Early environmental factors and rheumatoid arthritis

Abstract

The precise cause of autoimmune diseases such as rheumatoid arthritis (RA) remains uncertain. In recent years there has been extensive investment in pursuing genes important in RA. However, estimates suggest that the risk of developing RA is at most 50% determined by genes. There has been limited success defining the environmental factors important in developing RA. We hypothesize that this lack of success may be due to a concentration on the time around disease onset. There is evidence of production of the autoantibodies rheumatoid factor (RF) and anti-cyclic citrullinated peptides (anti-CCP) and increased levels of C-reactive protein (CRP) years before RA becomes clinically apparent. In addition, early life events including intrauterine growth retardation (IUGR) may have long lasting effects on immune function. We review the evidence that the early environment through effects on growth and infectious exposure may influence the likelihood of developing autoimmune diseases such as RA.

Introduction

The development of autoimmune diseases like rheumatoid arthritis (RA) depends on the interaction between genetic background and a number of environmental factors. The onset of clinical disease occurs at a threshold reached by the cumulative action of genetic and environmental factors beyond which the abortion of an auto-aggressive immune response becomes impossible. In recent years advances in molecular biology including high-throughput genome scanning have permitted the identification of genes important in RA [1,2]. These studies have confirmed the key role of major histocompatability complex (MHC) genes and identified other loci that warrant further exploration. The most important genetic association in RA is with the HLA-DRB1 gene within the major histocompatibility complex (MHC), where particular alleles within the DRB1*04 and *01 clusters encode the so-called ‘shared-epitope’ sequences within the expressed DRB1 molecule [3]. In contrast with the detailed study of the role of genes in the aetiology of RA, little attention has been directed towards the elucidation of environmental factors.

The limited historical descriptions of RA before industrialization suggest that changing environmental influences might be important in its aetiology. An examination of 800 medieval skeletons in the United Kingdom (UK) failed to show any evidence of RA [4], while the disorder is now present in 1·16% of women and 0·44% of men in the contemporary UK population [5]. Increased urbanization has been associated with an increased prevalence of RA in other populations also. In South Africa, a study of people from the Xhosa tribe showed a higher prevalence of RA in individuals living in an urban rather than rural environment [6]. Similar observations have also been described in urban, suburban and rural populations in Taiwan [7]; they suggest that environmental factors are important in RA and deserve more detailed study.

Can the environment cause permanent changes in the developing immune system?

The environment during fetal and infant life has crucial roles in the development of a number of adult diseases including coronary artery disease, hypertension and stroke. Individuals with low birth weight and intrauterine growth retardation (IUGR) had an increased risk of ischaemic heart disease and strokes in later life [8–10]. Fetal and infant growth also has effects on the likelihood of developing osteoporosis [11,12]. It appears that the early environment can permanently alter (‘programme’) many biological systems, such as the hypothalamic-pituitary-adrenal axis [13], during key stages of development.

There is also evidence that the developing immune system can be permanently altered or ‘programmed’ by the early environment. The major challenge to the immune system during development is to learn to recognize and destroy infection without inducing autoimmune damage. Of particular importance is the selection of T cells in the thymus leading to the deletion of auto-reactive clones. It appears that the thymus is vulnerable to poor nutrition and growth retardation during this critical period. Animal models show that intrauterine growth restriction (IUGR) produces a smaller thymus, which could have effects on ‘self-tolerance’[14]. In humans, IUGR produces long lasting effects on immunity including a diminished response to recall antigens from childhood vaccines [15]. In addition, autoimmunity can be induced in animal models by manipulating the immune system during critical periods of development. These include thymectomy of neonatal rodents at day 3 leading to autoimmune thyroiditis [16] and treatment of gravid rodents with cyclosporin A leading to autoimmunity in the offspring [17].

Environmental factors and rheumatoid arthritis

Studies carried out looking for environmental factors important in RA have identified numerous candidates. These include smoking and a number of infectious diseases. Long-term smoking is associated with an increased risk of developing seropositive RA [18]. A smoking history also has a strong influence on the risk of developing RA associated with the DRB1 ‘shared-epitope’[19]. Potential candidates implicated in an infectious aetiology have included Epstein-Barr virus (EBV), Mycobacterium tuberculosis, Escherichia coli, Proteus mirabilis, retroviruses and parvovirus B19 [20]. These associations have been supported by increased antibody titres to the infectious organism being present in RA or the possibility of molecular mimicry. However, there has been no consistent message that a single infectious agent or other environmental factor explains the influence of the environment in RA.

Estimates of heritability suggest that genetic factors are responsible for at least 50% of the risk of developing RA [21]. This means that gene–environment interactions and environmental factors must explain the rest. The lack of success in identifying environmental factors may be due to a concentration on the time around clinical disease onset. Evidence suggests that environmental factors important in RA may act years before clinical disease becomes apparent. Although autoimmune diseases are generally more common in adults they can occur in childhood. Both RA and SLE can occur in very young children and this supports the possibility that important environmental factors must be present during or before this time. In addition, the immune pathology in adult RA begins years before clinical disease. The RA associated autoantibodies rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) may be present more than 10 years before the onset of clinical disease [22,23]. The same has also been shown for autoantibodies such as antinuclear antibodies (ANAs) associated with SLE [24]. This suggests that important environmental factors are acting years before disease onset.

