The role of environmental/dietary mercury exposure in autoimmune response associated with T helper 17 (Th17) axis

Abstract

Autoimmunity encompasses a range of chronic inflammatory conditions resultant from inappropriate immune response against self-antigens. The exact etiology of autoimmune conditions remains elusive, with many genetic and environmental factors implicated. One of proposed environmental factor is mercury (Hg). Humans are primarily exposed to Hg predominantly through the consumtion of fish which contain methylmercury (MeHg). The impact of Hg exposure through fish consumption on autoimmunity has gained public health interest, owing to the high importance of fish in the human diet. Fish are a rich source of nutrients, especially the n-3 long chain polyunsaturated fatty acids (LCPUFA) which have immunomodulatory properties and have been proposed to mitigate against adverse effects of MeHg. Although, human studies were focused on the impact of Hg exposure on autoantibody production there is increasing interest in how Hg may influence Th17 response, an immune cell lineage implicated in autoimmune pathogenesis, notably in Systemic Lupus Erythematosus (SLE). Therefore, this PhD thesis aimed to investigate associations between Hg exposure and cytokines associated with the Th17 axis in both fish consumers and autoimmune patients with SLE. A narrative literature review was undertaken to evaluate the contribution of dietary sources to Hg/MeHg exposure. This chapter provided a comprehensive review of foods that may contain Hg/MeHg, including both plant and animal products and discussed how other nutrients present within these foods may influence the adverse effects of Hg exposure. A study of a high fish-
consuming young adults from the Republic of Seychelles, found no association between MeHg exposure (hair Hg concentrations 10.21 (5.98) ppm) and Th17 response, with or without adjustment for LCPUFA status. In this study, IL-17F was negatively associated with female status in models which controlled for total n-6 and n-3 LCPUFA (β = ‐0.292; 95% CI: ‐0.532, ‐0.052; p = 0.017) and n-6:n-3 LCPUFA ratio (β = ‐0.290; 95% CI: -0.529, -0.051; p = 0.018). Also, there was an association between IL-27 and maternal socioeconomic status (β = ‐0.005; 95% CI: -0.010, 0.000; p = 0.044) in the model adjusted for n-6:n-3 LCPUFA ratio and IL-27 concentrations were negatively associated with smoking status in adjusted for total n-6 and n-3 LCPUFA (β = -0.157; 95% CI: ‐0.284, ‐0.029; p = 0.016) and for n-6:n-3 LPCUFA ratio (β = -0.158; 95% CI: -0.285, -0.031; p = 0.015). A separate study investigated the relationship between Hg exposure and disease activity in a cohort of SLE patients, and demonstrated that exposure to Hg, measured as inorganic Hg (iHg) in urine (median 1.99 ng/g creatinine) and as MeHg in hair (median 0.59 ppm), did not significantly influence the relationship between Th17 cytokines and clinical measures of disease activity and disease-associated damage. Furthermore, in this study IL-17E was positively associated with SLICC/ACR+ in unadjusted (β = 0.465, 95% CI: 0.432, 0.786, p = 0.005) and adjusted (β = 0.355, 95% CI: 0.050, 0.660, p = 0.023) models. Finally, the influence of fish consumption on MeHg status and IL-17A and IL-22 was determined following an 8-week long intervention, in which women of child-bearing age consumed either one or two portions of fish high in MeHg (tuna), fish low in MeHg (sardines) or a meal without fish. Whilst the intervention with tuna resulted in a significant increase in MeHg status, no significant changes in Th17 cytokines were noted between the intervention groups, thereby indicating that MeHg exposure did not alter the Th17 response. Overall, results from this thesis suggest that exposure to MeHg, through regular fish intake, does not contribute to Th17-associated autoimmunity in young adults and has no effect on the cytokines associated with Th17 response in SLE or young women of child-bearing age. These findings contribute to the evidence supporting a public health message recommending regular fish intake, as a part of well-balanced diet among general population.

Date of Award	Mar 2022
Original language	English
Sponsors	Department for the Economy, United States National Institute of Environmental Health Sciences & Government of the Republic of the Seychelles
Supervisor	Violetta Naughton (Supervisor), Emeir McSorley (Supervisor), Philip Allsopp (Supervisor), Alison Yeates (Supervisor), Maria Mulhern (Supervisor) & Sean Strain (Supervisor)