Apoptosis and Apoptosis-Related Molecules in the Submandibular Gland of the Nonobese Diabetic Mouse Model for Sjögren's Syndrome: Limited Role for Apoptosis in the Development of Sialoadenitis

Blokland, Saskia C A van; Helden-Meeuwsen, Cornelia G van; Wierenga‐Wolf, Annet F.; Tielemans, Dennis; Drexhage, Hemmo A.; Merwe, J. P. van de; Homo‐Delarche, Françoise; Versnel, Marjan A.

doi:10.1097/01.lab.0000048721.21475.d1

Cited by 16 publications

(9 citation statements)

References 36 publications

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“…2). A role of apoptosis of epithelial cells in the effector phase of sialoadenitis in the NOD mouse was suggested after the study of some investigators (52)(53)(54)(55)(56)(57), while other investigators did not find evidence for a role of apoptosis in the effector phase of sialoadenitis (58). In addition, in our experiments we did not find evidence for a role of apoptosis in the initiation phase of IDDM and SS in either group of mice.…”

Section: Discussioncontrasting

confidence: 47%

E2f1Mutation Induces Early Onset of Diabetes and Sjögren’s Syndrome in Nonobese Diabetic Mice

Salam

Matin

Matsumoto

et al. 2004

The Journal of Immunology

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E2f1 is an important regulator of T cell proliferation, differentiation, and apoptosis that controls the transcription of a group of genes that are normally regulated at the G1 to S phase transition in the cell cycle. Insulin-dependent diabetes mellitus (IDDM) and Sjögren’s syndrome (SS) are highly regulated autoimmune diseases that develop spontaneously in NOD mice. The aim of the present in vivo study was to explore the functional importance of the E2f1 molecule in IDDM and SS, in the context of whole animal physiology and pathophysiology, using E2f1-deficient NOD mice. For the experiment, we produced NOD mice homozygous for a nonfunctional E2f1 allele onto a NOD background. E2f1-deficient NOD mice developed an early and increased onset of diabetes as compared with their littermates. These mice also exhibited a defect in T lymphocyte development, leading to excessive numbers of mature T cells (CD4+ and CD8+), due to a maturation stage-specific defect in the apoptosis of thymocytes and peripheral T cells. We also found that they also exhibited a more rapid and increased entry into the S phase following antigenic stimulation of spleen cells and thymocytes in vitro. Furthermore, E2f1-deficient mice showed a profound decrease of immunoregulatory CD4+CD25+ T cells, while the spleen cells of NOD mice lacking E2f1 showed a significant increase of the proinflammatory cytokine IFN-γ following antigenic stimulation in vitro. Consistent with these observations, E2f1 homozygous mutant NOD mice were highly predisposed to the development of IDDM and SS.

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Section: Discussioncontrasting

confidence: 47%

E2f1Mutation Induces Early Onset of Diabetes and Sjögren’s Syndrome in Nonobese Diabetic Mice

Salam

Matin

Matsumoto

et al. 2004

The Journal of Immunology

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“…Activated CD4 + T cells can trigger CD8 + T cell differentiation which could lead to lacrimal epithelial cell death through Fas-FasL system or by releasing perforin-granzyme. Expression of FasL and its receptor Fas, have been observed in the lacrimal (Tsubota et al, 2003) and salivary glands of SS patients (Matsumura et al, 1996) and in the salivary glands of the NOD mice (Van Blokland et al, 2003). The interaction of Fas and FasL initiates a chain of biochemical events which leads to cleavage and activation of caspase 3 with subsequent substrate cleavage and apoptosis (Manganelli and Fietta, 2003; Kulkarni et al, 2006; O’Brien and Kirby, 2008).…”

Section: Discussionmentioning

confidence: 99%

Influence of sex hormones and genetic predisposition in Sjögren’s syndrome: A new clue to the immunopathogenesis of dry eye disease

