研究者詳細 - 岩間　信太郎

Rapidly progressive interstitial lung disease with positive anti-MDA5 antibody as an immune-related complication of nivolumab: A case report 査読有り

Kato S, Sakamoto K, Sato T, Kobayashi T, Shindo Y, Morise M, Iwama S, Arima H, Ishii M.

Respir Investig 62 巻 ( 2 ) 頁： 313 - 316 2024年3月

Effects of Digitization of Self-Monitoring of Blood Glucose Records Using a Mobile App and the Cloud System on Outpatient Management of Diabetes: Single-Armed Prospective Study. 査読有り国際誌

Handa T, Onoue T, Kobayashi T, Maeda R, Mizutani K, Yamagami A, Kinoshita T, Yasuda Y, Iwama S, Miyata T, Sugiyama M, Takagi H, Hagiwara D, Suga H, Banno R, Azuma Y, Kasai T, Yoshioka S, Kuwatsuka Y, Arima H

JMIR diabetes 9 巻 ( 1 ) 頁： e48019 2024年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JMIR Diabetes

Background: In recent years, technologies promoting the digitization of self-monitoring of blood glucose (SMBG) records including app-cloud cooperation systems have emerged. Studies combining these technological interventions with support from remote health care professionals have reported improvements in glycemic control. Objective: To assess the use of an app-cloud cooperation system linked with SMBG devices in clinical settings, we evaluated its effects on outpatient management of diabetes without remote health care professional support. Methods: In this multicenter, open-label, and single-armed prospective study, 48 patients with diabetes (including type 1 and type 2) at 3 hospitals in Japan treated with insulin or glucagon-like peptide 1 receptor agonists and performing SMBG used the app-cloud cooperation system for 24 weeks. The SMBG data were automatically uploaded to the cloud via the app. The patients could check their data, and their attending physicians reviewed the data through the cloud prior to the patients’ regular visits. The primary outcome was changes in glycated hemoglobin (HbA1c) levels. Results: Although HbA1c levels did not significantly change in all patients, the frequency of daily SMBG following applying the system was significantly increased before induction at 12 (0.60 per day, 95% CI 0.19-1.00; P=.002) and 24 weeks (0.43 per day, 95% CI 0.02-0.84; P=.04). In the subset of 21 patients whose antidiabetic medication had not been adjusted during the intervention period, a decrease in HbA1c level was observed at 12 weeks (P=.02); however, this significant change disappeared at 24 weeks (P=.49). The Diabetes Treatment Satisfaction Questionnaire total score and “Q4: convenience” and “Q5: flexibility” scores significantly improved after using the system (all P<.05), and 72% (33/46) patients and 76% (35/46) physicians reported that the app-cloud cooperation system helped them adjust insulin doses. Conclusions: The digitization of SMBG records and sharing of the data by patients and attending physicians during face-to-face visits improved self-management in patients with diabetes.

DOI： 10.2196/48019

Improved glycemic control after the use of flash glucose monitoring accompanied by improved treatment satisfaction in patients with non-insulin-treated type 2 diabetes: A post-hoc analysis of a randomized controlled trial 査読有り国際誌

Clinical characteristics and potential biomarkers of thyroid and pituitary immune-related adverse events 査読有り

Kobayashi, T; Iwama, S; Arima, H

ENDOCRINE JOURNAL 71 巻 ( 1 ) 頁： 23 - 29 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Endocrine Journal

Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) in several organs including endocrine glands. Among endocrine irAEs, thyroid and pituitary irAEs are frequently observed, followed by primary adrenal insufficiency, insulin-dependent diabetes mellitus, and hypoparathyroidism. These conditions could lead to life-threatening consequences, such as adrenal crisis and diabetic ketoacidosis. On the other hand, several types of irAEs including thyroid and pituitary irAEs are reported to be associated with better overall survival. Therefore, it is important to understand and manage endocrine irAEs, which differ depending on the ICI regimen used. In this review, we describe the clinical features, potential biomarkers, management strategies, and possible mechanisms of thyroid and pituitary irAEs.

DOI： 10.1507/endocrj.EJ23-0524

Hayase, A; Onoue, T; Kobayashi, T; Wada, E; Handa, T; Kinoshita, T; Yamagami, A; Yasuda, Y; Iwama, S; Kawaguchi, Y; Miyata, T; Sugiyama, M; Takagi, H; Hagiwara, D; Suga, H; Banno, R; Kuwatsuka, Y; Ando, M; Goto, M; Arima, H

PRIMARY CARE DIABETES 17 巻 ( 6 ) 頁： 575 - 580 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Primary Care Diabetes

Aims: In our previously reported randomized controlled trial in patients with noninsulin-treated type 2 diabetes, the use of flash glucose monitoring (FGM) improved glycated hemoglobin (HbA1c), and the improvement was sustained after the cessation of glucose monitoring. In this post-hoc analysis, we examined data from our trial to identify the factors that influenced FGM efficacy. Methods: We analyzed data for 48 of 49 participants of the FGM group who completed the trial to clarify the changes in various parameters and factors related to HbA1c improvement with the use of FGM. Results: Analyses of the FGM data during the 12-week FGM provision period showed that the weekly mean blood glucose levels considerably decreased as early as at 1 week compared with the baseline values, and this decline continued for 12 weeks. An enhancement in the Diabetes Treatment Satisfaction Questionnaire regarding “willingness to continue the current treatment” score was significantly associated with the improvement in HbA1c at 12 (p = 0.009) and 24 weeks (p = 0.012). Conclusions: Glycemic control was improved soon after FGM initiation, accompanied by improved satisfaction with continuation of the current treatment in patients with noninsulin-treated type 2 diabetes.

