Photosensitivity and cGAS-Dependent IFN-1 Activation in Patients with Lupus and TREX1 Deficiency

Area of Science:

• Immunology
• Genetics
• Dermatology

Background:

• The exonuclease TREX1 prevents harmful DNA buildup in the cytosol, which can trigger innate immune responses and autoimmunity.
• TREX1 mutations are linked to autoimmune diseases like Aicardi-Goutières syndrome and lupus, involving chronic DNA damage and type I interferon (IFN-1) production.

Purpose of the Study:

• To investigate the link between TREX1 mutations, UV light sensitivity, and DNA damage in lupus pathogenesis.
• To understand the mechanisms underlying UV-induced flares in patients with TREX1 mutations.

Main Methods:

• Phototesting was used to assess UV light sensitivity in lupus patients with TREX1 mutations.
• TREX1-deficient fibroblasts and keratinocytes were analyzed for reactive oxygen species (ROS) and DNA lesion formation (8-oxo-guanine, cyclobutane pyrimidine dimers) after UV irradiation and oxidative stress.

Main Results:

• Patients with lupus and TREX1 mutations exhibited enhanced photosensitivity.
• TREX1-deficient cells showed increased ROS production and DNA damage, including cyclobutane pyrimidine dimers, upon UV exposure.
• Single-stranded DNA regions were identified as promoting cyclobutane pyrimidine dimer formation.
• A strong UV-induced DNA damage response correlated with cGAS-dependent IFN-1 activation.

Conclusions:

• Chronic DNA damage due to TREX1 deficiency contributes to photosensitivity and IFN-1 production.
• These findings elucidate how UV exposure triggers disease flares in lupus patients with TREX1 mutations.