Iron-dependent epigenetic modulation promotes pathogenic T cell differentiation in lupus.

Area of Science:

• Immunology
• Trace Element Metabolism
• Autoimmune Diseases

Background:

• Iron influences immune responses, but its role in autoimmune diseases like SLE is not well understood.
• Expansion of pathogenic T cells, particularly T follicular helper (Tfh) cells, is significant in SLE pathogenesis.

Purpose of the Study:

• To investigate the role of iron in regulating pathogenic T cell differentiation in systemic lupus erythematosus (SLE).
• To explore the potential of targeting iron metabolism for SLE management.

Main Methods:

• Utilized lupus-prone mouse models.
• Administered high-iron diets and iron chelation therapies.
• Analyzed Tfh cell expansion, cytokine secretion, autoantibody production, and germinal center (GC) responses.
• Investigated the miR-21/BDH2 axis, iron accumulation, TET enzyme activity, and BCL6 gene demethylation.

Main Results:

• Iron overload promoted Tfh cell expansion, pro-inflammatory cytokine secretion, and autoantibody production in lupus-prone mice.
• High-iron diet increased Tfh cells and antigen-specific GC response.
• Iron chelation inhibited Tfh cell differentiation.
• The miR-21/BDH2 axis was identified as a driver of iron accumulation, promoting Fe2+-dependent TET enzyme activity and BCL6 demethylation in Tfh cells.

Conclusions:

• Iron plays a critical role in regulating pathogenic T cell differentiation in SLE.
• Maintaining iron homeostasis may be essential for eliminating pathogenic T cells.
• Targeting iron metabolism presents a potential therapeutic strategy for managing SLE patients.