From pituitary expansion to empty sella: disease progression in a mouse model of autoimmune hypophysitis.
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ABSTRACT:
SUBMITTER: Lupi I
PROVIDER: S-EPMC3198994 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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-? 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.
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Project description:Amyotrophic lateral sclerosis (ALS) is a devastating incurable neurological disorder characterized by motor neuron (MN) death and muscle dysfunction leading to mean survival time after diagnosis of only 2-5 years. A potential ALS treatment is to delay the loss of MNs and disease progression by the delivery of trophic factors. Previously, we demonstrated that implanted mesoporous silica nanoparticles (MSPs) loaded with trophic factor peptide mimetics support survival and induce differentiation of co-implanted embryonic stem cell (ESC)-derived MNs. Here, we investigate whether MSP loaded with peptide mimetics of ciliary neurotrophic factor (Cintrofin), glial-derived neurotrophic factor (Gliafin), and vascular endothelial growth factor (Vefin1) injected into the cervical spinal cord of mutant SOD1 mice affect disease progression and extend survival. We also transplanted boundary cap neural crest stem cells (bNCSCs) which have been shown previously to have a positive effect on MN survival in vitro and in vivo. We show that mimetic-loaded MSPs and bNCSCs significantly delay disease progression and increase survival of mutant SOD1 mice, and also that empty particles significantly improve the condition of ALS mice. Our results suggest that intraspinal delivery of MSPs is a potential therapeutic approach for the treatment of ALS.
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Project description:Background: The goal of this study was to relate diffusion MR measures of white matter integrity of the retinofugal visual pathway with prolactin levels in a patient with downward herniation of the optic chiasm secondary to medical treatment of a prolactinoma. Methods: A 36-year-old woman with a prolactinoma presented with progressive bilateral visual field defects 9 years after initial diagnosis and medical treatment. She was diagnosed with empty-sella syndrome and instructed to stop cabergoline. Hormone testing was conducted in tandem with routine clinical evaluations over 1 year and the patient was followed with diffusion magnetic resonance imaging (dMRI), optical coherence tomography (OCT), and automated perimetry at three time points. Five healthy controls underwent a complementary battery of clinical and neuroimaging tests at a single time point. Results: Shortly after discontinuing cabergoline, diffusion metrics in the optic tracts were within the range of values observed in healthy controls. However, following a brief period where the patient resumed cabergoline (of her own volition), there was a decrease in serum prolactin with a corresponding decrease in visual ability and increase in radial diffusivity (p < 0.001). Those measures again returned to their baseline ranges after discontinuing cabergoline a second time. Conclusions: These results demonstrate the sensitivity of dMRI to detect rapid and functionally significant microstructural changes in white matter tracts secondary to alterations in serum prolactin levels. The inverse relations between prolactin and measures of white matter integrity and visual function are consistent with the hypothesis that prolactin can play a neuroprotective role in the injured nervous system.
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Project description: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.
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Project description:BackgroundPulmonary arterial hypertension is often associated with connective tissue disease. Although there are some animal models of pulmonary hypertension, an autoimmune disease-based model has not yet been reported. MRL/lpr mice, which have hypergammaglobulinemia, produce various autoimmune antibodies, and develop vasculitis and nephritis spontaneously. However, little is known about pulmonary circulation in these mice. In the present study, we examined the pulmonary arterial pressure in MRL/lpr mice.Methods and resultsWe used female MRL/lpr mice aged between 12 and 14 weeks. Fluorescent immunostaining showed that there was no deposition of immunoglobulin or C3 in the lung tissue of the MRL/lpr mice. Elevation of interferon-γ and interleukin-6 was recognized in the lung tissue of the MRL/lpr mice. Right ventricular systolic pressure, Fulton index and the ratio of right ventricular weight to body weight in the MRL/lpr mice were significantly higher than those in wild type mice with same background (C57BL/6). The medial smooth muscle area and the proportion of muscularized vessels in the lung tissue of the MRL/lpr mice were larger than those of the C57BL/6 mice. Western blot analysis demonstrated markedly elevated levels of prepro-endothelin-1 and survivin as well as decreased endothelial nitric oxide synthase phosphorylation in the lung tissue of the MRL/lpr mice. Terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling assay showed the resistance against apoptosis of pulmonary arterial smooth muscle cells in the MRL/lpr mice.ConclusionWe showed that MRL/lpr mice were complicated with pulmonary hypertension. MRL/lpr mice appeared to be a useful model for studying the mechanism of pulmonary hypertension associated with connective tissue diseases.
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Project description:Autoimmune hypophysitis is classified as primary if its origin is idiopathic and secondary if it develops as a consequence of treatment with immune checkpoint inhibitors. Expanding use of immunotherapy has been paralleled by the increasing hypophysitis prevalence. However, understanding of the immune responses driving the disease remains limited. Using a mouse model of primary hypophysitis, we have identified CD4+ T lymphocytes to be the main pituitary-infiltrating immune cell population. Functional analysis showed that they display a Th17 and Th1/Th17 phenotype. To examine involvement of proinflammatory Th1, Th17, and Th1/17 subsets in hypophysitis, we have isolated RNA from the formalin-fixed paraffin-embedded pituitary specimens from 16 hypophysitis patients (three of whom had hypophysitis secondary to immune checkpoint inhibitors), 10 patients with adenoma, and 23 normal pituitaries obtained at autopsy. Transcript levels of IFN-γ, IL-17A, IL-4, IL-10, TGF-β, CD4, CD8α, and class II MHC transactivator were analyzed by the reverse transcription-quantitative PCR (RT-qPCR). Pituitary glands of patients with hypophysitis showed significantly higher IL-17A, CD4, and class II MHC transactivator mRNA levels compared with adenoma and normal pituitaries. All three secondary hypophysitis patients showed detectable IL-17A levels, but other cytokines were not detected in their pituitaries. Levels of IFN-γ, IL-4, IL-10, and TGF-β did not differ between the groups. TGF-β transcript was found in significantly fewer hypophysitis pituitaries (2 out of 16) compared with adenoma (7 out of 10) and normal pituitaries (11 out of 23). Presence of TGF-β in two hypophysitis patients was associated with significantly lower IL-17A mRNA levels compared with hypophysitis patients with no detectable TGF-β (p = 0.03).
