Role of α-Fodrin Autoantigen in Sjogren's Syndrome

シェーグレン症候群における自己抗原α-Fodrinの役割 (武田憲昭教授退任記念総説集)


Mechanism of Activation-Induced Cell Death of T Cells and Regulation of FasL Expression.

Activation-induced cell death (AICD) of T cells is a process for regulating the peripheral immune system. The fate of a T cell is controlled by numerous signals derived from various stimuli, such as antigens, cytokines, and chemokines. In healthy humans, overactivated or autoreactive T cells are harmful and are eliminated to maintain the immune system. AICD in T cells by Fas/FasL-mediated apoptosis is triggered by the switch from life to death through several signaling molecules. The control or distribution of Fas or FasL expression largely affects AICD of T cells. Although autoimmune diseases are considered to be induced by multiple factors, an impaired immune system with AICD by Fas/FasL-mediated apoptosis leads to the onset or development of autoimmunity. Based on published reports, this review describes the regulatory mechanisms involved in AICD of T cells by Fas/ FasL-mediated apoptosis and the associations between AICD and autoimmunity in humans and animal models.


Sjögren症候群はドライアイやドライマウスを臨床症状とする原因不明の自己免疫疾患である．病因的アプローチを加えるため疾患モデルを開発し，ヒトとも共通する自己抗原120kDα-フォドリンを同定した．局所に浸潤するCD4陽性T細胞の多くがFasLを発現し，標的細胞のFas抗原との間でアポトーシスが成立している．また，唾液腺にエストロゲン欠乏依存性にアポトーシスを誘導するRbAp48遺伝子を同定した．

The Journal of the Japanese Society of Internal Medicine


Regulation of immune response by RANKL and Fas

RANKLとFasによる免疫応答の制御


Immunotherapeutic targets in estrogen deficiency-dependent Sjögren's syndrome-related manifestations

Although a number of autoimmune diseases are known to develop in postmenopausal women, the mechanisms by which estrogen deficiency influences autoimmunity remain unclear. Previously, we found that tissue-specific apoptosis in the exocrine glands in estrogen-deficient mice may contribute to the development of autoimmune exocrinopathy. We found that RbAp48 overexpression induces p53-mediated apoptosis in the exocrine glands depending on estrogen deficiency. RbAp48-inducible transfectants result in rapid apoptosis with p53 phosphorylation (Ser9), and alpha-fodrin cleavage. Indeed, transgenic expression of the RbAp48 gene induced apoptosis in the exocrine glands, resulting in the development of autoimmune exocrinopathy resembling Sjögren's syndrome (SS). CD4(+) T-cell-mediated autoimmune lesions were aggravated with age, in association with production of autoantibodies against SS-A, SS-B and alpha-fodrin. These findings demonstrated that estrogen deficiency initiates tissue-specific apoptosis in the exocrine gland cells through RbAp48 overexpression and exerts a possible gender-based risk of autoimmune exocrinopathy in postmenopausal women. Thus, these data indicate RbAp48 to be a novel immunotherapeutic target for preventing epithelial cell apoptosis and the development of gender-based autoimmune exocrinopathy.


Crosstalk between RANKL and Fas signaling in dendritic cells controls immune tolerance

RANKLとFasシグナルクロストークによる樹状細胞の機能調節機構


NF-kB2によるT細胞の新たな調節機構

NF-kB2によるT細胞の新たな調節機構


Crucial Roles of NF-κB for T Cell Activation


エストロゲンと自己免疫疾患

エストロゲンと自己免疫疾患


RbAp48遺伝子マウスにおけるシェーグレン様病態の出現

RbAp48遺伝子マウスにおけるシェーグレン様病態の出現


The possible etiopathogenic genes of Sjögren's syndrome

Sjögren's syndrome is a chronic autoimmune disease characterized by focal lymphocytic infiltration of lacrimal and salivary glands, but the precise mechanism of this syndrome is unclear. To clarify the pathogenesis of Sjögren's syndrome, the related genes must be identified. In the present study, we investigate the increased expression of genes and molecules related to Sjögren's syndrome and present our findings of cDNA microarray analysis in the mouse model. Furthermore, we present the results of immunohistochemical analysis of salivary glands in the mouse model and patients with Sjögren's syndrome. This approach might open a new discussion of the existence of principal pathogenic molecules in Sjögren's syndrome.