Mostafa

Seamon

Azzarolo

2012

Experimental Eye Research

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Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration, destruction of lacrimal and salivary glands and the presence of serum autoantibodies. Most women that suffer from SS are post-menopausal however, not all post-menopausal women develop SS, suggesting that other factors, in addition to the decrease in ovarian hormones, are necessary for the development of SS. The purposes of this study were to investigate a) the time course of lymphocytic infiltration and apoptosis in the lacrimal gland after ovariectomy, b) if a predisposed genetic background for SS aggravates the effects of decreasing levels of sex hormones in the lacrimal glands and c) if physiological doses of estrogen or androgen prevent the effects observed after ovariectomy. Six weeks old mice that are genetically predisposed to SS (NOD.B10.H2b) and control (C57BL/10) mice were either sham-operated, ovariectomized (OVX), OVX + 17β estradiol (E2) or OVX + Dihydrotestosterone (DHT). Lacrimal glands were collected at 3, 7, 21 or 30 days after surgery and processed for immunohistochemistry to measure CD4+ , CD8+ T cells, B220+ B cells, nuclear DNA degradation and cleaved caspase-3 activity. Quantification of the staining was done by light microscopy and Image Pro Plus software. The results of our study show that lymphocytic infiltration preceded lacrimal gland apoptosis after ovariectomy. Moreover, removal of ovarian sex hormones accelerated these effects in the genetically predisposed animal and these effects were more severe and persistent compared to control animals. In addition, sex hormone replacement at physiological levels prevented these symptoms. The mechanisms by which decreased levels of sex hormones caused lymphocytic infiltration and apoptosis and the interaction of lack of sex hormones with the genetic elements remain to be elucidated.

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“…Some studies suggested that apoptosis of the lacrimal and salivary gland epithelial cells in SS is responsible for the decreased secretory function of these glands (Humphreys-Beher et al, 1999, Tsubota et al, 2003. However, other studies showed limited roles for apoptosis in SS (Ohlsson et al, 2001, Van Blokland et al, 2003. The different experimental approaches used in these studies might explain some of the discrepancies.…”

Section: Mechanisms Of Lacrimal Gland Dysfunctionmentioning

confidence: 99%

Effect of inflammation on lacrimal gland function

Zoukhri

2006

Experimental Eye Research

226

157

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The lacrimal gland is the main contributor to the aqueous layer of the tear film. It secretes proteins, electrolytes and water, which helps to nourish and protect the ocular surface. Lacrimal gland secretion is primarily under neural control, which is achieved through a neural reflex arc. Stimuli to the ocular surface activate afferent sensory nerves in the cornea and conjunctiva. This in turn activates efferent parasympathetic and sympathetic nerves in the lacrimal gland to stimulate secretion. Sex steroid hormones are also important regulators of lacrimal gland functions. A decrease or lack of lacrimal gland secretion is the leading cause of aqueous tear deficient dry eye syndrome (DES). It has been suggested that DES is an inflammatory disorder that affects the ocular surface and the lacrimal gland. In several pathological instances, the lacrimal gland can become a target of the immune system and show signs of inflammation. This can result from autoimmune diseases (Sjögren's syndrome), organ transplantation (graft versus host disease), or simply as a result of aging. The hallmarks of lacrimal gland inflammation are the presence of focal lymphocytic infiltrates and increased production of proinflammatory cytokines. The mechanisms leading to lacrimal gland dysfunction are still poorly understood. Apoptosis, production of autoantibodies, hormonal imbalance, alterations in signaling molecules, neural dysfunction, and increased levels of proinflammatory cytokines have been proposed as possible mediators of lacrimal gland insufficiency in disease states.

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Apoptosis and Apoptosis-Related Molecules in the Submandibular Gland of the Nonobese Diabetic Mouse Model for Sjögren's Syndrome: Limited Role for Apoptosis in the Development of Sialoadenitis

Cited by 16 publications

References 36 publications

E2f1Mutation Induces Early Onset of Diabetes and Sjögren’s Syndrome in Nonobese Diabetic Mice

E2f1Mutation Induces Early Onset of Diabetes and Sjögren’s Syndrome in Nonobese Diabetic Mice

Influence of sex hormones and genetic predisposition in Sjögren’s syndrome: A new clue to the immunopathogenesis of dry eye disease

Effect of inflammation on lacrimal gland function

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