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Project description:BACKGROUND:Patients with pituitary metastasis (PM) have a relatively poor prognosis. We describe the presentation, management, and outcomes of patients with PM. SUBJECTS, MATERIALS, AND METHODS:We performed a retrospective review of patients diagnosed with PM at a single institution from 1996 to 2015. Eighty-five patients diagnosed with metastasis to the pituitary or sella turcica by pathology or based on a combination of neuroimaging and clinical findings were included. Univariate and multivariable Cox regressions evaluated associations between clinical factors and overall survival. RESULTS:The most frequent sites of primary malignancies resulting in PM were lung (26%) and breast (26%). Median age at diagnosis was 60?years (range, 18-95). The most common complaints at diagnosis included visual deficits (62%), headache (47%), and cranial nerve palsy (31%). Seventy percent of patients had pituitary insufficiency-adrenal insufficiency (59%), hypothyroidism (59%), or diabetes insipidus (28%). Management of PM included radiation therapy (76%), chemotherapy (68%), surgical resection (21%), or combination therapy (71%). Fifty percent and 52% of patients who received surgical treatment and irradiation, respectively, reported symptomatic improvement. Median overall survival (OS) was 16.5 months (95% confidence interval: 10.7-25.4). On multivariable analysis, a primary cancer site other than lung or breast (p = .020), age <60?years (p = .030), and surgical resection (p = .016) were associated with longer OS. CONCLUSION:Patients <60?years of age, those with primary tumor sites other than lung or breast, and those who undergo surgical resection of the pituitary lesion may have prolonged survival. Surgical resection and radiation treatment resulted in symptomatic improvement in ~50% of patients. IMPLICATIONS FOR PRACTICE:This study is the largest original series of patients with metastatic disease to the sella. In patients with pituitary metastasis, younger age, primary site other than lung or breast, and metastatic resection may prolong survival. Resection and radiation led to symptomatic improvement in ?50% of patients. Seventy percent of patients had hypopituitarism. These hormonal deficiencies can be life threatening and can result in substantial morbidity if left untreated. Patients should be treated using a multimodality approach-including a potential role for surgery, radiation, chemotherapy, and hormone replacement-with the goal of improving survival and quality of life.
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Project description:Adenoid cystic carcinoma (ACC) is a tumor of the exocrine glands that originates primarily from the minor and major salivary glands, nasopharynx, and lacrimal glands. ACC grows slowly but is locally aggressive and prone to recurrence. It is uncommon for ACCs to develop in the pituitary gland as a primary tumor. We present a case of primary pituitary ACC extending to the sphenoid sinus resembling an invasive adenoma in a 71-year-old woman with a history of nasal epistaxis. We reviewed other reported cases of pituitary ACCs with retrospective validation of whether the tumor was primary or not. The intrasellar tumor exhibited MYB rearrangement with enlargement and destruction of the sella turcica and dural tears toward the sphenoid sinus, which would be consistent for a tumor originating from the pituitary gland. Including our case, only four intrasellar and one suprasellar ACC have been confirmed as primary tumors. All intrasellar ACCs had the characteristic of some form of invasion of neighboring structures with evidence of hyperprolactinemia. ACC could develop in the pituitary gland as a form of salivary gland-like tumor derived from the ectopic salivary gland rests. ACCs rarely arise from the pituitary gland; however, the accurate determination of primary occurrence is difficult because of the invasive nature of these tumors, and the anatomical relationship with the sphenoid sinus and the cavernous sinus. Excessive bleeding from the tumor or unexpected internal carotid artery injury should be avoided during surgery for primary and secondary pituitary ACC.
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Project description:Autoimmune hypophysitis (AH) is an autoimmune disease of the pituitary for which the pathogenesis is incompletely known. AH is often treated with corticosteroids; however, steroids may lead to considerable side effects. Using a mouse model of AH (experimental autoimmune hypophysitis, EAH), we show that interleukin-1 receptor-associated kinase 1 (IRAK1) is upregulated in the pituitaries of mice that developed EAH. We identified rosoxacin as a specific inhibitor for IRAK1 and found it could treat EAH. Rosoxacin treatment at an early stage (day 0-13) slightly reduced disease severity, whereas treatment at a later stage (day 14-27) significantly suppressed EAH. Further investigation indicated rosoxacin reduced production of autoantigen-specific antibodies. Rosoxacin downregulated production of cytokines and chemokines that may dampen T cell differentiation or recruitment to the pituitary. Finally, rosoxacin downregulated class II major histocompatibility complex expression on antigen-presenting cells that may lead to impaired activation of autoantigen-specific T cells. These data suggest that IRAK1 may play a pathogenic role in AH and that rosoxacin may be an effective drug for AH and other inflammatory diseases involving IRAK1 dysregulation.
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