DOI： 10.1016/j.pcd.2023.09.009

Risk of Thyroid Dysfunction in PD-1 Blockade Is Stratified by the Pattern of TgAb and TPOAb Positivity at Baseline 査読有り

Zhou, X; Iwama, S; Kobayashi, T; Ando, M; Arima, H

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 108 巻 ( 10 ) 頁： E1056 - E1062 2023年9月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：The Journal of clinical endocrinology and metabolism

CONTEXT: Positive antithyroglobulin (TgAb) and/or antithyroid peroxidase antibodies (TPOAb) at baseline indicate a high risk of thyroid immune-related adverse events (irAEs) induced by antiprogrammed cell death-1 antibodies (anti-PD-1-Ab). However, whether the positivity patterns of both antibodies are associated with the risk of thyroid irAEs is unknown. OBJECTIVE: The aim of the present study was to clarify the association of the pattern of TgAb and TPOAb positivity at baseline with the risk of thyroid irAEs induced by anti-PD-1-Ab. METHODS: Patients (n = 516) were evaluated for TgAb and TPOAb at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after initiating anti-PD-1-Ab. RESULTS: Fifty-one (9.9%) patients developed thyroid irAEs (thyrotoxicosis in 34, hypothyroidism without prior thyrotoxicosis in 17). Twenty-five patients subsequently developed hypothyroidism following thyrotoxicosis. The cumulative incidence of thyroid irAEs differed among 4 groups classified by the presence of TgAb/TPOAb at baseline (group 1: TgAb-(-)/TPOAb-(-), 4.6% [19/415]; group 2: TgAb-(-)/TPOAb-(+), 15.8% [9/57]; group 3: TgAb-(+)/TPOAb-(-), 42.1% [8/19]; group 4: TgAb-(+)/TPOAb-(+), 60.0% [15/25]) as follows: groups 1 vs 2-4 (P ≤ .001) and groups 2 vs 3 (P = .008) and 4 (P < .001). There were different incidences of thyrotoxicosis (groups 1-4, 3.1%, 5.3%, 31.6%, 48.0%, respectively; P < .001) in groups 1 vs 3 and 4, and groups 2 vs 3 and 4, and of hypothyroidism (groups 1-4: 2.9%, 15.8%, 31.6%, 60.0%, respectively; P < .001) in groups 1 vs 2 to 4, and groups 2 vs 4. CONCLUSION: The risk of thyroid irAEs was affected by the pattern of TgAb and TPOAb positivity at baseline; there were high risks of thyrotoxicosis in patients with TgAb-(+) and of hypothyroidism in patients with TgAb-(+) and those with TPOAb-(+).

DOI： 10.1210/clinem/dgad231

Generation and purification of ACTH-secreting hPSC-derived pituitary cells for effective transplantation 査読有り国際誌

Taga, S; Suga, H; Nakano, T; Kuwahara, A; Inoshita, N; Kodani, Y; Nagasaki, H; Sato, Y; Tsumura, Y; Sakakibara, M; Soen, M; Miwata, T; Ozaki, H; Kano, M; Watari, K; Ikeda, A; Yamanaka, M; Takahashi, Y; Kitamoto, S; Kawaguchi, Y; Miyata, T; Kobayashi, T; Sugiyama, M; Onoue, T; Yasuda, Y; Hagiwara, D; Iwama, S; Tomigahara, Y; Kimura, T; Arima, H

STEM CELL REPORTS 18 巻 ( 8 ) 頁： 1657 - 1671 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Stem Cell Reports

Pituitary organoids are promising graft sources for transplantation in treatment of hypopituitarism. Building on development of self-organizing culture to generate pituitary-hypothalamic organoids (PHOs) using human pluripotent stem cells (hPSCs), we established techniques to generate PHOs using feeder-free hPSCs and to purify pituitary cells. The PHOs were uniformly and reliably generated through preconditioning of undifferentiated hPSCs and modulation of Wnt and TGF-β signaling after differentiation. Cell sorting using EpCAM, a pituitary cell-surface marker, successfully purified pituitary cells, reducing off-target cell numbers. EpCAM-expressing purified pituitary cells reaggregated to form three-dimensional pituitary spheres (3D-pituitaries). These exhibited high adrenocorticotropic hormone (ACTH) secretory capacity and responded to both positive and negative regulators. When transplanted into hypopituitary mice, the 3D-pituitaries engrafted, improved ACTH levels, and responded to in vivo stimuli. This method of generating purified pituitary tissue opens new avenues of research for pituitary regenerative medicine.

DOI： 10.1016/j.stemcr.2023.05.002

Anti-tumor effects of anti-programmed cell death-1 antibody treatment are attenuated in streptozotocin-induced diabetic mice 査読有り国際誌

Ito, M; Iwama, S; Sugiyama, D; Yasuda, Y; Okuji, T; Kobayashi, T; Zhou, X; Yamagami, A; Onoue, T; Miyata, T; Sugiyama, M; Hagiwara, D; Suga, H; Banno, R; Nishikawa, H; Arima, H

SCIENTIFIC REPORTS 13 巻 ( 1 ) 頁： 5939 - 5939 2023年4月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

Hyperglycemia impairs immune response; however, it remains unknown whether the anti-tumor effects of anti-programmed cell death-1 antibody (PD-1-Ab) treatment are changed in hyperglycemic conditions. We analyzed the effect of PD-1-Ab on tumor growth in streptozotocin-induced diabetic mice (STZ-mice) subcutaneously inoculated with MC38 (a colon carcinoma cell line). Furthermore, we assessed the expression of chemokines by polymerase chain reaction (PCR) array in tumor-draining lymph nodes (dLNs) of these mice and MC38 cells cultured in different glucose concentrations. The suppressive effect of PD-1-Ab on tumor growth was attenuated. This was accompanied by fewer tumor-infiltrating CD8+ T cells, and STZ-mice had fewer tumor-infiltrating CD11c+ dendritic cells (DCs) than normoglycemic mice. mRNA expression levels of CXCL9, a chemokine recruiting CD8+ T cells, were lower in dLNs of STZ-mice than in normoglycemic mice after PD-1-Ab treatment, and its protein was expressed in DCs. In MC38 cells cultured with 25 mM glucose, mRNA expression of CCL7, a chemokine recruiting DCs, was decreased compared to cells cultured with 5 mM glucose. These results suggest that the STZ-induced hyperglycemia impairs the effect of PD-1-Ab treatment on MC38 tumor growth, and is accompanied by reduced infiltration of DCs and CD8+ T cells and decreased expression of CCL7 and CXCL9.