What aspects of the early environment could be important in the development of rheumatoid arthritis?

Early growth and development in rheumatoid arthritis

Recent work has suggested that early growth can have long-lasting effects on autoimmune disease. The risk of developing RA may be influenced by early environmental factors such as growth and feeding. High birth weight was positively associated (OR 3·3) and initiation of breast-feeding during inpatient care was negatively associated (OR 0·2) with RA [25]. In addition, work from our group has shown an association between high weight at one year of age and having RF, an autoantibody strongly associated with RA [26].

Exposure to early infections and rheumatoid arthritis

More recently we have demonstrated significant associations between infant hygiene and RF status among adult women. Sharing a bedroom during childhood was associated with a lower risk of being RF positive (odds ratio, 0·48, 95% confidence interval 0·30–0·78, P = 0·003) [27]. There were trends towards low birth order (2nd−5th +) and lower social class (IIIN-V) being associated with a reduced likelihood of being RF positive. There were also trends towards higher birth weight and weight at 1 year being associated with an increased likelihood of having RF. This work suggests that early environmental factors including growth, feeding and infectious exposure may have a role in the development of RA. It appears that higher growth and less infectious exposure may increase the likelihood of developing RA and the RA-associated autoantibody RF.

Exposure to early infections in allergy and other autoimmune diseases

Parallels exist between an effect of hygiene on RF production and the effect of hygiene on allergy and asthma. The increasing prevalence of allergy has been explained by the ‘hygiene hypothesis’ in which decreased infectious exposure is associated with increased allergy in the developed world [28]. It had seemed unlikely that autoimmune and allergic diseases could be influenced in a similar way by infection. The predominantly TH-2 cytokine driven allergic diseases and TH-1 cytokine driven autoimmune diseases like RA were believed to be mutually exclusive. However, epidemiological evidence has now shown that autoimmune diseases such as type I diabetes are more likely in individuals exposed to a ‘cleaner’ environment during childhood and that atopy has an increased incidence in individuals with autoimmune diseases including RA [29,30]. Improved hygiene and reduced exposure to microorganisms is thought to result from higher social class, fewer siblings, having your own bedroom during childhood and living in an urban environment. These characteristics have previously been used in studies of other autoimmune diseases like type I diabetes [31–33] and allergies to define infectious exposure. The effects of these environmental characteristics may occur very early in life as a result of occult exposure to microorganisms rather than clinically apparent infectious episodes [34]. Recent data has shown that increased numbers of siblings also reduces the likelihood of developing multiple sclerosis [35]. These effects largely support the presence of early infections being protective in a number of autoimmune diseases. Early exposure to infectious organisms can alter the development and severity of animal models of inflammatory arthritis. The incidence and severity of adjuvant and collagen-induced arthritis in rodents, both animal models of RA, are increased when animals are reared in a germ-free environment [36,37].

How could early infections influence the development of rheumatoid arthritis?

There are a number of potential mechanisms by which early infection may alter the developing immune system. These include selecting the repertoire of B cells and T cells and changing the relative levels of pro and anti-inflammatory cytokines. Parasitic infections including schistosomiasis increase the production of the anti-inflammatory cytokine IL-10 [38,39]. It also appears that the cumulative effect of repeated infectious exposures, or ‘pathogen burden’, has long lasting effects on the level of inflammation in an individual. An association has been shown between a high pathogen burden and increased CRP levels. It appears that the aggregate exposure to common organisms including cytomegalovirus (CMV), hepatitis A virus, herpes simplex virus I and II, Chlamydia pneumoniae and Helicobacter pylori results in increased levels of IL-6 and C-reactive protein (CRP) [40]. This inflammatory cytokineaemia may induce autoimmune disease. There is evidence that, in addition to autoantibodies, cytokine levels may be raised before the clinical onset of RA. CRP is raised prior to RA and CRP production is under the control of factors including the cytokine IL-6 [41]. In a TNFα transgenic mouse, over-expression of TNFα leads to the development of inflammatory arthritis [42]. Cytokine levels are also affected by early growth and development. Maternal TNFα is increased in normal pregnancy but even more in IUGR with placental insufficiency [43]. Early environmental factors may influence the levels of cytokines present. Altered cytokine levels in the right contextual setting may alter the likelihood of developing autoimmunity. These effects may be shared with other autoimmune diseases.

However, infectious organisms may produce different effects at different times of life. There are a number of examples where infections occurring in the context of RA or SLE may produce a ‘flare’ of the disease [44,45]. In addition, some viral infections produce a less severe disease when they occur early in life. Chicken pox is often milder in childhood than adulthood. In addition, mumps in children is mainly benign but can lead to orchitis and infertility in adult males. The fact that early life infections are important for health in later life is also supported by the observation that exposure to infections through attending daycare reduces the risk of developing acute lymphoblastic leukaemia [46].

Conclusions

Our results suggest that a developing immune system exposed to improved standards of hygiene is more likely to produce RF and perhaps begin the pathological process that leads to RA. Common mechanisms may be shared between autoimmune and allergic disease whereby infections at critical periods of development produce permanent, and ultimately damaging, changes in immune functioning. These, in conjunction with specific genetic backgrounds and other environmental factors may lead to disease.