Autoimmune hypophysitis: Insights from a new mouse model

Autoimmune hypophysitis (AH) is a rare but increasingly recognized disease often misdiagnosed as a non-secreting pituitary adenoma. Unlike pituitary adenomas, which usually require surgery, AH can be managed medically. A better understanding of the pathogenesis and identification of causative autoantigens can aid in the development of an improved differential diagnosis for AH thus avoiding unnecessary surgery. However, current understanding of AH is hampered by lack of an appropriate animal model that can recapitulate the human disease. To attain this goal, a novel mouse model of experimental autoimmune hypophysitis (EAH) was developed by immunizing female SJL/J mice with mouse pituitary protein extracts. Upon immunization, mice developed severe lymphocytic infiltration that mimicked very closely the human disease. In the early phase of EAH, pituitary glands became enlarged, in keeping with radiological findings of AH patients at presentation. The appearance of multinucleated giant cells in the mid phase of EAH suggests that AH and granulomatous hypophysitis may represent a spectrum of the same disease in the pituitary gland. In the late phase of EAH, pituitary glands became atrophic, indicating that empty sella syndrome maybe an outcome of the disease. Endocrinologically, mice developed adrenal insufficiency and hypothyroidism suggesting that multiple pituitary deficiencies are endpoint outcomes of EAH. Finally, prohormone convertase 2 was identified as a candidate autoantigen in EAH by a proteomic approach that combined 2-dimensional gel electrophoresis, immunoblotting and mass spectrometry. Upon immunization, we found that PC2 can induce pituitary disease, although mild, highlighting its involvement in EAH pathogenesis. In conclusion, our mouse model recapitulates the human pathology and provides new insights to its pathogenesis, establishing a novel platform for future research in AH.