Tài liệu Báo cáo khoa học: Molecular aspects of rheumatoid arthritis: role of environmental factors pdf

MINIREVIEW
Molecular aspects of rheumatoid arthritis: role of
environmental factors
Shu Kobayashi, Shigeki Momohara, Naoyuki Kamatani and Hiroshi Okamoto
Institute of Rheumatology, Tokyo Women’s Medical University, Japan
Introduction
Rheumatoid arthritis (RA) is a systemic, chronic
inflammatory disease that affects 0.5–1% of the popu-
lation and causes progressive joint destruction that
leads to the restriction of activities of daily living and
deterioration of quality of life. Although the patho-
genesis of RA has not yet been fully elucidated, it is
considered to be a complex, multifarious disease that
is influenced by both genetic and environmental fac-
tors. Genetic influences that contribute to RA suscepti-
bility have been demonstrated in both studies of twins
[1] and families [2], as well as in genome-wide linkage
scans [3]. These studies estimated that genetic factors
are responsible for 50–60% of the risk of developing
RA and that environmental factors may explain the
remaining risk. This quantification was made by a
classical approach to separating the quantitative
influence of genetic factors in RA with nationwide
studies of twins with RA, as described previously [1].
This minireview focuses on the contribution of envi-
ronmental risk factors to the development of RA.
Infection
Several infectious agents have been reported to be risk
factors for RA (Table 1), including human parvovirus
B19 (B19), Epstein–Barr virus (EBV), retroviruses,
alphaviruses, hepatitis B virus, Mycobacterium tuberculo-

sis, Escherichia coli, Proteus mirabilis and Mycoplasma.
Human parvovirus B19 is a small, nonenveloped
DNA virus that is transmitted via the respiratory tract
as well as vertically from mother to fetus. Although
B19 is a significant human pathogen with a wide
Keywords
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD);
cytokines; environmental factors; hormone;
NF-jB; rheumatoid arthritis; smoking;
weather
Correspondence
H. Okamoto, Institute of Rheumatology,
Tokyo Women’s Medical University, 10-22
Kawada-cho, Shinjuku, Tokyo 162-0054,
Japan
Fax: +81 3 5269 1726
Tel: +81 3 5269 1725
E-mail:
(Received 14 March 2008, revised 1 June
2008, accepted 20 June 2008)
doi:10.1111/j.1742-4658.2008.06581.x
Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease that
affects 0.5–1% of the population. RA causes progressive joint destruction
that leads to the restriction of activities of daily living and deterioration of
quality of life. Although the pathogenesis of RA has not yet been fully elu-
cidated, it is considered to be a complex, multifarious disease that is influ-
enced by both genetic and environmental factors. Genetic influences that
contribute to RA susceptibility have been demonstrated both in studies of
twins and families, as well as in genome-wide linkage scans, and it is esti-
mated that genetic factors are responsible for 50–60% of the risk of devel-

oping RA. Thus, environmental factors may explain the remaining risk of
developing RA. A large variety of environmental factors such as infectious
agents, smoking, sex hormones, pregnancy etc. have been extensively
studied previously. Understanding of how these factors contribute to the
development of RA may lead to the better understanding of pathogenesis
of RA.
Abbreviations
AhR, aryl hydrocarbone receptor; B19, human parvovirus B19; CCP, cyclic citrullinated peptide; EBV, Epstein–Barr virus; HLA, human
leukocyte antigen; IL, interleukin; JCP, Japanese cedar pollinosis; RA, rheumatoid arthritis; RF, rheumatoid factor; TCDD, 2,3,7,8-
tetrachlorodibenzo-p-dioxin; Th, T helper; TNF-a, tumor necrosis factor-a.
4456 FEBS Journal 275 (2008) 4456–4462 ª 2008 The Authors Journal compilation ª 2008 FEBS
clinical spectrum, 25–68% of infections are asymptom-
atic. The most common clinical manifestation of acute
infection is erythema infectiosum, characterized by a
‘slapped cheek’ rash. Interestingly, 50% of adults and
10% of children with erythema infectiosum have joint
manifestations, which tend to occur 2 weeks after
infection. Arthritis caused by B19 infection is usually
symmetrical, primarily affecting the small joints of the
hands, wrists and knees, and it is more commonly
observed in female subjects than in male subjects (as is
RA). Certain evidence suggests that B19 may play a
role in the pathogenesis of RA. For example, B19
arthritis often meets the clinical diagnostic criteria for
RA and is sometimes accompanied by bone erosion
and – at least transiently – by rheumatoid factor (RF)
positivity. Human parvovirus B19 DNA may be
detected in the synovial fluid, synovial cells and ⁄ or
synovial tissue of affected joints. Furthermore, a posi-
tive association with the human leukocyte antigen