Revised Japanese criteria for Sjögrens syndrome (1999): availability and validity


Crucial Role of Tissue-Specific Apoptosis on the Development of Primary Sjogren's Syndrome


Apoptosis and Estrogen Deficiency in Primary Sjögren Syndrome

Primary Sjögren syndrome is an autoimmune disorder characterized by lymphocytic infiltrates and destruction of the salivary and lacrimal glands, and systemic production of autoantibodies to the ribonucleoprotein particles SS-A/Ro and SS-B/La. The purpose of this review is to discuss recent advances in the pathogenesis of primary Sjögren syndrome. Although several candidate autoantigens including alpha-fodrin have been reported in Sjögren syndrome, the pathogenic roles of the autoantigens in initiation and progression of SS are still unclear. It is possible that individual T cells activated by an appropriate self antigen can proliferate and form a restricted clone. Recent evidence suggests that the apoptotic pathway plays a central role in tolerizing T cells to tissue-specific self antigen, and may drive the autoimmune phenomenon. Cleavage of certain autoantigens during apoptosis may reveal immunocryptic epitopes that could potentially induce autoimmune response. The studies reviewed imply that Fas-mediated cytotoxicity and caspase-mediated alpha-fodrin proteolysis are involved in the progression of tissue destruction in Sjögren syndrome. Fas ligand (FasL), and its receptor Fas are essential in the homeostasis of the peripheral immune system. It can be considered that a defect in activation-induced cell death of effector T cells may result in the development of autoimmune exocrinopathy in Sjögren syndrome. Although the mechanisms by which estrogen deficiency influences autoimmune lesions remain unclear, it is possible that antiestrogenic actions might be a potent factor in the formation of pathogenic autoantigens.


日本アフェレシス学会雑誌

日本アフェレシス学会雑誌


自己免疫疾患の発症とアポトーシス

自己免疫疾患の発症とアポトーシス


The role of caspase cascade on the development of primary Sjogren'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 the 120 kDa alpha-fodrin as an important autoantigen on the development of SS in both animal model and SS patients, but the mechanism of a -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 significant 51Cr release against mouse salivary gland (MSG) cells. In vitro studies demonstrated that apoptotic MSG cells result in a specific alpha-fodrin cleavage into 120 kDa, and preincubation with caspase-inhibitor peptides blocked alpha-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 alpha-fodrin proteolysis and tissue destruction on the development of SS.

The Journal of Medical Investigation : JMI


シェーグレン症候群発症の分子機構

シェーグレン症候群発症の分子機構


接触性過敏症における樹状細胞の役割

接触性過敏症における樹状細胞の役割


自己免疫疾患における分子模倣仮説

自己免疫疾患における分子模倣仮説

Journal of Clinical and Experimental Medicine


シェ-グレン症候群発症の分子機構

シェ-グレン症候群発症の分子機構


シェーグレン症候群の新しい話題 --- III.病因・組織障害機序

シェーグレン症候群の新しい話題 --- III.病因・組織障害機序


シェーグレン症候群と動物モデル

シェーグレン症候群と動物モデル


シェーグレン症候群の病因抗原

シェーグレン症候群の病因抗原


An essential role of apoptotic protease cascade in the pathogenesis of Sjogren's syndrome


シェーグレンモデルマウス

シェーグレンモデルマウス


難治性口腔免疫疾患:シェーグレン症候群，ベーチェット病，天疱瘡など

難治性口腔免疫疾患:シェーグレン症候群，ベーチェット病，天疱瘡など


シェーグレン症候群自己抗原αーフォドリンの病因的意義

シェーグレン症候群自己抗原αーフォドリンの病因的意義


IL-10とシェーグレン症候群

IL-10とシェーグレン症候群


Involvement of apoptotic protease cascade for tissue destruction in Sjogren's syndrome

Sjögren syndrome (SS) is an autoimmune disease characterized by diffuse lymphoid cell infiltrates in the salivary and lacrimal glands, resulting in symptoms of dry mouth and eyes due to insufficient secretion. Although it has been assumed that a combination of immunologic, genetic and environmental factors may play a key role in the development of autoimmune lesions in the salivary and lacrimal glands, little is known about the disease pathogenesis of SS in humans. We have identified the 120 kDa alpha-fodrin as an important autoantigen in the development of SS in both an animal model and SS patients, but the mechanism of alpha-fodrin cleavage leading to tissue destruction in SS remains unclear. Tissue-infiltrating CD4+ T cells purified from the salivary glands of a mouse model for SS bear a large proportion of Fas ligand and the salivary gland duct cells possess apoptotic receptor Fas. Anti-Fas antibody-induced apoptotic salivary gland cells result in specific alpha-fodrin cleavage to the 120 kDa fragment in vitro. Preincubation with a combination of calpain and caspase inhibitor peptides could be responsible for inhibition of the 120 kDa alpha-fodrin cleavage. Thus, an increase in apoptotic protease activities including calpain and caspases may be involved in the progression of alpha-fodrin proteolysis and tissue destruction in the development of SS.

