Symposium

Symposium 11 Neuropsychological diseases and immune system シンポジウム11 日本神経化学会優秀賞受賞者企画シンポジウム神経精神疾患と免疫系

SY11-1 Pathophysiological role of astroglial MHCI following systemic immune activation 免疫活性化によって誘導されるアストロサイト由来MHC class Iの病態生理学的役割 Nagai Taku（永井拓） Dept. Neuropsychopharmacol. Hosp. Pharm., Nagoya Univ. Grad. Sch. Med., Nagoya, Japan Major histocompatibility complex class I (MHCI) molecules are expressed by most cells in the body, and mediate adaptive and innate immune responses. In the CNS, accumulating evidence suggests a role for neuronal MHCI molecules in neurite outgrowth, cortical connections, activity-dependent refinement in the visual system, and plasticity. The glial expression of MHCI molecules in the brain is minimal in normal and healthy brains, but is up-regulated under pathological conditions. The systemic immune activation induced by a peripheral injection of lipopolysaccharide in rodents led to the activation of astrocytes and microglia in the brain, and induced MHCI gene expression in non-neuronal cells and MHCII in microglia. We recently found that systemic immune activation by an intraperitoneal injection of polyI:C [(a synthetic analog of double-stranded RNA (dsRNA) that is recognized by toll-like receptor 3 (TLR3)] or hydrodynamic IFN-γ gene delivery in mice induces glial MHCI gene expression in the mPFC of mice. In the astrocytic cell line C8-DIA, MHCI/H-2D or its soluble form (sH-2D) co-localized with the exosome marker CD63, and sH-2D was efficiently packaged into exosomes. Astrocyte-spescific H-2D or sH-2D-expressing mice showed impairments in social behavior, object recognition memory and visual discrimination, which were accompanied by the activation of microglia (Iba1 (+) cells), decreases in the number of PV-positive cells (PV (+) cells), and reductions in neuronal spine density in the mPFC. Our results suggest that the up-regulated expression of MHCI in astrocytes following systemic immune activation has a significant impact on behavioral function, and neuropathology, possibly via exosomes secreted by astrocytes.		SY11-2 Psychiatric disorders and immune system: based on genetic findings 遺伝子からみた精神疾患・免疫 Ikeda Masashi（池田匡志） Department of Psychiatry, Fujita Health University School of Medicine 統合失調症や双極性障害は、遺伝疫学的研究から、遺伝要因の高い疾患と認識されており、メタ解析の結果からは、両疾患の遺伝率は80％程度と推測されている。従って、遺伝子からその病態生理にアプローチする意義が証明されているわけであるが、昨今のゲノム医科学進展による全ゲノム関連解析（GWAS）の成果が現れるまで、確定的なリスク遺伝子同定には至らなかった。現在では、統合失調症では100個以上、双極性障害では30個以上の領域がそのリスク遺伝子（領域）と報告されているが、これら遺伝子多型のeffect sizeは、極めて小さく、オッズ比にして1.1程度というものである（PGC, Nature 2014）。その中で、最も強く関連する領域（言い換えれば、effect sizeが大きい領域）は、統合失調症における6番染色体に位置するMHC領域である。このMHC領域は、もちろん、免疫系に関連する遺伝子が集中してコードされているが、特に補体であるC4の関連に興味が持たれている（Selar et al. Nature 2016）。またパスウェイ解析の結果などからも免疫系の関連が報告されていることから、疫学研究を含めた他の結果を統合すると、統合失調症の病態生理に免疫系が関与する蓋然性は高いと考えられる。このように、精神疾患と免疫系は、遺伝子研究の観点からも興味深いものである。本シンポジウムでは、精神疾患における遺伝子研究の最近の知見を概説するとともに、それらの結果の中から、特に免疫系遺伝子をコードする領域にも着目した内容を紹介する。

SY11-3 Application of stem cell-derived immune cells as a therapeutic strategy for dementia 幹細胞由来免疫細胞を用いた認知症の治療戦略 Takata Kazuyuki（高田和幸） Div. of Integ. Pharm. Sci., Kyoto Pharm. Univ., Kyoto, Japan Microglia belong to the macrophage lineage and serve as phagocytic immune cells in the brain and are also involved in the formation and processing of neuronal spines. Thus, microglia contribute to brain immunity and development as well as the acquisition of learning and memory. Alzheimer's disease (AD) is characterized by progressive cognitive impairment as a consequence of neural loss. According to the amyloid cascade hypothesis, the accumulation of amyloid-β peptides (Aβ) may be a critical trigger of AD pathogenesis. We previously demonstrated that rat microglia phagocytose Aβ, and that transplantation of these cells ameliorates the Aβ burden in brains of rats. Based on the evidence, we have been focusing on the reproduction of microglia-like cells by the differentiation of hematopoietic stem cells for the development of cell therapeutic strategy against AD, and we found the therapeutic potentials of the cells by means of Aβ reduction, adjustment of inflammatory condition, and improvement of cognitive impairment in in vivo and/or in vitro. In contrast, resident microglia arise from the yolk sac as primitive macrophages derived from primitive hematopoiesis in prenatal period. We recently also demonstrated that primitive hematopoiesis induced in the yolk sac can be recapitulated to produce primitive macrophages in induced pluripotent stem (iPS) cells, and that cells strongly reminiscent of microglia can be generated by co-culture of the primitive macrophages with neurons differentiated from the same batch of iPS cells. In this symposium, our recent studies described above will be shared, and we discuss regarding the therapeutic potentials of stem cell-derived microglia-like cells for brain diseases.		SY11-4 The roles of 2-ways communication between the nervous and immune systems in the progression of pain hypersensitivity caused by injury or disease of the somatosensory system 神経-免疫システムの 2-way コミュニケーションから考える神経障害性疼痛の発症機序 Imai Satoshi（今井哲司） Dept. Clin. Pharmacol. Therap., Kyoto Univ. Hosp. Neuropathic pain is a pathological pain state occurring in approximately 7-10% of the general population caused by lesion or disease of the somatosensory system. Many animal models of neuropathic pain have been utilized to investigate the mechanisms that underlie the development and maintenance of neuropathic pain. An important aspect of neuropathic pain is the reciprocal communication between the innate peripheral and central immune systems with the nervous system. Following nerve injury, peripheral immune cells, such as neutrophils, macrophages, and T cells, are activated and endowed with the ability to secrete chemokines, cytokines, and neurotrophins. Secreted factors facilitate 2-ways communication between the nervous and immune systems, and consequently induce peripheral sensitization. In the dorsal horn of the spinal cord, the lasting pain signaling due to nerve injury can induce the activation of spinal glial cells, such as microglia and astrocytes. Activated glial cells can affect neuronal excitability and pain transmission in the spinal dorsal horn neurons by releasing extracellular signaling molecules following peripheral nerve injury, which induces the long-lasting activation of ascending pain transmission. Some of the candidate immune factors have been identified as one of key players in the pathogenesis of neuropathic pain. To date, we have focused on the role of 2-ways communication between the nervous and immune systems and have studied on the pathogenesis of chronic pain caused by injury or disease of the somatosensory system. I would like to introduce a series of our novel findings in this presentation.