DOI： 10.1038/s41598-023-33049-7

Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors 査読有り

Inaba, H; Morita, S; Kosugi, D; Asai, Y; Kaido, Y; Ito, S; Hirobata, T; Inoue, G; Yamamoto, Y; Jinnin, M; Kimura, H; Ota, M; Okudaira, Y; Nakatani, H; Kobayashi, T; Iwama, S; Arima, H; Matsuoka, T

FRONTIERS IN IMMUNOLOGY 14 巻頁： 1165004 2023年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers in Immunology

Introduction: Immune-checkpoint inhibitors are effective in various advanced cancers. Type 1 diabetes mellitus induced by them (ICI-T1DM) is a serious complication requiring prompt insulin treatment, but the immunological mechanism behind it is unclear. Methods: We examined amino acid polymorphisms in human histocompatibility leukocyte antigen (HLA) molecules and investigated proinsulin epitope binding affinities to HLA molecules. Results and Discussion: Twelve patients with ICI-T1DM and 35 patients in a control group without ICI-T1DM were enrolled in the study. Allele and haplotype frequencies of HLA-DRB1*04:05, DQB1*04:01, and most importantly DPB1*05:01 were significantly increased in patients with ICI-T1DM. In addition, novel amino acid polymorphisms in HLA-DR (4 polymorphisms), in DQ (12 polymorphisms), and in DP molecules (9 polymorphisms) were identified. These amino acid polymorphisms might be associated with the development of ICI-T1DM. Moreover, novel human proinsulin epitope clusters in insulin A and B chains were discovered in silico and in vitro peptide binding assays to HLA-DP5. In conclusion, significant amino acid polymorphisms in HLA-class II molecules, and conformational alterations in the peptide-binding groove of the HLA-DP molecules were considered likely to influence the immunogenicity of proinsulin epitopes in ICI-T1DM. These amino acid polymorphisms and HLA-DP5 may be predictive genetic factors for ICI-T1DM.

DOI： 10.3389/fimmu.2023.1165004

Resting energy expenditure depends on energy intake during weight loss in people with obesity: a retrospective cohort study. 査読有り国際誌

Handa T, Onoue T, Kobayashi T, Wada E, Hayase A, Kinoshita T, Yamagami A, Yasuda Y, Iwama S, Kawaguchi Y, Miyata T, Sugiyama M, Takagi H, Hagiwara D, Suga H, Banno R, Goto M, Arima H

Archives of endocrinology and metabolism 67 巻 ( 2 ) 頁： 233 - 241 2023年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Archives of endocrinology and metabolism

Objective: Resting energy expenditure (REE) decreases if there is reduced energy intake and body weight (BW). The decrease in REE could make it difficult for patients with obesity to maintain decreased BW. This study aimed to investigate the correlation among changes in REE, energy intake, and BW during the weight loss process in patients with obesity. Materials and methods: We conducted a retrospective cohort study of patients hospitalized for the treatment of obesity in Japan. Patients received fully controlled diet during hospitalization and performed exercises if able. REE was measured once a week using a hand-held indirect calorimetry. Energy intake was determined by actual dietary intake. Results: Of 44 inpatients with obesity, 17 were included in the analysis. Their BW decreased significantly after 1 week (-4.7 ± 2.0 kg, P < 0.001) and 2 weeks (-5.7 ± 2.2 kg, P < 0.001). The change in REE after 1 and 2 weeks was positively correlated with the energy intake/energy expenditure ratio (r = 0.66, P = 0.004 at 1 week, r = 0.71, P = 0.002 at 2 weeks). Using a regression equation (y = 0.5257x - 43.579), if the energy intake/energy expenditure ratio within the second week was 82.9%, the REE after 2 weeks was similar to the baseline level. There was no significant correlation between the change in REE and BW. Conclusion: Our data suggest that changes in REE depend on energy intake/energy expenditure ratio and that the decrease in REE can be minimized by matching energy intake to energy expenditure, even during the weight loss process.

DOI： 10.20945/2359-3997000000532

Knockdown of endoplasmic reticulum chaperone BiP leads to the death of parvocellular AVP/CRH neurons in mice 国際誌

Generation of hypothalamic neural stem cell-like cells in vitro from human pluripotent stem cells.

Miwata T, Suga H, Kawaguchi Y, Sakakibara M, Kano M, Taga S, Soen M, Ozaki H, Asano T, Sasaki H, Miyata T, Yasuda Y, Kobayashi T, Sugiyama M, Onoue T, Takagi H, Hagiwara D, Iwama S, Arima H

Stem cell reports 2023年3月

Kawaguchi Yohei, Hagiwara Daisuke, Tsumura Tetsuro, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Yasuda Yoshinori, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Grinevich Valery, Arima Hiroshi

JOURNAL OF NEUROENDOCRINOLOGY 35 巻 ( 1 ) 頁： e13223 2023年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Neuroendocrinology

