ジコ メンエキ シッカン ノ ビョウタイ カイメイ ニ ムケタ タカクテキ ケンキュウ

Immune cells normally attack exogenous bacteria or viruses without harming the body's cells or tissues. However, any abnormality in these immune cells could consequently result in cell or tissue damage of various organs, including the pancreas, salivary glands, and joints as the targets of autoimmune diseases. Autoimmune diseases result from complex and multigenic phenotypes that affect by a variety of genetic and environmental or stochastic factors. Fundamental treatments for autoimmune diseases have not yet been established. In this review, we introduce the following: (1) useful animal models for Sjögren's syndrome (SS), (2) the critical role of estrogen in autoimmunity, (3) the influence of environmental hormones on autoimmunity, (4) the cell signaling in autoimmunity, and (5) the therapeutic strategy for autoimmune disease

シェーグレン ショウコウグン シッカン モデル マウス ニオケル エストロジェン ノ ヤクワリ

自己免疫疾患の発症に性差が存在することはよく知られているが、その詳細なメカニズ ムに関しては全く不明である。シェーグレン症候群疾患モデルNFS/sldマウスにおいても 雌優位に自己免疫性唾液腺炎・涙腺炎を発症することから、本研究は本モデルマウスにお ける自己免疫病変の発症におけるエストロジェンの役割を詳細に解析し、性差のメカニズ ムを解明することを目的とする。 NFS/sld雌マウスに生後3日目に胸腺を摘出(Tx) した後、卵巣摘出(Ovx)を施し、自 己免疫病変の動態、免疫調節系への影響を観察し、さらに、Tx+Ovxマウスへのエストロ ジェン，そのアンタゴニスト(タモキシフェン)やテストステロンの投与による病態の変 動を検討した。また、in vivo及びin vitroにおけるエフェクター細胞のエストロジェンに 対する反応性・エストロジェンレセプターの発現について検索した。加えて、エストロジ ェンが標的臓器に及ぼす影響を腺組織破壊という観点から解析した。 シェーグレン症候群疾患モデルNFS/sldマウスにおいて、Ovxを施すことにより、自己免 疫病変はさらに増悪することが判明した。その病変局所においてCD4陽性T細胞の浸潤が 主体を成し、各種炎症性サイトカイン(IL-1β，IL-4，IL-7，TNF-α)の産生亢進が認められ た。Tx+Ovxによる変化として、T細胞系ではTxマウスに比較して脾細胞中のCD8陽性細胞 の有意な低下が認められ、B細胞系では唾液腺特異的な自己抗原(α-fodrin)に対する自己抗 体の産生が亢進していた。また、Tx+Ovxによって増悪した自己免疫病変はエストロジェ ン投与により回復し、エストロジェンが自己反応性T細胞の活性化を抑制する作用のある ことが判明した。そのメカニズムの一つとして、in vitroにおいてCD8陽性細胞がエストロ ジェンに対して有意に反応し、エストロジェンレセプターの強い発現が認められたことか ら、レセプターを介したCD8陽性細胞のサプレッサー機能をエストロジェンが制御してい る可能性が示唆された。さらに、adoptive transfer によりCD4陽性細胞が直接病態形成を調 節することが判明した。一方、標的臓器である唾液腺の組織破壊のメカニズムにFas/Fas Ligand(FasL)を介したアポトーシスが関与し、エストロジェンは唾液腺細胞のFas発現及び 浸潤Tリンパ球のFasL発現の両者に影響を与えている可能性が示唆された。本実験系から 得られた結果はヒトの自己免疫疾患発症における性差のメカニズムを解明する上で有用で あり、シェーグレン症候群の病因に基づいた治療法の開発に重要な知見をもたらすものと 考えられた

Matrix Metalloproteinases : The Gene Expression Signatures of Head and Neck Cancer Progression

Extracellular matrix degradation by matrix metalloproteinases (MMPs) plays a pivotal role in cancer progression by promoting motility, invasion and angiogenesis. Studies have shown that MMP expression is increased in head and neck squamous cell carcinomas (HNSCCs), one of the most common cancers in the world, and contributes to poor outcome. In this review, we examine the expression pattern of MMPs in HNSCC by microarray datasets and summarize the current knowledge of MMPs, specifically MMP-1, -3, -7 -10, -12, -13, 14 and -19, that are highly expressed in HNSCCs and involved cancer invasion and angiogenesis

