A novel thymoma-associated autoimmune disease: Anti-PIT-1 antibody syndrome

Bando, Hironori; Iguchi, Genzo; Okimura, Yasuhiko; Odake, Yukiko; Matsumoto, Ryusaku; Suda, Kentaro; Nishizawa, Hitoshi; Fukuoka, Hidenori; Mokubo, Atsuko; Tojo, Katsuyoshi; Maniwa, Yoshimasa; Ogawa, Wataru; Takahashi, Yutaka

doi:10.1038/srep43060

Cited by 19 publications

(15 citation statements)

References 36 publications

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“…ELISPOT assays were performed using ELISpotPRO for Human IFN-γ (Mabtech, RRID:AB_2877719) [ 26 ], following the manufacturer’s instructions as previously described [ 2 , 6 ]. Briefly, a total of 2.5 × 10 5 isolated PBMCs were seeded into each well and incubated with recombinant PIT-1 protein (10 µg/mL, Santa Cruz Biotechnology) in 96-well microtiter plates precoated with 10 μg/mL of antihuman IFN-γ antibody [ 26 ] for 40 hours.…”

Section: Methodsmentioning

confidence: 99%

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Two Cases of anti–PIT-1 Hypophysitis Exhibited as a Form of Paraneoplastic Syndrome not Associated With Thymoma

Kanie

Iguchi

Inuzuka

et al. 2020

Journal of the Endocrine Society

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Anti–pituitary-specific transcription factor 1 (PIT-1) hypophysitis (anti–PIT-1 antibody syndrome) is a thymoma-associated autoimmune disease characterized by acquired growth hormone (GH), prolactin (PRL), and thyrotropin (TSH) deficiencies due to autoimmunity against PIT-1. Ectopic expression of PIT-1 in the thymoma plays a causal role in development of the disease. Here, we report 2 cases of anti–PIT-1 hypophysitis exhibiting as a form of paraneoplastic syndrome with conditions other than thymoma. A 79-year-old woman (case 1) and an 86-year-old man (case 2) were referred with a suspicion of anti–PIT-1 hypophysitis because of acquired GH, PRL, and TSH deficiencies. Case 1 was complicated by diffuse large B-cell lymphoma (DLBCL) of the bladder and case 2 was diagnosed with malignancy with multiple metastases of unknown origin. Because circulating anti–PIT-1 antibody was detected, both patients were diagnosed with anti–PIT-1 hypophysitis. Circulating PIT-1–reactive T cells were detected in case 1 via enzyme-linked immunospot (ELISPOT) assay. Interestingly, the PIT-1 protein was ectopically expressed in the DLBCL cells of case 1, whereas DLBCL tissues derived from patients without anti–PIT-1 hypophysitis were negative for PIT-1. In case 2, the materials were not available because of best supportive care was under way. These data show that anti–PIT-1 hypophysitis is associated not only with thymoma but also with other malignancies. Additionally, the ectopic expression of PIT-1 in the DLBCL tissues and presence of PIT-1–reactive T cells suggested that the underlying mechanisms were similar to those observed in thymoma. Thus, anti–PIT-1 hypophysitis is defined as a form of paraneoplastic syndrome.

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Section: Methodsmentioning

confidence: 99%

“…In previous cases of anti–PIT-1 hypophysitis associated with thymoma, ectopic expression of PIT-1 was observed in the tumor tissue [ 6 ]. Therefore, we examined the DLBCL tissue in case 1.…”

Section: Case Presentationmentioning

confidence: 99%

Two Cases of anti–PIT-1 Hypophysitis Exhibited as a Form of Paraneoplastic Syndrome not Associated With Thymoma

Kanie

Iguchi

Inuzuka

et al. 2020

Journal of the Endocrine Society

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“…Several APA have been identified and, despite background issues and the absence of universal standardization, indirect immunofluorescence remains the preferred method for their identification (for review see Guaraldi et al 2017). In some cases, clinical correlates between APA and hormone deficiencies have been reported, such as GH/TSH/PRL insufficiency in the setting of an anti-Pit syndrome (Bando et al 2017).…”

Section: Part I: Autoimmune Lymphocytic Hypophysitis (Lyh) In Systemimentioning

confidence: 99%

“…AI endocrinopathies and gastritis have also been recently associated with the "anti-Pit1 syndrome" which therefore enter the spectrum of APS. Importantly, this rare syndrome was recently associated with the presence of a thymoma, ectopic expression of Pit1 in the thymus may be causative, and thymectomy has proven to reduce the concentrations of anti-Pit-1 antibodies (Bando et al 2017).…”