Arginine vasopressin (AVP) is expressed in both magnocellular (magnAVP) and parvocellular AVP (parvAVP) neurons of the paraventricular nucleus, and AVP colocalizes with corticotropin-releasing hormone (CRH) only in the parvocellular neurons. The immunoglobulin heavy chain binding protein (BiP) is a major endoplasmic reticulum (ER) chaperone which regulates the unfolded protein response under ER stress. We previously demonstrated that knockdown of BiP in magnAVP neurons exacerbated ER stress, which resulted in the autophagy-associated cell death of magnAVP neurons. Using the same approach, in the present study we examined the role of BiP in mouse parvAVP/CRH neurons. Our data demonstrate that BiP is expressed in mouse parvAVP/CRH neurons under nonstress conditions and is upregulated in proportion to the increase in CRH expression after adrenalectomy. For BiP knockdown in parvAVP/CRH neurons, we utilized a viral approach in combination with shRNA interference. Knockdown of BiP expression induced ER stress in parvAVP/CRH neurons, as reflected by the expression of C/EBP homologous protein. Furthermore, BiP knockdown led to the loss of parvAVP/CRH neurons after 4 weeks. In summary, our results demonstrate that BiP plays a pivotal role in parvAVP/CRH neurons, which function as neuroendocrine cells producing a large number of secretory proteins.

DOI： 10.1111/jne.13223

Differentiation of human induced pluripotent stem cells into hypothalamic vasopressin neurons with minimal exogenous signals and partial conversion to the naive state

Mineralocorticoids induce polyuria by reducing apical aquaporin-2 expression of the kidney in partial vasopressin deficiency

Kurimoto Junki, Takagi Hiroshi, Miyata Takashi, Kawaguchi Yohei, Hodai Yuichi, Tsumura Tetsuro, Hagiwara Daisuke, Kobayashi Tomoko, Yasuda Yoshinori, Sugiyama Mariko, Onoue Takeshi, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Katsuki Takeshi, Ando Fumiaki, Uchida Shinichi, Arima Hiroshi

ENDOCRINE JOURNAL advpub 巻 ( 0 ) 2022年11月

Ozaki Hajime, Suga Hidetaka, Sakakibara Mayu, Soen Mika, Miyake Natsuki, Miwata Tsutomu, Taga Shiori, Nagai Takashi, Kano Mayuko, Mitsumoto Kazuki, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Iwama Shintaro, Banno Ryoichi, Iguchi Genzo, Takahashi Yutaka, Muguruma Keiko, Inoue Haruhisa, Arima Hiroshi

SCIENTIFIC REPORTS 12 巻 ( 1 ) 頁： 17381 2022年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons, whereas human ESCs/iPSCs die. Human ESCs/iPSCs are generally more similar to mouse epiblast stem cells (mEpiSCs) compared to mouse ESCs. In this study, we converted human FNDI-specific iPSCs by the naive conversion kit. Although the conversion was partial, we found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.

DOI： 10.1038/s41598-022-22405-8

Elevated TSH Level, TgAb, and Prior Use of Ramucirumab or TKIs as Risk Factors for Thyroid Dysfunction in PD-L1 Blockade 査読有り国際誌

Kobayashi Tomoko, Iwama Shintaro, Yamagami Ayana, Yasuda Yoshinori, Okuji Takayuki, Ito Masaaki, Zhou Xin, Ando Masahiko, Onoue Takeshi, Miyata Takashi, Sugiyama Mariko, Hagiwara Daisuke, Suga Hidetaka, Banno Ryoichi, Hase Tetsunari, Morise Masahiro, Ito Takanori, Kikumori Toyone, Inoue Megumi, Ando Yuichi, Masuda Norikazu, Kawashima Hiroki, Hashimoto Naozumi, Arima Hiroshi

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 107 巻 ( 10 ) 頁： E4115 - E4123 2022年9月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：The Journal of clinical endocrinology and metabolism

BACKGROUND: Thyroid dysfunction is frequently caused by treatment with antiprogrammed cell death-1 ligand 1 antibodies (PD-L1-Abs) and anticancer drugs, including ramucirumab (RAM) and multitargeted tyrosine kinase inhibitors (multi-TKIs), which are often used prior to PD-L1-Ab treatment in cancer patients. METHODS: A total of 148 patients treated with PD-L1-Abs were evaluated for antithyroid antibodies at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then were observed until the visits stopped. RESULTS: Of the 148 patients, 15 (10.1%) developed thyroid dysfunction after PD-L1-Ab treatment (destructive thyroiditis in 8 and hypothyroidism without preceding thyrotoxicosis in 7). The prevalence of an elevated thyroid-stimulating hormone (TSH) level at baseline (3/15 [20.0%] vs 4/133 [3.0%], P < .05), positive antithyroglobulin antibodies (TgAbs) at baseline (4/15 [26.7%] vs 5/133 [3.8%], P < .05) and prior treatment with RAM or multi-TKIs (3/15 [20.0%] vs 5/133 [3.8%], P < .05) were significantly higher in patients with vs without thyroid dysfunction. In a multivariate analysis, elevated TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs were significantly associated with the development of thyroid dysfunction, with ORs of 7.098 (95% CI 1.154-43.638), 11.927 (95% CI 2.526-56.316), and 8.476 (95% CI 1.592-45.115), respectively. CONCLUSION: The results of this real-world study suggest that the risk of thyroid dysfunction induced by PD-L1-Abs can be predicted by the TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs.

