Antibody-induced modulation of TSH receptor post-translational processing

Area of Science:

• Endocrinology
• Immunology
• Molecular Biology

Background:

• The TSH receptor (TSHR) undergoes post-translational processing, including cleavage and subunit formation.
• TSHR antibodies (TSHR-Abs) can modulate TSHR signaling, affecting thyroid function.
• Some TSHR-Abs bind without influencing signaling, termed neutral antibodies.

Purpose of the Study:

• To investigate the impact of monoclonal TSHR-Abs on TSHR processing.
• To determine if TSHR-Abs can inhibit TSHR cleavage and affect TSHR expression.
• To explore the epitope-dependency of TSHR-Ab effects on receptor processing.

Main Methods:

• Characterization of a series of monoclonal TSHR-Abs.
• Analysis of TSHR cleavage and expression levels in response to TSHR-Abs.
• Epitope mapping of TSHR-Abs to identify critical regions for activity.

Main Results:

• Many monoclonal TSHR-Abs inhibited TSHR cleavage and enhanced TSHR expression.
• Neutral TSHR-Abs targeting the cleaved ectodomain region (aa 316-366) were particularly effective.
• Inhibition was epitope-dependent, with antibodies targeting regions after aa 335-354 showing no activity.

Conclusions:

• TSHR-Abs can aberrantly influence TSHR antigen processing.
• This modulation of receptor processing represents a novel mechanism in autoimmune thyroid disease.
• The findings suggest a new pathway for disease maintenance and exacerbation in autoimmune thyroid conditions.