The Thyrotropin Receptor Antibody Reactome Determines Thyroid and Retro-orbital Responsiveness

Area of Science:

• Endocrinology
• Immunology
• Translational Medicine

Background:

• The roles of different thyrotropin (TSH) receptor (TSHR) antibodies in Graves' disease (GD) and thyroid eye disease (TED) are not fully understood.
• Existing animal models often fail to replicate the complexity of human GD and TED, overlooking the complete TSHR reactome.

Purpose of the Study:

• To evaluate a novel mouse model for Graves' disease (GD) focusing on TSHR antibodies with varying bioactivities.
• To investigate the impact of different TSHR antibody types on thyroid function and orbital changes in a murine model.

Main Methods:

• Female Balb/c mice were immunized with an adenovirus expressing human TSHR residues 1-289.
• Thyroid function was assessed via T4 and TSH levels; antibody bioactivity (TSAb, TBAb) was measured using cell-based assays.
• Thyroid and orbital tissues were analyzed using ultrasound, micro-MRI, and histology after 30 weeks.

Main Results:

• 56% (9/16) of mice developed hyperthyroidism, characterized by elevated T4 and decreased TSH levels, and thyroid enlargement.
• All mice developed TSHR antibodies; hyperthyroid mice predominantly had low-level stimulating TSHR antibodies (TSAb) alongside blocking TSHR antibodies (TBAb).
• Five hyperthyroid mice exhibited mild eye signs, with micro-MRI and histology showing retrobulbar tissue changes and macrophage infiltration.

Conclusions:

• The study highlights that developing TSHR antibodies does not guarantee hyperthyroidism in this GD model.
• The balance between TSAb and TBAb activity appears crucial in determining thyroidal outcomes, with TBAb potentially mitigating hyperthyroidism.
• This model underscores the importance of evaluating the complete TSHR antibody reactome for understanding GD pathogenesis.