Role of environmental factors in autoantibody production - importance of a detailed analysis in a small cohort

In the previous issue of Arthritis Research & Therapy, Muro and colleagues reported a detailed epidemiologic analysis in central Japan on one of the new myositis-specific autoantibodies to MDA-5 (melanoma differentiation-associated gene 5), which is associated with clinically amyopathic dermatomyositis accompanying interstitial lung disease. The increasing prevalence of anti-MDA-5, higher prevalence in small rural towns, and geographical clustering in two areas along the Kiso River suggest a role of environmental factors associated with rural communities or the river/water system or both. A detailed analysis of a small cohort may offer clues, which is ignored in multi-center studies, to the pathogenesis of systemic rheumatic diseases and autoantibody production.

Many autoantibodies to cellular constituents are useful biomarkers associated with a certain diagnosis or clinical manifestations or both. Autoantibodies in polymyositis/ dermatomyositis (PM/DM) have been actively studied in recent years, and several myositis-specifi c antibodies (MSAs) have been newly described.
In the previous issue of Arthritis Research & Th erapy, Muro and colleagues [1] reported a detailed epidemi ologic analysis in central Japan on one of the recently described MSAs, anti-MDA-5 (melanoma diff erentiation-associated gene 5). Th is autoantibody was originally named anti-CADM-140 because of its association with clinically amyopathic DM (CADM) and the molecular size (approximately 140 kDa) of the target antigen [2].
Th e antigen was only recently identifi ed as MDA-5, a cytoplasmic viral RNA receptor with RNA helicase activity [3]. MDA-5 is a part of anti-viral innate immunity. Stimulation of MDA-5 by its ligand induces type Iinterferon (I-IFN) production, and I-IFN also upregulates MDA-5. A strong association of anti-MDA-5 with CADM accompanying interstitial lung disease (ILD) was confi rmed in several independent studies [3,4]. ILD in this subset is often rapidly progressive and resistant to treatment, making the detection of anti-MDA-5 clinically important. Reports on anti-MDA-5 were limited to Japan and Korea until recently, when a study in the US confi rmed the presence of this specifi city [5].
MDA-5 as a target of autoantibodies in a subset of DM makes an attractive story because both viruses and I-IFN have been implicated in the pathogenesis of DM. Muro and colleagues [1] showed that, in recent years at their institute, an increasing prevalence of anti-MDA-5 in a subset of patients was more prevalent in small rural towns compared with large cities. Furthermore, clustering of anti-MDA-5-positive cases to certain years and geographical areas is documented. In fact, fi ve out of six and four out of four patients with anti-MDA-5 in 2002 and 2010, respectively, were from the two small areas along the Kiso River. Th ese clustering patterns are consistent with the role of environmental factors associated with a rural community or the river/water system (or both) in the development of anti-MDA-5-positive CADM cases.
Among environmental factors in DM, ultraviolet (UV) exposure has been considered important since the percentage of DM within PM/DM and prevalence of anti-Mi-2 antibodies correlate with the UV index of the area [6]. In vitro upregulation of a major DM autoantigen, Mi-2, by UV exposure supports this idea. However, given the history and occupation of the patients, the role of sun exposure seems unlikely in this cohort [1]. Seasonal diff erence in onset and relapse in PM/DM was reported in several studies and is another factor consistent with the role of environmental factors; seasonally skewed

Abstract
In the previous issue of Arthritis Research & Therapy, Muro and colleagues reported a detailed epidemiologic analysis in central Japan on one of the new myositis-specifi c autoantibodies to MDA-5 (melanoma diff erentiation-associated gene 5), which is associated with clinically amyopathic dermatomyositis accompanying interstitial lung disease. The increasing prevalence of anti-MDA-5, higher prevalence in small rural towns, and geographical clustering in two areas along the Kiso River suggest a role of environmental factors associated with rural communities or the river/ water system or both. A detailed analysis of a small cohort may off er clues, which is ignored in multi-center studies, to the pathogenesis of systemic rheumatic diseases and autoantibody production. onset of PM/DM with anti-Jo-1, all anti-aminoacyl tRNA synthetases combined, anti-SRP (anti-signal recognition particle), and anti-7SL RNA has been reported [7]. Also, other studies show a diff erence in prevalence of PM/DM in rural versus urban communities but without a clear explanation [8]. Others reported an increased prevalence of anti-nuclear antibody among rural populations and suggested environmental factors such as certain crops, animals, or pesticides as potential causes [9]. Th e role of the river/water as environmental factors for produc tion of anti-nuclear antibody has been considered mainly on the basis of pollution by heavy metals and other chemicals, consumption of contaminated fi sh, and diseases transmitted via water or water-related insects [10]. Whether the river/water plays a critical role in clustering in the study [1] remains to be clarifi ed.
Large-scale multi-center studies have been a trend in recent years and are based on the assumption that environmental or minor genetic diff erences within the same country do not have signifi cant eff ects. Samples and data from diff erent institutes are pooled together; when the diff erences in prevalence of autoantibodies or other clinical features between institutions are found, they are usually interpreted as bias in recruitment or methodological heterogeneity between institutions. However, in other studies, regional diff erences in prevalence or geographical clustering of patients with PM/DM, scleroderma, or systemic lupus erythematosus or in production of certain autoantibodies [11,12] have been reported without clear explanation. Genetic heterogeneity within the same ethnicity, which may signifi cantly aff ect autoantibody production pattern, is also well known. Some of the samples from this cohort [1] were included in a previous multi-center study in Japan, which reports 11% prevalence of anti-MDA-5 in DM [13]. In contrast, prevalences of anti-MDA-5 in this small cohort are 27% overall, as high as 42% in the last 8 years, and 45% in rural areas [1]. Th is diff erence seems to be too much to be explained on the basis of recruitment bias or methodo logical errors, especially when the data show clustering in small areas.
As shown in Muro's study [1], the diff erence in genetic or environmental factors (or both) related to a specifi c geographic area should be carefully evaluated. Th is study may also off er clues that are not apparent in the large number of pooled samples in multi-center studies and that elucidate the patho genesis of specifi c autoimmune disease and production of autoantibodies.