe disease process of RA. We found that cells in the●●cell surface marker identified the parvovirus B 19‑infectedsynovium and bone marrow from patients with RA which

synovial cells as immune cells, including macrophages, fol‑developed after parvovirus B 19 arthritis were persistently

licular dendritic cells, T cells, and B cells, but not synovial

infected with B 19 and expressed the viral capsid protein VPl

fibroblasts or endothelial cells (22). In early studies, it wasfor years (21 ). Evidence of persistent infection with parvovirus

shown that parvovirus B 19 has a very narrow target cell range

B 19 was also obtained from an analysts Ofthe synovium fromand is highly tropic for human erythroid cells (50). A receptor

other patients with RA (22).
The persistent expre!sl0n Of VPl in infected synovial●●of parvovirus B 1 9 was identified to be globoside (blood group
P antigen) (51), and its tissue distribution wa.s shown to be

immune cells suggests apersistent pro.duction of B 19 NSl in

consistent with the known tropism of parvovlruS B19 (52).

these cells, since the production of NS 1 precedes that ofVPl

However, the synovium has recently been shown to contain(56). Moffatt et al･ demonstrated that NSI can inducethe

globoside (53), and parvovirus B19 has been detected inperipheral blood leukocytes, macrophages, and myocardial

production of IL‑6 in THP‑ I cells, as a trans‑acting transcrlP‑tion activator on the IL‑6 promoter (58)･ NSl is expected tocells in vivo (54, 55)･ It is necessary to elucidate whether

control the expression of other cytokine genes in B 191infected●

globoside and/or other parvovlruS B 1 9‑specific receptors aresynovial immune cells･ We observed the enhanced secretion

expressed on the su血ce of those immune cells in the RA

ofTNFα and IL‑6 in a c∝ulture system of RA synovial cells

synovial membrane.

and B 19‑negative immune cells including U937 and THP‑1

Shimomura et･ al. reported serial appearance of RNA for

cells representing macrophages (22). In addition, the prduction

nonstructural proteins, replicative fbms of paⅣovirus B 19

ofTNFα mRNA was stimulated by the induction of NSl in

DNA, and RNA for capsid proteins, in synchronized and B 1 9‑

The expression ofVPl in the RA‑synovial cells suggests the

an inducible expression system with U937 cells (Ishii et al･,
unpublished data). NS I probably functions as a transcription‑
activating factor also on the TNFa promoter in B I 9‑infected

production of complete progeny in these cells. The ability ofmacrophages.

infected cells from a megakaryoblastoid cell line, UT‑7 (56).

●parvovirus B 19 in the synovialimmune cells to cause infection

Synovial macrophages play Important roles in the pr∝ess

in B 19‑megative immune cells was evaluated by incubatingof RA through the release ofTNFα and ILl, both of which

the cells from patients (donor cells) and one of a variety ofstimulate the secretion of cytokines and tissue‑damaglng

immune cells (recipient cells) in the same well partitioned by aenzymes from synovial fibroblasts and chondrocytes (59)･

filter membrane (22). The recipient cells, such as tonsil cells andAmong the macrophage‑derived cytokines, the apparent

cells from the human mononuclear cell lines, U937 and THP‑

importance of TNFα as an inflammatory mediator in RA is

1 , became VPl ‑positive when cultured with the collagenase‑suggested (2), by the findings that the unregulated production

treated cells from RA synovium as donor cells. Similar resultsof TNFα in transgenic mice leads to spontaneousarthritis (60)were obtained when bone marrow mononuclear cells fromand that the treatment of RA patients with anti‑TNFα

patients with RA were used as donor cells. The vims trans一monoclonal antibodies leads to an attenuation of the severity

mission was blocked by anti‑B19 VPトspecific antibody

of innammation and joint destruction (61 )･ Up‑regulation of

FAR3. No VPliX)Sitive cells were detected in the combination

TNFα expression by NS I in macrophages may be a key pruessof synovial tissue cells from patients with OA used as donor●

in the pathogenesis of RA and an available target fわr new●

cells and tonsil cells as reclplent Cells and the combination oftherapeutic methods.