Virus Infections Play Crucial Roles in the Pathogenesis of Sjögren’s Syndrome

Sjögren’s syndrome (SS) is an autoimmune disease especially targeting exocrine glands, such as the salivary and lacrimal glands. A radical therapy for SS based on its etiology has not been established because of the complex pathogenesis of the disease. Several studies have demonstrated a relationship between virus infection and SS pathogenesis. In particular, infection with the Epstein-Barr (EB) virus among others is a potent factor associated with the onset or development of SS. Specifically, virus infection in the target organs of SS triggers or promotes autoreactive responses involving the process of autoantigen formation, antigen-presenting function, or T-cell response. Our review of recent research highlights the crucial roles of virus infection in the pathogenesis of SS and discusses the critical association between virus infection and the etiology of autoimmunity in SS

The role of caspase cascade on the development of primary Sjögren's syndrome

Primary Sjögren syndrome (SS) is an autoimmune disease characterized by diffuse lymphoid cell infiltrates in the salivary and lacrimal glands, resulting in symptoms of dry eye and dry mouth due to insufficient secretion. Previously, we have identified the120 kDa α-fodrin as an important autoantigen on the development of SS in both animal model and SS patients, but the mechanism of α-fodrin cleavage leading to tissue destruction in SS remains unclear. In murine primary SS model, tissue-infiltrating CD4+ T cells purified from the salivary glands bear a large proportion of Fas ligand (FasL), and the salivary gland duct cells constitutively possess Fas. Infiltrating CD4+ T cells identified significant51Cr release against mouse salivary gland (MSG) cells. In vitro studies demonstrated that apoptotic MSG cells result in a specific α-fodrin cleavage into 120 kDa, and preincubation with caspase-inhibitor peptides blocked α-fodrin cleavage. The treatment with caspase-inhibitors in vivo prevented the development of autoimmune lesions in the salivary and lacrimal glands. Thus, an increased activity in caspase cascade may be involved in the progression of α-fodrin proteolysis and tissue destruction on the development of SS

Salivary gland and autoimmunity

Recent evidences suggest that the apoptotic pathway plays a central role in tolerazing T cells to tissue-specific self antigen, and may drive the autoimmune phenomenon in the salivary glands. We found that retinoblastoma-associated protein RbAp48 overexpression induces p53-mediated apoptosis in the salivary glands caused by estrogen deficiency. We demonstrated that transgenic (Tg) expression of RbAp48 resulted in the development of autoimmune exocrinopathy resembling Sjögren’s syndrome (SS). CD4+T cell-mediated autoimmune lesions in the salivary glands were aggravated with age, in association with autoantibody productions. We obtained evidences that salivary epithelial cells can produce interferon-γ(IFN-γ) besides interleukin (IL)-18, which activates interferon regulatory factor-1 (IRF-1), and class II transactivator (CIITA). Indeed, the autoimmune lesions into Rag2-/- mice were induced by the adoptive transfer of lymph node cells from RbAp48-Tg mice. These results indicate a novel immunocompetent role of epithelial cells that can produce IFN-γ, resulting in loss of local tolerance prior to developing gender-based autoimmunity. The studies reviewed the molecular mechanisms on the development of salivary gland autoimmunity, and gender-related differences in SS

Formation of Autoimmune Lesions Is Independent of Antibiotic Treatment in NOD Mice

The relationship between autoimmunity and changes in intestinal microbiota is not yet fully understood. In this study, the role of intestinal microbiota in the onset and progression of autoimmune lesions in non-obese diabetic (NOD) mice was evaluated by administering antibiotics to alter their intestinal microenvironment. Flow cytometric analysis of spleen cells showed that antibiotic administration did not change the proportion or number of T and B cells in NOD mice, and pathological analysis demonstrated that autoimmune lesions in the salivary glands and in the pancreas were also not affected by antibiotic administration. These results suggest that the onset and progression of autoimmunity may be independent of enteral microbiota changes. Our findings may be useful for determining the appropriate use of antibiotics in patients with autoimmune diseases who are prescribed drugs to maintain systemic immune function

Involvement of adiponectin in age-related increases in tear production in mice

Common age-related changes in the human eye contribute to the development of dry eye, including decreases in aqueous tear production. Although the infiltration of lymphocytes into the lacrimal glands occurs with age, age-related increases in tear production have also been observed in mice; however, the mechanisms underlying this increase remain unclear. We herein demonstrated that increases in tear production were not dependent on body weight gain or systemic conditions, such as insulin resistance, using aged mice and high-fat diet-fed mice. The results obtained also showed that senescence-associated T (SA-T) cells accumulated in the lacrimal glands of aged mice, particularly females. Expression levels of the nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) in whole lacrimal glands and epithelial cells isolated from lacrimal glands were significantly higher in aged mice than in young mice. The expression levels of adiponectin and one of its receptors, AdipoR2, also increased in the lacrimal glands of aged mice, but not in those of high-fat diet-fed mice. Collectively, the present results indicate that PPARγ and adiponectin-mediated signaling contribute to age-related increases in tear production in mice and have potential as therapeutic targets for the treatment of dry eye in humans