Variations in IIM clinical features and serologic expression were noted across U.S. geographic regions and were found to correlate with the intensity of UVR. These findings suggest that gradients of DM and anti-Mi-2 autoantibodies exist in the U.S., as they do elsewhere, and are related to UVR intensity (6
). This is the first investigation to show evidence of a gender influence on UVR associations in autoimmune disorders.
There were certain limitations in the approaches we used that could have influenced our results. Because data to assess the population-based incidence or prevalence of DM and PM at each location are not available, we used information from referral centers that evaluate myositis patients in the region as a practical approach. It is likely that myositis patients seen at referral centers are not representative of the larger myositis population. While we are not aware of any systematic referral biases based on autoantibodies or clinical phenotype to these centers that could account for these findings, referral bias remains a possibility. Another limitation is that we had only state of residence at the time of myositis onset available to us for this study, and UVR intensities can vary considerably from one part of a state to another. Environmental exposures or factors other than UVR may also account for these findings. Moreover, we have no way to take individual-level exposure, or differences in UVR exposure at different locations over time, into account. Finally, the use of personal photoprotective measures, as well as occupations and avocations, can greatly influence an individual’s cumulative UVR exposure. Future investigations should address these issues and possible alternative explanations.
The significant associations of ethnic groups with the clinical and autoantibody phenotypes in IIM are also potentially revealing in terms of pathogenesis. While known risk factors for these phenotypes include selected polymorphisms in immune response genes, they do not fully account for these differences. Of course, the increased skin pigmentation in African Americans could alter their circulating levels of vitamin D and also reduce the damaging effects of UVR, thus limiting UVR-induced alterations that may lead to DM and anti-Mi-2 autoantibodies (11
). It is not known why African Americans are more likely to produce anti-SRP autoantibodies, but since these do not seem to be influenced by UVR, mechanisms other than skin pigmentation are likely responsible.
The reasons for the female gender effects seen in this investigation remain unclear, although some studies have suggested differential impacts of UVR in males and females. It is known that 17β-estradiol prevents UVB-induced suppression of the contact hypersensitivity response caused by immunosuppressive cytokines produced by keratinocytes in mice (12
). Also, men were immunosuppressed by solar-simulated UVR doses three times lower than those required to immunosuppress women (13
). Since these studies imply a greater impact of UVR on immune effects in men than women, other mechanisms would need to be operative to potentially explain how UVR preferentially results in the development of DM and anti-Mi-2 autoantibodies in women.
How UVR might result in DM or anti-Mi-2 autoantibodies is also unknown, however, many potential mechanisms are suggested from the published UVR effects on immunosuppression and promotion of autoimmunity (14
). UVR induces a cascade of events involving type I interferon signatures, which have been associated with DM. Additionally, there is a wide range of effects of UVR involving many other immune networks involved in the pathogenesis of myositis, including alterations in stress proteins, IL-1, IL-6, TNFα, nuclear factor (NF)-kappaB and adhesion molecule pathways (15
). Another recent finding is the rapid upregulation of Mi-2 antigen following UVR, which is mediated via more efficiently translated messages and increased stability of the protein (4
). Given these data, it is tempting to speculate that the development of DM and DM-specific anti-Mi-2 autoantibodies, which are associated with certain major histocompatibility loci, are related to UV-induced increased expression of target autoantigens, combined with altered immune responses, in genetically susceptible individuals. Alternatively, our data are consistent with the possibility that UVR exposure, or a correlate of UVR exposure, is protective for the development of PM. Understanding these mechanisms more fully, as well as the gender and ethnic influences on them, should allow for insights into the pathogenesis of myositis and could have implications for deciphering the causes of other autoimmune diseases.