DOI： 10.1210/clinem/dgac467

Inflammation in VTA Caused by HFD Induces Activation of Dopaminergic Neurons Accompanied by Binge-like Eating 国際誌

Sun Runan, Sugiyama Mariko, Wang Sixian, Kuno Mitsuhiro, Sasaki Tomoyuki, Hirose Tomonori, Miyata Takashi, Kobayashi Tomoko, Tsunekawa Taku, Onoue Takeshi, Yasuda Yoshinori, Takagi Hiroshi, Hagiwara Daisuke, Iwama Shintaro, Suga Hidetaka, Arima Hiroshi

NUTRIENTS 14 巻 ( 18 ) 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nutrients

Binge eating is a characteristic symptom observed in obese individuals that is related to dysfunction of dopaminergic neurons (DNs). Intermittent administration of a high-fat diet (HFD) is reported to induce binge-like eating, but the underlying mechanisms remain unclear. We generated dopaminergic neuron specific IKKβ deficient mice (KO) to examine the effects of inflammation in DNs on binge-like eating under inflammatory conditions associated with HFD. After administration of HFD for 4 weeks, mice were fasted for 24 h, and then the consumption of HFD was measured for 2 h. We also evaluated that the mRNA expressions of inflammatory cytokines, glial markers, and dopamine signaling-related genes in the ventral tegmental area (VTA) and striatum. Moreover, insulin was administered intraventricularly to assess downstream signaling. The consumption of HFD was significantly reduced, and the phosphorylation of AKT in the VTA was significantly increased in female KO compared to wild-type (WT) mice. Analyses of mRNA expressions revealed that DNs activity and inflammation in the VTA were significantly decreased in female KO mice. Thus, our data suggest that HFD-induced inflammation with glial cell activation in the VTA affects DNs function and causes abnormal eating behaviors accompanied by insulin resistance in the VTA of female mice.

DOI： 10.3390/nu14183835

Protein Tyrosine Phosphatase 1B Deficiency Improves Glucose Homeostasis in Insulin-Dependent Diabetes Mellitus Treated with Leptin. 査読有り国際誌

Ito Y, Sun R, Yagimuma H, Taki K, Mizoguchi A, Kobayashi T, Sugiyama M, Onoue T, Tsunekawa T, Takagi H, Hagiwara D, Iwama S, Suga H, Konishi H, Kiyama H, Arima H, Banno R

Diabetes 2022年6月

Immune checkpoint inhibitor-related thyroid dysfunction. 招待有り査読有り

Iwama S, Kobayashi T, Yasuda Y, Arima H

Best practice & research. Clinical endocrinology & metabolism 36 巻 ( 3 ) 頁： 101660 2022年5月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Best Practice and Research: Clinical Endocrinology and Metabolism

Immune-related adverse events (irAEs) are caused by immune checkpoint inhibitors in several organs including the endocrine glands. Thyroid dysfunction (thyroid irAEs) is often observed among endocrine irAEs and is induced by blockade of programmed cell death 1 (PD-1), programmed death ligand 1, or PD-1 plus cytotoxic T-lymphocyte antigen 4. Endocrinologically, destructive thyroiditis or hypothyroidism is observed in most cases, whereas hyperthyroidism (Graves' disease) is rare. Most patients who develop destructive thyroiditis or hypothyroidism subsequently require thyroid hormone replacement therapy. Thyroid irAE development is associated with prolonged survival in patients with non-small cell lung carcinoma. The incidence of thyroid irAEs is higher in patients who are positive versus negative for anti-thyroid antibodies at baseline, suggesting that these antibodies can predict thyroid irAE development. Cytotoxic T cells, especially CD4 T cells, are reportedly involved in the development of destructive thyroiditis. In this review, we describe the clinical features, potential biomarkers, and mechanism of thyroid irAEs.

DOI： 10.1016/j.beem.2022.101660

Increased Risk of Thyroid Dysfunction by PD-1 and CTLA-4 Blockade in Patients Without Thyroid Autoantibodies at Baseline 査読有り

Iwama Shintaro, Kobayashi Tomoko, Yasuda Yoshinori, Okuji Takayuki, Ito Masaaki, Ando Masahiko, Zhou Xin, Yamagami Ayana, Onoue Takeshi, Kawaguchi Yohei, Miyata Takashi, Sugiyama Mariko, Takagi Hiroshi, Hagiwara Daisuke, Suga Hidetaka, Banno Ryoichi, Hase Tetsunari, Morise Masahiro, Wakahara Keiko, Yokota Kenji, Kato Masashi, Nishio Naoki, Tanaka Chie, Miyata Kazushi, Ogura Atsushi, Ito Takanori, Sawada Tsunaki, Shimokata Tomoya, Niimi Kaoru, Ohka Fumiharu, Ishigami Masatoshi, Gotoh Momokazu, Hashimoto Naozumi, Saito Ryuta, Kiyoi Hitoshi, Kajiyama Hiroaki, Ando Yuichi, Hibi Hideharu, Sone Michihiko, Akiyama Masashi, Kodera Yasuhiro, Arima Hiroshi

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 107 巻 ( 4 ) 頁： E1620 - E1630 2022年3月

Functional Lactotrophs in Induced Adenohypophysis Differentiated From Human iPS Cells 査読有り

Miyake Natsuki, Nagai Takashi, Suga Hidetaka, Osuka Satoko, Kasai Takatoshi, Sakakibara Mayu, Soen Mika, Ozaki Hajime, Miwata Tsutomu, Asano Tomoyoshi, Kano Mayuko, Muraoka Ayako, Nakanishi Natsuki, Nakamura Tomoko, Goto Maki, Yasuda Yoshinori, Kawaguchi Yohei, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Hagiwara Daisuke, Iwama Shintaro, Iwase Akira, Inoshita Naoko, Arima Hiroshi, Kajiyama Hiroaki

ENDOCRINOLOGY 163 巻 ( 3 ) 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Endocrinology (United States)

