Nishida Yoriko, Aida Kaoru, Kihara Makoto, Kobayashi Tetsuro
Department of Nursing, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
PLoS One. 2014 Oct 16;9(10):e107664. doi: 10.1371/journal.pone.0107664. eCollection 2014.
There are no reports of proteomic analyses of inflamed islets in type 1 diabetes.
Proteins expressed in the islets of enterovirus-associated fulminant type 1 diabetes (FT1DM) with extensive insulitis were identified by laser-capture microdissection mass spectrometry using formalin-fixed paraffin-embedded pancreatic tissues.
Thirty-eight proteins were identified solely in FT1DM islets, most of which have not been previously linked to type 1 diabetes. Five protein-protein interacting clusters were identified, and the cellular localization of selected proteins was validated immunohistochemically. Migratory activity-related proteins, including plastin-2 (LCP1), moesin (MSN), lamin-B1 (LMNB1), Ras GTPase-activating-like protein (IQGAP1) and others, were identified in CD8+ T cells and CD68+ macrophages infiltrated to inflamed FT1DM islets. Proteins involved in successive signaling in innate/adaptive immunity were identified, including SAM domain and HD domain-containing protein 1 (SAMHD1), Ras GTPase-activating-like protein (IQGAP1), proteasome activator complex subunit 1 (PSME1), HLA class I histocompatibility antigen (HLA-C), and signal transducer and activator of transcription 1-alpha/beta (STAT1). Angiogenic (thymidine phosphorylase (TYMP)) and anti-angiogenic (tryptophan-tRNA ligase (WARS)) factors were identified in migrating CD8+ T cells and CD68+ macrophages. Proteins related to virus replication and cell proliferation, including probable ATP-dependent RNA helicase DEAD box helicase 5 (DDX5) and heterogeneous nuclear ribonucleoprotein H (HNRNPH1), were identified. The anti-apoptotic protein T-complex protein 1 subunit epsilon (CCT5), the anti-oxidative enzyme 6-phosphogluconate dehydrogenase (PDG), and the anti-viral and anti-apoptotic proteins serpin B6 (SERPINB6) and heat shock 70 kDa protein1-like (HSPA1L), were identified in FT1DM-affected islet cells.
The identified FT1DM-characterizing proteins include those involved in aggressive beta cell destruction through massive immune cell migration and proteins involved in angiogenesis and islet vasculature bleeding, cell repair, and anti-inflammatory processes. Several target proteins for future type 1 diabetes interventions were identified.
尚无关于1型糖尿病中炎症胰岛蛋白质组分析的报道。
使用福尔马林固定石蜡包埋的胰腺组织，通过激光捕获显微切割质谱法鉴定肠道病毒相关暴发性1型糖尿病（FT1DM）且伴有广泛胰岛炎的胰岛中表达的蛋白质。
仅在FT1DM胰岛中鉴定出38种蛋白质，其中大多数以前未与1型糖尿病相关联。鉴定出五个蛋白质 - 蛋白质相互作用簇，并通过免疫组织化学验证了所选蛋白质的细胞定位。在浸润到炎症性FT1DM胰岛的CD8 + T细胞和CD68 +巨噬细胞中鉴定出与迁移活性相关的蛋白质，包括质体肌动蛋白-2（LCP1）、埃兹蛋白（MSN）、核纤层蛋白B1（LMNB1）、Ras GTP酶激活样蛋白（IQGAP1）等。鉴定出参与先天/适应性免疫连续信号传导的蛋白质，包括含SAM结构域和HD结构域的蛋白1（SAMHD1）、Ras GTP酶激活样蛋白（IQGAP1）、蛋白酶体激活复合物亚基1（PSME1）、HLA I类组织相容性抗原（HLA - C）以及信号转导和转录激活因子1 - α/β（STAT1）。在迁移的CD8 + T细胞和CD68 +巨噬细胞中鉴定出血管生成因子（胸苷磷酸化酶（TYMP））和抗血管生成因子（色氨酸 - tRNA连接酶（WARS））。鉴定出与病毒复制和细胞增殖相关的蛋白质，包括可能的ATP依赖性RNA解旋酶DEAD盒解旋酶5（DDX5）和不均一核核糖核蛋白H（HNRNPH1）。在受FT1DM影响的胰岛细胞中鉴定出抗凋亡蛋白T - 复合物蛋白1亚基ε（CCT5）、抗氧化酶6 - 磷酸葡萄糖酸脱氢酶（PDG）以及抗病毒和抗凋亡蛋白丝氨酸蛋白酶抑制剂B6（SERPINB6）和热休克70 kDa蛋白1样（HSPA1L）。
鉴定出的FT1DM特征性蛋白质包括通过大量免疫细胞迁移参与侵袭性β细胞破坏的蛋白质，以及参与血管生成、胰岛血管出血、细胞修复和抗炎过程的蛋白质。确定了未来1型糖尿病干预的几个靶蛋白。
