Abstract
Autoimmune hypophysitis (AH) is a chronic inflammatory disease characterized by infiltration of T and B lymphocytes in the pituitary gland. The mechanisms through which infiltrating lymphocytes cause disease remain unknown. Using a mouse model of AH we assessed whether T lymphocytes undergo activation in the pituitary gland. Infiltrating T cells co-localized with dendritic cells in the pituitary and produced increased levels of interferon-γ and interleukin-17 upon stimulation in vitro. Assessing proliferation of CD3- and B220-postive lymphocytes by double immunohistochemistry (PCNA-staining) and flow cytometry (BrdU incorporation) revealed that a discrete proportion of infiltrating T cells and B cells underwent proliferation within the pituitary parenchyma. This proliferation persisted into the late disease stage (day 56 post-immunization), indicating the presence of a continuous generation of autoreactive T and B cells within the pituitary gland. T cell proliferation in the pituitary was confirmed in patients affected by autoimmune hypophysitis. In conclusion, we show that pituitary-infiltrating lymphocytes proliferate in situ during AH, providing a previously unknown pathogenic mechanism and new avenues for treatment.
Highlights
Autoimmune hypophysitis (AH) is an inflammatory disease of pituitary gland[1], typically manifesting with headache, visual disturbances, and various degrees of hypopituitarism
We first tested whether dendritic cells and T cells co-localize in the pituitary glands of mice immunized with growth hormone
We found that IFN-γand IL-17 were more strongly produced by T cells isolated from growth hormone-immunized mice than by cells isolated from control complete Freund’s adjuvant (CFA)-immunized mice (Fig. 2a)
Summary
Autoimmune hypophysitis (AH) is an inflammatory disease of pituitary gland[1], typically manifesting with headache, visual disturbances, and various degrees of hypopituitarism. AH can occur spontaneously without identifiable causes (primary AH), or be caused by the administration of cancer immunotherapies (secondary AH) In the latter group, the greatest number of patients have been reported after treatment with monoclonal antibodies directed against cytotoxic T lymphocyte antigen-4 (CTLA-4)[8,9]. Few reports have far attempted to investigate the pathologies of autoimmune hypophysitis[5,17,18] These papers focused on the histochemical delineation of cell types and the activation status of the infiltrating cells that may present in the pituitary sections of hypophysitis patients. A similar phenotype, albeit to a lesser extent, was found in T cells infiltrating the pituitary gland of patients affected by autoimmune hypophysitis These data reveal a previously unknown pathogenic mechanism in autoimmune hypophysitis and may be relevant to the human disease
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