(HLA)-DR4 antigen has been reported in patients who
developed arthritis after B19 infection [4]. Ray et al.
reported the ability of B19 to induce certain properties
in normal human synovial fibroblasts [5]. These inves-
tigators observed that incubation with B19-containing
serum induces an invasive phenotype in normal human
synovial fibroblasts and that B19 serum-treated
synovial fibroblasts exhibit an increase in invasiveness
compared with fibroblasts cultured in medium contain-
ing B19-negative serum or in medium alone. Synovio-
cyte migration has been shown to be induced by the
B19 VP1 protein unique region, with the phospholi-
pase activity of the VP1 protein unique region being
prerequisite for this process [6]. Infection of the macro-
phage cell line U937 or bone marrow cells with B19
has been shown to induce the expression of interleukin
(IL)-6 and tumor necrosis factor- a (TNF-a), which are
both key cytokines in RA pathogenesis [7]. A recent
report showed evidence of the high prevalence of B19
DNA in patients with RA [8]. However, a significant
amount of evidence contradicts a role of B19 infection
in RA pathogenesis. For example, a long-term (median
5 years) follow-up study among 54 patients with recent
B19 infection revealed that none of the patients with
acute-phase arthalgia developed chronic arthritis [9]. In
addition, genomic B19 DNA has been shown to persist
not only in the synovial membranes of patients with
chronic arthropathy, but also in healthy, immuno-
competent individuals [10]. Furthermore, nested PCR
amplification of both NS1 and VP genes of B19 DNA

in synovial membranes has revealed that the levels of
B19 DNA are similar in RA and control synovial
membranes [11]. Thus, the contribution of B19 infec-
tion in RA remains controversial.
Epstein–Barr virus is a 172-kb, double-stranded
DNA virus. It causes infectious mononucleosis and has
been linked to the development of several malignant
tumors, including Burkitt’s lymphoma, Hodgkin’s
disease and nasopharyngeal carcinoma. In most indivi-
duals, primary infection is asymptomatic. Epstein–Barr
virus first infects B lymphocytes or epithelial cells of the
oropharynx and then activates resting B lymphocytes,
which is followed by proliferation; the virus then estab-
lishes a so-called ‘latent infection’ in memory B lympho-
cytes. A potential role of EBV in RA pathogenesis has
been proposed for many years [12]. For example, it has
been reported that sera from RA patients contains high-
titer antibodies to latent and replicative EBV antigens,
such as Epstein–Barr nuclear antigen, viral capsid anti-
gen and early antigen [13,14]. Furthermore, RA patients
tend to have more EBV-infected B lymphocytes in their
peripheral blood than normal control individuals, and
the mean frequency of spontaneously transforming B
lymphocytes is five times higher in RA patients than in
controls. The QKRAA amino acid sequence of the
HLA-DRB1*0401 allele, which is associated with RA
disease susceptibility, is also found on the EBV glyco-
protein gp110 [15], a major replicative antigen impli-
cated in the control of infection and that is expressed
on the surface of lymphoblastoid cell lines and on the