RA synovial cells as donor cells and synovial fibroblasts as
recIPlent Cells. These results indicate that the synovialcells andthe synovial tissue and bone marrow from patients with RA

bone ma汀OW Cells from patients with RA produce complete

is unknown･ NSl of parvovirus B19 has been shown to have●

The mode of parvovirus B19 infection in immune cells of●

parvovirus B 19 which causes infection in immune cells but

cytotoxic activity which may be responsible for the lytic infec‑

not in fibroblasts.

tion in erythroid lineage cells (50) and abortive infection in

The continuous and enhanced production of a variety of

nonpemissive cells (62). The cytotoxicity of NS 1 has recently

inflammatory cytokines, as observed in the RA joint, is essen‑been understood to be a function of apoptosis induction (63)･

tial for the development of RA (57). We examined the effect

Quantitative control of NSl and/Or modification of itsof parvovirus B 19 infection on the production ofTNFα andcytotoxic activity by some host factors might be responsible

IL6 in the same system as described above (Fig. 2) (22). A

for the persistent infection with parvovirus B 19･ The reason

why cells expresslng the viralcapsid protein canescapelmmune●●

slgnificant increase in cytokine levels was obseⅣed when●

the synovial cells from patients with RA were cultured withsurveillance for years is also unknown･ Elucidation of these

B19‑negative immune cells, compared with the cytokine

issues will provide clues to vims‑host interactions which cause

secretion in each culture alone. PAR3 inhibited the increasein cytokine secretion. OA synovial cells failed to stimulate

autoimmune disease.

reclplent Cells to secrete the cytokines. These results suggest

6. Conclusions

that parvovirus B 19 released from cells of the RA synovium
can cause infection in immune cells and stimulate the newly

We observed patients with RA which developed after the

infected cells to produce proteins, including innammatory

polyarthritis associated with parvovirusB 1 9･ Parvovirus B 1 9cytokines.

was persistently present in their synovium and bone ma汀OW

and continued to express its gene products･ Infection with
paⅣovims B 1 9 probably stimulates the synovial immune cells

204to produce innammatory cytokines by the activity of NSl.

ll. Krane, S. M., Conca,W, Stephenson, M.し.,Amento, E.

Once a paracrine and autocrine network of cytokines is

P. and Goldring, M.B. (1990): Mechanism of matrix

induced, inflammationpersistsand tissue destruction, including

degradation in rheumatoid arthritis. Ann. N. Y. Acad･ Sci･,

cartilageand bone erosion, Progresses. Treatment with disease‑580, 340‑354.

modifying anti‑rheumatic drugs or immune suppressors did

1 2. Firestein, G. S. (1996): Inv卵ive fibroblast‑like synovi∝ytes

not provide complete remission to patients with RA. Removal

in rheumatoid arthritis. Arthritis Rheum., 39, 178ト1790.

of the cause of the disease was required. Treatment with

13. Janusz, M. J. and Hare, M. (1993): Cartilage degradation

immunoglobulin reduced parvovims B19 in the synovium

by c∝ultures of transformed macrophage and fibroblastand improved the arthritis at the same time･ These findings

cell lines: a model of metalloproteinase‑mediated connec‑

suggest that paⅣovirus B19 is at least one of the causative

tive tissue degradation. ∫. Immuno1., 150, 1922‑1931･

agents of RA･ Identification of the etiology provides anopportunity to target RA uslng Specific therapleS.
●

14. Krause, A., Kamradt, T. and Burmester, G. 良. (1996):●

Potentialinfectious agents in the induction of arthritides･

Curr. Opin. Rheumato1., 8, 203‑209･
15. Kingsley, G･ (1997)‥ Microbial DoNA in the synovium‑a

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