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: hokamoto@ior.twmu.ac.jp (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]. 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