envelope of the budding virion during EBV replication.
Table 1. Risk and defensive factors for RA.
Risk factors Defensive factors
Infection Human parvovirus B19 [4–8]
Epstein–Barr virus [12–17]
Human retrovirus 5 [18]
Alphaviruses [22–24]
Hepatitis B virus [25]
Mycoplasma [26]
Mycobacterium
tuberculosis [27]
Smoking Smoking [28–36]
Sex hormones Estrogen [37] Testosterone [37]
Oral contraceptive
pill [39]
Pregnancy Pregnancy [41–47]
Complications Type 1 diabetes
mellitus [48]
Autoimmune thyroid
disease [48]
Diet Omega-3 fatty
acids [50]
Vitamin D [52],
vitamin K [53]
Weather Low temperature [54,55]
High atmospheric
pressure [54]
High humidity [54]
S. Kobayashi et al. Role of environmental factors in RA
FEBS Journal 275 (2008) 4456–4462 ª 2008 The Authors Journal compilation ª 2008 FEBS 4457

Healthy individuals with prior EBV infection have
serum antibodies to gp110, and their T lymphocytes
recognize peptides containing the QKRAA motif. gp110
is a target for both T lymphocytes and certain anti-
bodies, recognition of which allows control of infection.
Conversely, HLA-DRB1*0404, an RA predisposing
allele, is associated with low T-lymphocyte responses to
gp110. In RA patients, poor control of EBV replication
may result in a higher EBV load. In situ hybridization
experiments have demonstrated the presence of EBV-
encoded RNAs in synovial tissue B lymphocytes from
RA patients, but not in tissue from osteoarthritis
patients. Furthermore, semiquantitative PCR tech-
niques have been used to show that EBV DNA is
detected more frequently in peripheral blood mononu-
clear cells, synovial fluid and saliva from RA patients
than from controls and patients with other arthritides
[16]. An EBV DNA quantification assay using real-time
PCR revealed that the EBV DNA load is significantly
higher in peripheral blood mononuclear cells from RA
patients than in peripheral blood mononuclear cells
from patients with non-RA inflammatory diseases and
normal control individuals. In addition, the EBV load
in RA patients expressing HLA-DRB1*0404 is slightly
higher than that observed in patients expressing
HLA-DRB1*07 [17].
Although human retroviruses have long been
suspected as triggering factors in autoimmune diseases,
no conclusive evidence confirming these suspicions has
been reported thus far. One group reported that

human retrovirus 5 proviral DNA was detected in
53% of synovial samples from arthritic joints, in 12%
of blood samples from RA patients and in 16% of
blood samples from patients with systemic lupus eryth-
ematosus [18]. However, data from another group con-
tradicts this initial observation, with no association
identified between human retrovirus 5 and RA [19,20].
Human retrovirus 5 has been suggested to be a rabbit
endogenous retrovirus [21].
Infections with alphaviruses, such as chikungunya
virus, Ross Rover virus and Sindbis virus have been
reported to be associated with the onset of arthritis
[22–24]. There are some reports showing that chronic
infection with HBV may cause arthritis similar to RA
and that RF is present in 20–75% of the patients, but
rarely is antibody against cyclic citrullinated peptide
(anti-CCP) detected, which is a more specific marker
of RA than RF [25]. Although these types of arthritis
are not always acute and chronic arthritis can be
developed, there is no evidence to date showing that
these types of arthritis progress into RA.
In one study, Mycoplasma DNA was reported to be
amplified from the peripheral blood of 53.6% (15 ⁄ 28)
of RA patients, suggesting that a high percentage of
RA patients have systemic mycoplasmal infections
[26]. M. tuberculosis is a chronic infectious disease
affecting the lungs. Although a mild increase in the
risk of encountering tuberculosis in RA patients was
reported more recently, this increase was found even
among patients receiving therapies with biological

agents [27].
These associations between RA and infectious agents
have been supported by increased antibody titers or
DNA to the infectious organism in RA patients com-
pared with other individuals. However, some epidemi-
ological studies oppose these possible links, and there
has been no consistent evidence that a single infectious
agent or other environmental factor is responsible for
the effect of the environment on RA. Therefore, the
pathological role of these and other infectious agents
needs to be explored further.
Smoking
A large number of epidemiological studies have dem-
onstrated an association between cigarette smoking
and the development of RA [28–31]. In particular,
smoking is known to be associated with RF-positive
RA and anti-CCP-positive RA [32], and to interact
with the HLA-DRB1 shared epitope alleles [33]. In
addition, some studies have suggested that smoking
also influences RA disease severity [34,35], although
this remains controversial. While the mechanisms
responsible for the influence of smoking in RA are not
clear, some studies have shown an association between
RA and the toxic compounds found in cigarette
smoke, such as nicotine, 2,3,7,8-tetrachlorodibenzo-
p-dioxin (TCDD) and reactive oxygen species. We
found that the mRNA and protein levels of aryl
hydrocarbone receptor (AhR) were higher in RA syno-
vial tissue than in osteoarthritis tissue, and that TCDD
upregulated the expression of IL-1b, IL-6 and IL-8

