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The interaction between environmental triggers and epigenetics in autoimmunity.

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  • 1Department of Internal Medicine, Division of Rheumatology, University of Michigan, SRB 3007, 109 Zina Pitcher Pl., Ann Arbor, MI 48109-2200, United States.

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Summary

Environmental factors like infections and sunlight trigger systemic lupus erythematosus (SLE) flares by impairing DNA methylation in CD4+ T cells. This epigenetic alteration in T cells contributes to lupus pathogenesis and flares in susceptible individuals.

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Area of Science:

  • Immunology
  • Epigenetics
  • Environmental Health

Background:

  • Systemic lupus erythematosus (SLE) is an autoimmune disease often triggered by environmental factors in genetically predisposed individuals.
  • The precise mechanisms by which environmental agents like infections and sunlight induce SLE flares remain incompletely understood.
  • Epigenetic alterations, specifically in CD4+ T cells, have been implicated in lupus pathogenesis, with DNA methylation changes playing a key role.

Purpose of the Study:

  • To investigate how environmental triggers such as infections and sunlight exposure influence T cell DNA methylation.
  • To elucidate the role of DNA methyltransferase 1 (Dnmt1) and S-adenosylmethionine in the context of environmental lupus triggers.
  • To identify potential mechanisms contributing to lupus flares at the epigenetic and cellular level.

Main Methods:

  • Utilizing drug-induced lupus models to study the effects of DNA methylation inhibitors on CD4+ T cells.
  • Analyzing DNA methylation patterns in CD4+ T cells from animal models and human patients with active lupus.
  • Investigating the impact of reactive oxygen species and methyl donor availability on Dnmt1 regulation and DNA methylation.

Main Results:

  • Drug-induced lupus models showed that epigenetically altered CD4+ T cells can induce lupus.
  • Similar T cell epigenetic alterations were observed in patients experiencing active lupus flares.
  • Reactive oxygen species were found to inhibit the upregulation of Dnmt1, while a diet deficient in methyl donors exacerbated lupus development in animal models.

Conclusions:

  • Environmental factors causing oxidative stress and poor methyl donor intake can impair T cell DNA methylation, contributing to lupus flares.
  • Inhibiting Dnmt1 upregulation and reducing methyl donor availability are key mechanisms linking environmental triggers to lupus pathogenesis.
  • These findings provide a mechanistic link between environmental exposures and the initiation of lupus flares through epigenetic modifications in CD4+ T cells.