Prolactin (PRL), a hormone involved in lactation, is mainly produced and secreted by the lactotrophs of the anterior pituitary (AP) gland. We previously reported a method to generate functional adrenocorticotropic hormone-producing cells by differentiating the AP and hypothalamus simultaneously from human induced pluripotent stem cells (iPSCs). However, PRL-producing cells in the induced AP have not been investigated. Here, we confirmed the presence of PRL-producing cells and evaluated their endocrine functions. We differentiated pituitary cells from human iPSCs using serum-free floating culture of embryoid-like aggregates with quick reaggregation (SFEB-q) method and evaluated the appearance and function of PRL-producing cells. Secretion of PRL from the differentiated aggregates was confirmed, which increased with further culture. Fluorescence immunostaining and immunoelectron microscopy revealed PRL-producing cells and PRL-positive secretory granules, respectively. PRL secretion was promoted by various prolactin secretagogues such as thyrotropin-releasing hormone, vasoactive intestinal peptide, and prolactin-releasing peptide, and inhibited by bromocriptine. Moreover, the presence of tyrosine hydroxylase-positive dopaminergic nerves in the hypothalamic tissue area around the center of the aggregates connecting to PRL-producing cells indicated the possibility of recapitulating PRL regulatory mechanisms through the hypothalamus. In conclusion, we generated pituitary lactotrophs from human iPSCs; these displayed similar secretory responsiveness as human pituitary cells in vivo. In the future, this is expected to be used as a model of human PRL-producing cells for various studies, such as drug discovery, prediction of side effects, and elucidation of tumorigenic mechanisms using disease-specific iPSCs. Furthermore, it may help to develop regenerative medicine for the pituitary gland.

DOI： 10.1210/endocr/bqac004

Human Leukocyte Antigens and Biomarkers in Type Diabetes Mellitus Induced by Immune-Checkpoint Inhibitors 査読有り

Inaba Hidefumi, Kaido Yosuke, Ito Saya, Hirobata Tomonao, Inoue Gen, Sugita Takakazu, Yamamoto Yuki, Jinnin Masatoshi, Kimura Hiroaki, Kobayashi Tomoko, Iwama Shintaro, Arima Hiroshi, Matsuoka Takaaki

ENDOCRINOLOGY AND METABOLISM 37 巻 ( 1 ) 頁： 84 - + 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Endocrinology and Metabolism

Background: Type 1 diabetes mellitus induced by immune-checkpoint inhibitors (ICI-T1DM) is a rare critical entity. However, the etiology of ICI-T1DM remains unclear. Methods: In order to elucidate risk factors for ICI-T1DM, we evaluated the clinical course and immunological status of patients with ICI-T1DM who had been diagnosed during 2016 to 2021. Results: Seven of 871 (0.8%, six men and one woman) patients developed ICI-T1DM. We revealed that the allele frequencies of human leukocyte antigen (HLA)-DPA1*02:02 and DPB1*05:01 were significantly higher in the patients with ICI-T1DM In comparison to the controls who received ICI (11/14 vs. 10/26, P= 0.022; 11/14 vs. 7/26, P= 0.0027, respectively). HLA-DRB1*04:05, which has been found to be a T1DM susceptibility allele in Asians, was also observed as a high-risk allele for ICI-T1DM. The significance of the HLA-DPB1*05:01 and DRB1*04:05 alleles was confirmed by an analysis of four additional patients. The absolute/relative neutrophil count, neutrophils-lymphocyte ratio, and neutrophil-eosinophil ratio increased, and the absolute lymphocyte count and absolute/relative eosinophil count decreased at the onset as compared with 6 weeks before. In two patients, alterations in cytokines and chemokines were found at the onset. Conclusion: Novel high-risk HLA alleles and haplotypes were identified in ICI-T1DM, and peripheral blood factors may be utilized as biomarkers.

DOI： 10.3803/EnM.2021.1282

Predicting non-insulin-dependent state in patients with slowly progressive insulin-dependent (type 1) diabetes mellitus or latent autoimmune diabetes in adults. Reply to Sugiyama K and Saisho Y [letter]

Wada Eri, Onoue Takeshi, Kinoshita Tamaki, Hayase Ayaka, Handa Tomoko, Ito Masaaki, Furukawa Mariko, Okuji Takayuki, Kobayashi Tomoko, Iwama Shintaro, Sugiyama Mariko, Takagi Hiroshi, Hagiwara Daisuke, Suga Hidetaka, Banno Ryoichi, Goto Motomitsu, Arima Hiroshi

DIABETOLOGIA 65 巻 ( 1 ) 頁： 252 - 253 2022年1月

Peripheral combination treatment of leptin and an SGLT2 inhibitor improved glucose metabolism in insulin-dependent diabetes mellitus mice 査読有り

Yaginuma H., Banno R., Sun R., Taki K., Mizoguchi A., Kobayashi T., Sugiyama M., Tsunekawa T., Onoue T., Takagi H., Hagiwara D., Ito Y., Iwama S., Suga H., Arima H.

Journal of Pharmacological Sciences 147 巻 ( 4 ) 頁： 340 - 347 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Pharmacological Sciences

We investigated whether peripheral combination treatment of a sodium–glucose cotransporter 2 (SGLT2) inhibitor and leptin improves glucose metabolism in insulin-dependent diabetes mellitus (IDDM) model mice. Twelve-week-old male C57BL6 mice were intraperitoneally administered a high dose of streptozotocin to produce IDDM. IDDM mice were then divided into five groups: SGLT2 inhibitor treatment alone, leptin treatment alone, leptin and SGLT2 inhibitor co-treatment, untreated IDDM mice, and healthy mice groups. The blood glucose (BG) level at the end of the dark cycle was measured, and a glucose tolerance test (GTT) was performed and compared between the five groups. Leptin was peripherally administered at 20 μg/day using an osmotic pump, and an SGLT2 inhibitor, ipragliflozin, was orally administered at 3 mg/kg/day. Monotherapy with SGLT2 inhibitor or leptin significantly improved glucose metabolism in mice as evaluated by BG and GTT compared with the untreated group, whereas the co-treatment group with SGLT2 inhibitor and leptin further improved glucose metabolism as compared with the monotherapy group. Notably, glucose metabolism in the co-treatment group improved to the same level as that in the healthy mice group. Thus, peripheral combination treatment with leptin and SGLT2 inhibitor improved glucose metabolism in IDDM mice without the use of insulin.