through binding to AhR, with this effect transmitted
via the nuclear factor-jB and extracellular signal-regu-
lated kinase signaling cascades. In addition, AhR
expression in synovial cells was upregulated by TNF-a.
These data suggest that TNF-a activates AhR expres-
sion in RA synovial tissue, and that cigarette smoking
and exposure to TCDD enhance RA inflammatory pro-
cesses (Fig. 1). Thus, TCDD exposure, such as smoking,
appears to exacerbate RA pathogenesis [36].
Sex hormones
The increased risk of RA in women has led to evaluation
of the role of sex hormones in disease susceptibility. It is
Role of environmental factors in RA S. Kobayashi et al.
4458 FEBS Journal 275 (2008) 4456–4462 ª 2008 The Authors Journal compilation ª 2008 FEBS
well known that the levels of male sex hormones, parti-
cularly testosterone, are lower in men who have RA. By
contrast, the levels of female sex hormones do not differ
significantly between RA patients and control individu-
als [37]. It has been reported that bone erosion occurs
more frequently in men than in women, and that arthri-
tis tends to occur earlier in men. Furthermore, male
gender is correlated with a higher risk of bony erosions
and an accelerated disease course, while female gender
is correlated with structural consequences of joint
destruction. Joint surgery is performed more frequently
in female RA patients than in male patients. In addition,
gender influences the risk, as well as the pattern, of
organ involvement in RA: nodules and rheumatoid lung
disease are typical manifestations in men, whereas
women typically develop sicca syndrome [38].

Exogenous hormones have also been reported to
influence RA disease risk. For example, several studies
have shown that women who use oral contraceptive pills
have a reduced risk of developing RA [39]. On the other
hand, Walitt et al. reported that there were no statisti-
cally significant differences in the risk of developing RA
or the severity of RA between postmenopausal hormone
therapy groups and placebo groups [40]. The molecular
mechanisms underlying hormone involvement in RA
pathogenesis require further elucidation.
Pregnancy
It is widely accepted that RA frequently remits during
pregnancy. Although the mechanism for this is
unclear, Nelson et al. [41] reported that the amelio-
ration of RA during pregnancy is associated with a
disparity in HLA class II antigens between mother and
fetus. These investigators suggested that the maternal
immune response to paternal HLA antigens may play
a role in pregnancy-induced RA remission. By con-
trast, several studies have suggested that nulliparous
women have an increased risk of developing RA,
although there is no increased risk in women who are
single [42]. These reports support the hypothesis that
pregnancy is related to the development of RA. Recent
studies have also suggested that the risk of disease
development is increased during the postpartum
period, particularly after the first pregnancy [43,44].
Subsequent investigations demonstrated that much of
this increased risk is associated with breastfeeding, and
that women who breastfeed after their first pregnancy

are at the greatest risk of developing RA [45]. These
researchers also suggested that the association among
breastfeeding, pregnancy and RA may be related to
either increased prolactin levels or an abnormal,
pro-inflammatory response to prolactin [46]. Recently,
Forger et al. showed that the amelioration of disease
activity in the third trimester corresponded to the
increased number of regulatory T cells that induced a
400A
B
300
IL-6
IL-8
200
IL-6 or IL-8 (ng
·
mL
–1
)
0
100
1.2
IL-1β
0.4
0.8
IL-1
β
(ng
·
mL