Section: Lyh In Autoimmune Polyendocrine Syndromes (Aps)mentioning

confidence: 99%

Hypophysitis and Granulomatous Pituitary Lesions in Systemic Diseases

Jaffrain-Rea¹,

Filipponi²

2019

Endocrinology

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In clinical practice, expansive sellar lesions are largely represented by primary diseases of the pituitary gland, mostly pituitary tumors, which can be managed by endocrinologists and/or multidisciplinary pituitary teams. Hypophysitis has long been considered as a rare disease, and is classified on the basis of pathological findings, and as primary or secondary. Nowadays, an enlarging spectrum of pituitary and/or hypothalamic inflammatory, granulomatous, or even neoplastic disorders can be recognized, which may be part of systemic conditions and require appropriate multidisciplinary management involving a variety of specialists. For example, hypophysitis is being increasingly recognized in the setting of systemic IgG4-related disorders or as side effects of immune checkpoints inhibitors in oncological patients. Lymphocytic hypophysitis may sometimes be part of autoimmune polyendocrine syndromes. Significant knowledge has been added in the last decade in the pathogenesis and management of histiocytic disorders, which may infiltrate the pituitary and/or the hypothalamus Infective causes of pituitary inflammation should not be underestimated and are increasingly recognized in immunocompromised patients. Based on updated literature on these topics, this chapter aims to place pituitary inflammatory, granulomatous, and histiocytic disorders in their systemic context and stimulate multidisciplinary collaboration in order to optimize their diagnosis and clinical management.

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“…PIT-1 plays an essential role in the differentiation of somatotrophs, lactotrophs, and thyrotrophs in the anterior pituitary and regulates the expression of GH, PRL, and TSH. Recently, it has been reported that breakdown of immune tolerance toward PIT-1 is caused by aberrant expression of PIT-1 protein in the thymoma [3]. In addition, circulating PIT-1–reactive cytotoxic T lymphocytes (CTLs) were detected in patients with anti–PIT-1 antibody syndrome, and the infiltration of these cells was observed in the pituitary, indicating that CTLs play a pivotal role in the development of the syndrome [4].…”

mentioning

confidence: 99%

Pathogenesis of Anti–PIT-1 Antibody Syndrome: PIT-1 Presentation by HLA Class I on Anterior Pituitary Cells

Kanie

Bando

Iguchi

et al. 2019

Journal of the Endocrine Society

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Context Anti–pituitary-specific transcriptional factor-1 (anti–PIT-1) antibody syndrome is characterized by acquired and specific deficiencies in growth hormone, prolactin, and thyroid-stimulating hormone. Although PIT-1–reactive cytotoxic T lymphocytes (CTLs) have been speculated to recognize anterior pituitary cells and to cause the injury in the pathogenesis of the syndrome, it remains unclear whether endogenous PIT-1 protein is processed through the proteolytic pathway and presented as an antigen on anterior pituitary cells. Objective To examine how PIT-1 protein is processed and whether its epitope is presented by major histocompatibility complex (MHC)/HLA class I on anterior pituitary cells. Materials and Methods Immunofluorescence staining and proximity ligation assay (PLA) were performed using anti–PIT-1 antibody and patients’ sera on PIT-1–expressing cell line GH3 cells and human induced pluripotent stem cell (iPSC)-derived pituitary tissues. Results PIT-1 was colocalized with MHC class I molecules, calnexin, and GM130 in the cytosol. PLA results showed that PIT-1 epitope was presented by MHC/HLA class I molecules on the cell surface of GH3 cells and iPSC-derived pituitary cells. The number of PIT-1/HLA complexes on the cell surface of pituitary cells in the patient was comparable with that in the control subject. Conclusions Our data indicate that PIT-1 protein is processed in the antigen presentation pathway and that its epitopes are presented by in MHC/HLA class I on anterior pituitary cells, supporting the hypothesis that PIT-1–reactive CTLs caused the cell-specific damage. It is also suggested that number of epitope presentation was not associated with the pathogenesis of anti–PIT-1 antibody syndrome.

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A novel thymoma-associated autoimmune disease: Anti-PIT-1 antibody syndrome

Cited by 19 publications

References 36 publications

Two Cases of anti–PIT-1 Hypophysitis Exhibited as a Form of Paraneoplastic Syndrome not Associated With Thymoma

Two Cases of anti–PIT-1 Hypophysitis Exhibited as a Form of Paraneoplastic Syndrome not Associated With Thymoma

Hypophysitis and Granulomatous Pituitary Lesions in Systemic Diseases

Pathogenesis of Anti–PIT-1 Antibody Syndrome: PIT-1 Presentation by HLA Class I on Anterior Pituitary Cells

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