DOI： 10.1016/j.jphs.2021.08.010

Adult-onset autoimmune diabetes identified by glutamic acid decarboxylase autoantibodies: a retrospective cohort study 査読有り

DIABETOLOGIA 64 巻 ( 10 ) 頁： 2183 - 2192 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Diabetologia

Aims/hypothesis: Patients with GAD antibodies (GADAb) showing clinical features of type 2 diabetes typically exhibit progression to an insulin-dependent state in several months or years. This condition is diagnosed as slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) or latent autoimmune diabetes in adults, a subtype of adult-onset autoimmune diabetes. However, some patients diagnosed with adult-onset autoimmune diabetes do not progress to an insulin-dependent state. We conducted a retrospective cohort study to identify patients with non-insulin-dependent diabetes among those diagnosed with adult-onset autoimmune diabetes using measurable indicators in routine clinical practice. Methods: We surveyed data from the electronic medical records of all patients with GADAb from eight medical centres in Japan for selecting and analysing patients who matched the diagnostic criteria of SPIDDM. Results: Overall, 345 patients were analysed; of these, 162 initiated insulin therapy (insulin therapy group), whereas 183 did not (non-insulin therapy group) during the follow-up period (median 3.0 years). Patients in the non-insulin therapy group were more likely to be male and presented a later diabetes onset, shorter duration of diabetes, higher BMI, higher blood pressure levels, lower HbA1c levels, lower GADAb levels and lesser antidiabetic agent use than those in the insulin therapy group when GADAb was first identified as positive. A Cox proportional hazards model showed that BMI, HbA1c levels and GADAb levels were independent factors for progression to insulin therapy. Kaplan–Meier analyses revealed that 86.0% of the patients with diabetes having GADAb who presented all three factors (BMI ≥ 22 kg/m2, HbA1c < 75 mmol/mol [9.0%] and GADAb <10.0 U/ml) did not require insulin therapy for 4 years. Conclusions/interpretation: Higher BMI (≥22 kg/m2), lower HbA1c (<75 mmol/mol [9.0%]) and lower GADAb levels (<10.0 U/ml) can predict a non-insulin-dependent state for at least several years in Japanese patients with diabetes having GADAb. Graphical abstract: [Figure not available: see fulltext.]

DOI： 10.1007/s00125-021-05516-1

GABA(B) receptor signaling in the caudate putamen is involved in binge-like consumption during a high fat diet in mice 査読有り国際共著

Sun Runan, Tsunekawa Taku, Hirose Tomonori, Yaginuma Hiroshi, Taki Keigo, Mizoguchi Akira, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Takagi Hiroshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Bettler Bernhard, Arima Hiroshi

SCIENTIFIC REPORTS 11 巻 ( 1 ) 頁： 19296 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

Previous studies suggest that signaling by the gamma-aminobutyric acid (GABA) type B receptor (GABABR) is involved in the regulation of binge eating, a disorder which might contribute to the development of obesity. Here, we show that intermittent access to a high fat diet (HFD) induced binge-like eating behavior with activation of dopamine receptor d1 (drd1)-expressing neurons in the caudate putamen (CPu) and nucleus accumbens (NAc) in wild-type (WT) mice. The activation of drd1-expressing neurons during binge-like eating was substantially increased in the CPu, but not in the NAc, in corticostriatal neuron-specific GABABR-deficient knockout (KO) mice compared to WT mice. Treatment with the GABABR agonist, baclofen, suppressed binge-like eating behavior in WT mice, but not in KO mice, as reported previously. Baclofen also suppressed the activation of drd1-expressing neurons in the CPu, but not in the NAc, during binge-like eating in WT mice. Thus, our data suggest that GABABR signaling in CPu neurons expressing drd1 suppresses binge-like consumption during a HFD in mice.

DOI： 10.1038/s41598-021-98590-9

Glucocorticoid receptor signaling in ventral tegmental area neurons increases the rewarding value of a high-fat diet in mice. 査読有り

Mizoguchi A, Banno R, Sun R, Yaginuma H, Taki K, Kobayashi T, Sugiyama M, Tsunekawa T, Onoue T, Takagi H, Hagiwara D, Ito Y, Iwama S, Suga H, Nagai T, Yamada K, Arima H

Scientific reports 11 巻 ( 1 ) 頁： 12873 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

The reward system, which consists of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and caudate-putamen in the striatum, has an important role in the pathogenesis of not only drug addiction but also diet-induced obesity. In the present study, we examined whether signaling through glucocorticoid receptors (GRs) in the reward system affects the rewarding value of a high-fat diet (HFD). To do so, we generated mice that lack functional GRs specifically in dopaminergic neurons (D-KO mice) or corticostriatal neurons (CS-KO mice), subjected the mice to caloric restriction stress conditions, and evaluated the rewarding value of a HFD by conditioned place preference (CPP) test. Caloric restriction induced increases in serum corticosterone to similar levels in all genotypes. While CS-KO as well as WT mice exhibited a significant preference for HFD in the CPP test, D-KO mice exhibited no such preference. There were no differences between WT and D-KO mice in consumption of HFD after fasting or cognitive function evaluated by a novel object recognition test. These data suggest that glucocorticoid signaling in the VTA increases the rewarding value of a HFD under restricted caloric stress.

