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Autoimmune Hypophysitis of SJL Mice: Clinical Insights from a New Animal Model

Department of Pathology (S.-C.T., I.L., M.L., A.G., H.K., N.R.R., P.C.), The Johns Hopkins University, School of Medicine, and Feinstone Department of Molecular Microbiology and Immunology (N.R.R., P.C.), The Johns Hopkins, Bloomberg School of Public Health, Baltimore, Maryland 21205; Department of Endocrinology and Metabolism (I.L.), University of Pisa, 43-56126 Pisa, Italy; Department of Neurosurgery (A.G.), Georg-August-University Goettingen, 37077 Goettingen, Germany; Department of Nutrition & Food Science (Y.-M.T.), Auburn University, Auburn, Alabama 36849; and Endocrinology Unit (G.P.), Department of Medical Science "M. Aresu," Azienda Ospedaliera, University of Cagliari, 09042 Monserrato (CA), Italy

Address all correspondence and requests for reprints to: Patrizio Caturegli, Department of Pathology, Johns Hopkins University, School of Medicine, Ross Building, Room 632, 720 Rutland Avenue, Baltimore, Maryland 21205. E-mail: pcat{at}jhmi.edu.

Autoimmune hypophysitis (AH) is a rare but increasingly recognized disease of the pituitary gland. Its autoantigens are unknown, and the management is difficult because it is often misdiagnosed as a nonsecreting adenoma. By immunizing female SJL/J mice with mouse pituitary extracts, we established a new mouse model of experimental AH. Immunized mice developed severe lymphocytic infiltration in the anterior pituitary that closely mimicked the human pathology. In the early phase of experimental AH, the pituitary enlarged, consistent with the compression symptoms reported by hypophysitis patients at presentation. In the florid phase, adrenal insufficiency and pituitary antibodies developed, in strong correlation with the pituitary pathology. In the late phase, hypothyroidism ensued, and the pituitary gland became atrophic. Using immune sera as probes in a two-dimensional immunoblotting screen followed by mass spectrometry, we identified several proteins that could function as pituitary autoantigens. These findings provide new insights into the pathogenesis of AH, and establish a platform for developing novel diagnostic biomarkers and therapeutics.