Archivum Immunologiae et Therapiae Experimentalis


シェーグレン症候群:モデルマウスとヒトの疾患

シェーグレン症候群:モデルマウスとヒトの疾患


シェーグレン症候群の発症に関与する自己抗原

シェーグレン症候群の発症に関与する自己抗原


免疫異常からみたリウマチ性疾患の臓器病変:口腔内病変

免疫異常からみたリウマチ性疾患の臓器病変:口腔内病変


Sjogren症候群のターゲット，αーフォドリン

Sjogren症候群のターゲット，αーフォドリン


Sjogren症候群の臓器特異的自己抗原の検出とその成立機序

Sjogren症候群の臓器特異的自己抗原の検出とその成立機序


シェーグレン症候群における臓器特異的自己抗原の同定

シェーグレン症候群における臓器特異的自己抗原の同定


シェーグレン症候群における自己抗原αーフォドリンの同定とその意義

シェーグレン症候群における自己抗原αーフォドリンの同定とその意義


シェーグレン症候群の原因抗原

シェーグレン症候群の原因抗原


シェーグレン症候群とその病因の解明

シェーグレン症候群とその病因の解明


Sjogren症候群の新たな自己抗原

Sjogren症候群の新たな自己抗原


The immunology of Sjogren's syndrome: emphasis on the role of salivary gland autoantigen


シェーグレン症候群における免疫機構

シェーグレン症候群における免疫機構


シェーグレン症候群 原因自己抗原の解明

シェーグレン症候群 原因自己抗原の解明


シェーグレン症候群モデルマウスにおける臓器特異的自己抗体

シェーグレン症候群モデルマウスにおける臓器特異的自己抗体


Sjogren症候群疾患モデルと臓器特異的自己抗原

Sjogren症候群疾患モデルと臓器特異的自己抗原


Cytokines, adhesion molecules, and immune deviation in autoimmune salivary

The immunopathology of most autoimmune diseases has been well defined, but the mechanisms responsible for the breakdown of self-tolerance and which lead to the development of autoimmune lesions are still unclear. Primary Sjogren's syndrome in humans is known to be an autoimmune disease characterized by diffuse lymphoid cell infiltration in the exocrine organs, involving in particular the salivary and lacrimal glands. The pathogenesis of this syndrome remains unclear, but the majority of infiltrating cells in the salivary glands were CD4^+ T cells both in humans and rodents. Since many cytokines and adhesion molecules are involved in the development of T cell-mediated autoimmunity, we have investigated local eytokine, and adhesion molecule gene expression using animal model for primary Sjogren's syndrome in MRL/lpr, and NFS/sld mice. Overexpression of interleukin-1(IL-1) β and tumor necrosis factor(TNF)-α, interferon(IFN)-γ, IL-6, IL-10, IL-12(p40) was detected in the salivary gland, and the up-regulation of ICAM-1, LFA-1, CD44, Mel-14 mRNA was found in accordance with autoimmune sialadenitis. In addition, we have analysed the expression of T cell antigen receptor(TCR)Vβ transcripts in the salivary gland tissues. Transcript for Vβ 8 was predominantly detected in the T cell infiltrating sialadenitis from the onset of the disease, suggesting that CD4^+ T cells bearing TCR Vβ 8 are play essential roles to recognize unknown autopeptide in the autoimmune salivary gland disease.


老化と自己免疫，免疫疾患

老化と自己免疫，免疫疾患


シェーグレン症候群各種動物モデルによる実験的研究の動向と成果

シェーグレン症候群各種動物モデルによる実験的研究の動向と成果

Nihon Rinsho. Japanese Journal of Clinical Medicine


Sjogren's Syndrome,Systemic Lupus Erythematosus and Oral Mucosal Immunity


Pathogenesis of Sjogren's syndrome-like autoimmune lesions in MRL/lpr mice


シェーグレン症候群の病因解析

シェーグレン症候群の病因解析


老化と自己免疫 エイジングの科学

老化と自己免疫 エイジングの科学


自己免疫疾患の発症機構におけるT細胞の役割

自己免疫疾患の発症機構におけるT細胞の役割


Sjogren症候群の病態と病理

Sjogren症候群の病態と病理


Sjogren症候群疾患モデルの現状と展望

Sjogren症候群疾患モデルの現状と展望


シェーグレン症候群疾患モデルによる病因解析の展望

シェーグレン症候群疾患モデルによる病因解析の展望


Interstitial renal leions as a autoimmune phenomenon in the aged


加齢に伴う自己免疫性臓器病変

加齢に伴う自己免疫性臓器病変


Autoimmune sialadenitis: possible models for Sjogren's syndrome and a common aging phenomenon


高齢者剖検例にみられる自己免疫性臓器病変

高齢者剖検例にみられる自己免疫性臓器病変


ヒト唾液腺癌細胞の増殖と分化

ヒト唾液腺癌細胞の増殖と分化


徳島大学先端医療開発研究センター設置準備室成果報告書

徳島大学先端医療開発研究センター設置準備室成果報告書