Autoantigen-Specific CD4+CD28low T Cell Subset Prevents Autoimmune Exocrinopathy in Murine Sjögren’s Syndrome

Saegusa, Kaoru; Ishimaru, Naozumi; Yanagi, Kumiko; Haneji, Norio; Nishino, Mizuho; Azuma, Miyuki; Hayashi, Yoshio

doi:10.4049/jimmunol.165.4.2251

Cited by 18 publications

(9 citation statements)

References 49 publications

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“…On the other hand, there are no differences in body weight, gross pelage aspect, reproductive capacity between control and thymectomized NFS/ sld mice. As for immunological aspects such as decreased T cell number, enhanced Th1-type cytokine production, and autoantibody production in addition to autoimmune lesions in salivary and lacrimal glands were observed in the thymectomized mice [25]–[27].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, thymectomized NFS/ sld mice have been established as a model of primary SS [10]. As inflammatory lesions in this model are localized in salivary and lacrimal glands, resembling human primary SS, and immune phenotypes and responses including cytokine profile, autoantibody production, or antigen-specific T cell responses are similar to those of human SS, this animal model has been used for analyzing the pathogenesis of SS and establishing new therapeutic strategies [25]–[27]. In addition, autoimmune lesions have an earlier onset in young mice (aged 6–8 weeks), with the frequency of onset being almost 100%.…”

Section: Discussionmentioning

confidence: 99%

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Anti-Inflammatory Effects of Rebamipide Eyedrop Administration on Ocular Lesions in a Murine Model of Primary Sjögren's Syndrome

et al. 2014

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BackgroundTopical therapy is effective for dry eye, and its prolonged effects should help in maintaining the quality of life of patients with dry eye. We previously reported that the oral administration of rebamipide (Reb), a mucosal protective agent, had a potent therapeutic effect on autoimmune lesions in a murine model of Sjögren's syndrome (SS). However, the effects of topical treatment with Reb eyedrops on the ocular lesions in the murine model of SS are unknown.Methods and FindingReb eyedrops were administered to the murine model of SS aged 4–8 weeks four times daily. Inflammatory lesions of the extraorbital and intraorbital lacrimal glands and Harderian gland tissues were histologically evaluated. The direct effects of Reb on the lacrimal glands were analyzed using cultured lacrimal gland cells. Tear secretions of Reb-treated mice were significantly increased compared with those of untreated mice. In addition to the therapeutic effect of Reb treatment on keratoconjunctivitis, severe inflammatory lesions of intraorbital lacrimal gland tissues in this model of SS were resolved. The mRNA expression levels of IL-10 and mucin 5Ac in conjunctival tissues from Reb-treated mice was significantly increased compared with those of control mice. Moreover, lactoferrin production from lacrimal gland cells was restored by Reb treatment.ConclusionTopical Reb administration had an anti-inflammatory effect on the ocular autoimmune lesions in the murine model of SS and a protective effect on the ocular surfaces.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Effects of Rebamipide Eyedrop Administration on Ocular Lesions in a Murine Model of Primary Sjögren's Syndrome

et al. 2014

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“…Interestingly, transfer of CD4+CD28low T cells into 4 week old NFS/ sld mice prevented the development of autoimmune lesions and autoantibody production. These results suggest that a CD4+CD28low T cell subset that is continuously activated by an organ-specific autoantigen may play a regulatory role in the development of organ-specific SjS-like exocrinopathy in this animal model [93]. Moreover, intraperitoneal administration of anti-CD86 antibodies into NFS/ sld mice resulted in dramatic inhibition of autoimmune lesion development, which supports the crucial roles of CD86 co-stimulatory molecule in the initiation of T H 1-mediated autoimmunity in the exocrine glands [94].…”

Section: Mouse Modelsmentioning

confidence: 99%

Mouse Models of Primary Sjogren’s Syndrome

Park¹,

Gauna²,

Cha

2015

CPD

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Sjögren’s syndrome (SjS) is a chronic autoimmune disorder characterized by immune cell infiltration and progressive injury to the salivary and lacrimal glands. As a consequence, patients with SjS develop xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). SjS is the third most common rheumatic autoimmune disorder, affecting 4 million Americans with over 90% of patients being female. Current diagnostic criteria for SjS frequently utilize histological examinations of minor salivary glands for immune cell foci, serology for autoantibodies, and dry eye evaluation by corneal or conjunctival staining. SjS can be classified as primary or secondary SjS, depending on whether it occurs alone or in association with other systemic rheumatic conditions, respectively. Clinical manifestations typically become apparent when the disease is relatively advanced in SjS patients, which poses a challenge for early diagnosis and treatment of SjS. Therefore, SjS mouse models, because of their close resemblance to the human SjS, have been extremely valuable to identify early disease markers and to investigate underlying biological and immunological dysregulations. However, it is important to bear in mind that no single mouse model has duplicated all aspects of SjS pathogenesis and clinical features, mainly due to the multifactorial etiology of SjS that includes numerous susceptibility genes and environmental factors. As such, various mouse models have been developed in the field to try to recapitulate SjS. In this review, we focus on recent mouse models of primary SjS and describe them under three categories of spontaneous, genetically engineered, and experimentally induced development of SjS-like disease. In addition, we discuss future perspectives of SjS mouse models highlighting pros and cons of utilizing mouse models and demands for improved models.

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“…Neonatal thymectomy of NFS/ sld mice produced the primary SS model used in this study. Using this model, we previously reported a salivary gland-specific SS autoantigen, described an antigen-specific response of T-helper 1 (Th1) cells, and evaluated several molecular mechanisms and agents for SS therapy [6,7,10,25]. …”

Section: Discussionmentioning

confidence: 99%

Pathological Analysis of Ocular Lesions in a Murine Model of Sjögren’s Syndrome

Ushio

Arakaki

Eguchi

et al. 2017

IJMS

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Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by severe inflammation of exocrine glands such as the salivary and lacrimal glands. When it affects the lacrimal glands, many patients experience keratoconjunctivitis due to severely dry eyes. This study investigated the pathological and immunological characteristics of ocular lesions in a mouse model of SS. Corneal epithelial injury and hyperplasia were confirmed pathologically. The number of conjunctival mucin-producing goblet cells was significantly decreased in the SS model mice compared with control mice. Expression levels of transforming growth factor (TGF)-β, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-X-C motif chemokine (CXCL) 12 were significantly higher in the corneal epithelium of the SS model mice than in control mice. Inflammatory lesions were observed in the Harderian, intraorbital, and extraorbital lacrimal glands in the SS model mice, suggesting that the ocular glands were targeted by an autoimmune response. The lacrimal glands of the SS model mice were infiltrated by cluster of differentiation (CD)4+ T cells. Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed significantly increased mRNA expression of TNF-α, TGF-β, CXCL9, and lysozyme in the extraorbital lacrimal glands of the SS model mice compared with control mice. These results add to the understanding of the complex pathogenesis of SS and may facilitate development of new therapeutic strategies.

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Autoantigen-Specific CD4+CD28low T Cell Subset Prevents Autoimmune Exocrinopathy in Murine Sjögren’s Syndrome

Cited by 18 publications

References 49 publications

Anti-Inflammatory Effects of Rebamipide Eyedrop Administration on Ocular Lesions in a Murine Model of Primary Sjögren's Syndrome

Anti-Inflammatory Effects of Rebamipide Eyedrop Administration on Ocular Lesions in a Murine Model of Primary Sjögren's Syndrome

Mouse Models of Primary Sjogren’s Syndrome

Pathological Analysis of Ocular Lesions in a Murine Model of Sjögren’s Syndrome

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