DOI： 10.1038/s41598-021-92386-7

CD4+ T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice. 査読有り

Yasuda Y, Iwama S, Sugiyama D, Okuji T, Kobayashi T, Ito M, Okada N, Enomoto A, Ito S, Yan Y, Sugiyama M, Onoue T, Tsunekawa T, Ito Y, Takagi H, Hagiwara D, Goto M, Suga H, Banno R, Takahashi M, Nishikawa H, Arima H

Science translational medicine 13 巻 ( 593 ) 2021年5月

High-fat Feeding Causes Inflammation and Insulin Resistance in the Ventral Tegmental Area in Mice. 査読有り

Mizoguchi A, Banno R, Sun R, Yaginuma H, Taki K, Kobayashi T, Sugiyama M, Tsunekawa T, Onoue T, Takagi H, Hagiwara D, Ito Y, Iwama S, Suga H, Arima H

Neuroscience 461 巻頁： 72 - 79 2021年5月

Arginine vasopressin-Venus reporter mice as a tool for studying magnocellular arginine vasopressin neurons 査読有り

Hagiwara Daisuke, Tochiya Masayoshi, Azuma Yoshinori, Tsumura Tetsuro, Hodai Yuichi, Kawaguchi Yohei, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Takagi Hiroshi, Ito Yoshihiro, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Arima Hiroshi

PEPTIDES 139 巻頁： 170517 2021年5月

Anti-pituitary antibodies and susceptible human leukocyte antigen alleles as predictive biomarkers for pituitary dysfunction induced by immune checkpoint inhibitors. 査読有り

Kobayashi T, Iwama S, Sugiyama D, Yasuda Y, Okuji T, Ito M, Ito S, Sugiyama M, Onoue T, Takagi H, Hagiwara D, Ito Y, Suga H, Banno R, Nishikawa H, Arima H

Journal for immunotherapy of cancer 9 巻 ( 5 ) 2021年5月

Efficacies of programmed cell death 1 ligand 1 blockade in non-small cell lung cancer patients with acquired resistance to prior programmed cell death 1 inhibitor and development of diabetic ketoacidosis caused by two different etiologies: a retrospective case series. 査読有り

Ishi A, Tanaka I, Iwama S, Sakakibara T, Mastui T, Kobayashi T, Hase T, Morise M, Sato M, Arima H, Hashimoto N

Endocrine journal 68 巻 ( 5 ) 頁： 613 - 620 2021年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本内分泌学会

The programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis is vital for immune resistance during tumor development, while PD-L1 inhibitors can also inhibit the PD-L1/B7-1 (CD80) interaction, indicating one of the molecular differences between PD-1 and PD-L1 inhibitors. However, the clinical benefits of PD-L1 inhibitors in patients previously treated with PD-1 inhibitors remain unknown. In this study, we retrospectively analyzed the clinical data of eight patients with non-small cell lung cancer who received the PD-L1 inhibitor atezolizumab and previously treated with the PD-1 inhibitor nivolumab. The median progression-free survival was 2.1 months (1.8–18.7 months), and 4 of 8 patients achieved at least stable disease. In two of these patients, atezolizumab treatment resulted in longer progression-free survival (PFS) compared with that of nivolumab. Conversely, one patient exhibited grade 4 diabetic ketoacidosis (DKA) within 2 weeks after the initial administration of atezolizumab. Another patient had developed type 1 diabetes mellitus (T1DM) during the prior nivolumab treatment and then developed DKA due to an infection after the initiation of atezolizumab. Both of them had high-risk human leukocyte antigen-DR/DQ types relevant to T1DM. These results demonstrate the potential efficacy of PD-L1 inhibitors to some tumors that have acquired resistance to PD-1 inhibitors and suggest that appropriate managements are required for not only a newly onset of T1DM but also blood glucose control after the development of T1DM during a reiteration of the PD-1/PD-L1 blockade.

DOI： 10.1507/endocrj.EJ20-0769

Dietary sodium chloride attenuates increased beta-cell mass to cause glucose intolerance in mice under a high-fat diet 査読有り

Clinical Characteristics, Management, and Potential Biomarkers of Endocrine Dysfunction Induced by Immune Checkpoint Inhibitors. 招待有り査読有り

Iwama S, Kobayashi T, Arima H

Endocrinology and metabolism (Seoul, Korea) 36 巻 ( 2 ) 頁： 312 - 321 2021年4月

Taki Keigo, Takagi Hiroshi, Hirose Tomonori, Sun Runan, Yaginuma Hiroshi, Mizoguchi Akira, Kobayashi Tomoko, Sugiyama Mariko, Tsunekawa Taku, Onoue Takeshi, Hagiwara Daisuke, Ito Yoshihiro, Iwama Shintaro, Suga Hidetaka, Banno Ryoichi, Sakano Daisuke, Kume Shoen, Arima Hiroshi

PLOS ONE 16 巻 ( 3 ) 頁： e0248065 2021年3月

Deficiency of WFS1 leads to the impairment of AVP secretion under dehydration in male mice 査読有り

Kurimoto Junki, Takagi Hiroshi, Miyata Takashi, Hodai Yuichi, Kawaguchi Yohei, Hagiwara Daisuke, Suga Hidetaka, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Ito Yoshihiro, Iwama Shintaro, Banno Ryoichi, Tanabe Katsuya, Tanizawa Yukio, Arima Hiroshi

PITUITARY 2021年3月

Anti-pituitary antibodies as a marker of autoimmunity in pituitary glands. 招待有り査読有り

Iwama S, Arima H

Endocrine journal 67 巻 ( 11 ) 頁： 1077 - 1083 2020年11月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Endocrine Journal

Autoimmunity contributes to the pathogenesis of hypophysitis, a chronic inflammatory disease in the pituitary gland. Although primary hypophysitis is rare, the number of pituitary dysfunction cases induced by immune checkpoint inhibitors (ICIs) is increasing. While it is difficult to prove the involvement of autoimmunity in the pituitary glands, circulating anti-pituitary antibodies (APAs) can be measured by indirect immunofluorescence and used as a surrogate marker of pituitary autoimmunity. APAs are present in several pituitary diseases, including lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis (LINH), IgG4-related hypophysitis, and pituitary dysfunction induced by ICIs. Mass spectrometry analysis of antigens targeted by APAs clarified rabphilin-3A as an autoantigen in LINH. This demonstrates that APAs can be applied as a probe to identify novel autoantigens in other pituitary autoimmune diseases, including pituitary dysfunction induced by ICIs, which can aid in biomarker discovery.

DOI： 10.1507/endocrj.EJ20-0436