–1
)
None
TCDD (nM)
0.01 0.1 1 10 100
0
TCDD (smoking, etc.)
(RA joint space)
AhR
AhR
TNF-α
AhR
(RA synoviocyte)
ERK
NF-κΒ
IL-
β
, IL-6, IL-8
Target gene
(nucleus)
Fig. 1. (A) TCDD increases IL-1b, IL-6 and IL-8 production from
fibroblast-like synoviocytes obtained from patients with RA. Fibro-
blast-like synoviocytes were stimulated with various concentrations
of TCDD (0–100 n
M) for 12 h and the cytokine concentrations in
fibroblast-like synoviocyte culture supernatants were determined
using cytokine-specific ELISA kits [36]. (B) Schematic representa-
tion of the role of AhR in RA. TCDD, a major component of ciga-
rette smoke, enhances the RA inflammatory process. TCDD
induces inflammatory cytokines via its association with AhR, result-

ing in stimulation of the nuclear factor-jB (NF-jB) and extracellular
signal-regulated kinase (ERK) signaling cascades. In RA joints,
strong expression of AhR occurs as a result of TNF-a over-produc-
tion, a well-known pathological feature of RA. Exposure to TCDD
induces the release of additional pro-inflammatory cytokines, result-
ing in RA exacerbation.
S. Kobayashi et al. Role of environmental factors in RA
FEBS Journal 275 (2008) 4456–4462 ª 2008 The Authors Journal compilation ª 2008 FEBS 4459
pronounced anti-inflammatory cytokine milieu. They
suggested that pregnancy leads to a beneficial effect of
regulatory T cells on RA disease activity [47].
Complications
Numerous studies have examined disease-related com-
plications that occur at an increased frequency in both
RA patients and their families. The most widely investi-
gated of these complications are other autoimmune
diseases, particularly type 1 diabetes mellitus and
autoimmune thyroid disease [48]. Rheumatoid arthritis
is known to be a T helper (Th) 1-dominant disease,
whereas atopic allergy is a Th2-dominant disease.
Therefore, a functional dichotomy between Th1-domi-
nated immune reactions in RA and Th2-mediated
immune reactions typical of atopic allergy, including
Japanese cedar pollinosis (JCP), has been suggested. We
investigated the occurrence of JCP in RA patients and
compared RA disease activity between RA patients with
JCP and those without JCP using a large observational
cohort study of RA patients [The 6th Japanese version
of the IORRA study (Institute Of Rheumatology, Rheu-
matoid Arthritis)]. We concluded that RA disease activ-

ity tends to be negatively associated with the presence of
JCP and speculated that patients with JCP have a
genetic predisposition to develop milder RA [49].
Diet
Few reports have addressed the influence of diet on RA
development and progression. The addition of omega-3
fatty acids to the diets of RA patients has been associ-
ated with improvement in RA [50]. Furthermore, diets
high in eicosapentaenoic acid have a favourable effect
on the clinical outcome of RA [51]. Although the asso-
ciation between diet and RA onset is unclear, it is
accepted that such fatty acids compete with arachidonic
acids, the latter of which are involved in inflammation.
Some reports have demonstrated the influence of vita-
mins on RA. For example, greater intake of vitamin D,
primarily from fish and fish products, has been associ-
ated with a lower risk of RA [52]. In addition, we
recently reported that vitamin K, which is primarily
derived from vegetables and legumes [particularly fer-
mented soybeans (natto)], could inhibit the proliferation
of fibroblast-like synoviocytes and the development of
collagen-induced arthritis [53].
Weather conditions
Although no good biologic hypotheses have been
proposed that might explain the association between
RA and weather conditions, Strusberg et al. reported
that low temperature, high atmospheric pressure and
high humidity were significantly correlated with pain
in RA patients [54]. Verges et al. suggested that some
meteorological variables affect the occurrence of pain

in RA and that low temperature increases the risk of
joint pain [55].
Concluding remarks
A large variety of environmental factors have been
proposed to be associated with RA development.
However, many epidemiological studies have reported
inconsistent results, so such associations are controver-
sial. In addition, little is known about the underlying
mechanisms. Further research is required to gain a
better understanding of the impact of these environ-
mental factors on human immunity and their effects
on RA disease outcomes.
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