The TSH Receptor Antibody Reactome Contributes to Retro-Orbital Inflammation

Area of Science:

• Endocrinology
• Immunology
• Ophthalmology

Background:

• Graves disease often involves thyroid eye disease (TED), characterized by retro-orbital inflammation and fibroblast activity.
• Thyroid-stimulating hormone receptor (TSHR) antibodies are implicated in TED, but the TSHR reactome includes antibodies with diverse activities.
• The role of neutral TSHR antibodies (N-TSHR-mAbs) in TED pathogenesis remains unclear.

Purpose of the Study:

• To investigate the effects of N-TSHR-mAbs, targeting the TSHR hinge region, on fibroblasts.
• To determine if N-TSHR-mAbs can contribute to the inflammatory processes observed in TED.

Main Methods:

• Exposure of TSHR-expressing fibroblasts to a specific N-TSHR-mAb.
• Analysis of cellular stress, signaling pathways, and cell death mechanisms.
• Evaluation of inflammasome activation, caspase 8, and gasdermin D.

Main Results:

• N-TSHR-mAb induced significant cellular stress in fibroblasts.
• This stress activated inflammasome signaling pathways.
• The process culminated in pyroptosis, a form of programmed cell death, mediated by caspase 8 and gasdermin D.

Conclusions:

• N-TSHR-mAbs can provoke inflammatory responses and cell death in retro-orbital fibroblasts.
• These antibodies may exacerbate the inflammation seen in thyroid eye disease (TED).
• The TSHR reactome's diverse antibody activities contribute to TED pathogenesis beyond stimulating antibodies.