Increased degradation of extracellular matrix structures of lacrimal glands implicated in the pathogenesis of Sjögren's syndrome

Primary Sjögren’s syndrome is an autoimmune disease that is predominantly seen in women. The disease is characterized by exocrine gland dysfunction in combination with serious systemic manifestations. At present, the causes of pSS are poorly understood. Pulmonary and renal inflammation are observed in pSS mice, reminiscent of a subset of pSS patients. A growing body of evidence indicates that inflammation mediated by Damage-Associated Molecular Patterns (DAMPs) contributes to autoimmunity, although this is not well-studied in pSS. Degraded extracellular matrix (ECM) constituents can serve as DAMPs by binding pattern-recognition receptors and activating Myd88-dependent signaling cascades, thereby exacerbating and perpetuating inflammatory cascades. The ECM components biglycan (Bgn) and decorin (Dcn) mediate sterile inflammation and both are implicated in autoimmunity. The objective of this study was to determine whether these ECM components and anti-ECM antibodies are altered in a pSS mouse model, and whether this is dependent on Myd88 activation in immune cells. Circulating levels of Bgn and Dcn were similar among pSS mice and controls and tissue expression studies revealed pSS mice had robust expression of both Bgn and Dcn in the salivary tissue, saliva, lung and kidney. Sera from pSS mice displayed increased levels of autoantibodies directed against ECM components when compared to healthy controls. Further studies using sera derived from conditional knockout pSS mice demonstrated that generation of these autoantibodies relies, at least in part, on Myd88 expression in the hematopoietic compartment. Thus, this study demonstrates that ECM degradation may represent a novel source of chronic B cell activation in the context of pSS.

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Myoepithelial cell-driven acini contraction in response to oxytocin receptor stimulation is impaired in lacrimal glands of Sjögren’s syndrome animal models

Scientific Reports ◽

10.1038/s41598-018-28227-x ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 10

Author(s):

Dillon Hawley ◽

Xin Tang ◽

Tatiana Zyrianova ◽

Mihir Shah ◽

Srikanth Janga ◽

...

Keyword(s):

Animal Models ◽

Sjögren’S Syndrome ◽

Myoepithelial Cell ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Oxytocin Receptor ◽

Lacrimal Glands ◽

Receptor Stimulation ◽

Sjögren‘S Syndrome

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Altered Distribution of Aquaporin 5 and its C-Terminal Binding Protein in the Lacrimal Glands of a Mouse Model for Sjögren's Syndrome

Current Eye Research ◽

10.1080/02713680802262819 ◽

2008 ◽

Vol 33 (8) ◽

pp. 621-629 ◽

Cited By ~ 20

Author(s):

Yoshiki Ohashi ◽

Kensei Tsuzaka ◽

Tsutomu Takeuchi ◽

Yasumasa Sasaki ◽

Kazuo Tsubota

Keyword(s):

Mouse Model ◽

Sjögren’S Syndrome ◽

Sjögren's Syndrome ◽

Binding Protein ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Lacrimal Glands ◽

Aquaporin 5 ◽

Sjögren‘S Syndrome

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LTBR-Pathway in Sjogren’s Syndrome: CXCL13 Levels and B-cell-Enriched Ectopic Lymphoid Aggregates in NOD Mouse Lacrimal Glands Are Dependent on LTBR

Advances in Experimental Medicine and Biology - Advances in TNF Family Research ◽

10.1007/978-1-4419-6612-4_39 ◽

2010 ◽

pp. 383-390 ◽

Cited By ~ 8

Author(s):

Roy A. Fava ◽

Jeffrey L. Browning ◽

Margaret Gatumu ◽

Kathrine Skarstein ◽

Anne-Isine Bolstad

Keyword(s):

B Cell ◽

Sjögren’S Syndrome ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Nod Mouse ◽

Lacrimal Glands ◽

Lymphoid Aggregates ◽

Sjögren‘S Syndrome

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Subclass Expression of IgA in Lacrimal Glands of Patients with Sjögren’s Syndrome

Advances in Experimental Medicine and Biology - Lacrimal Gland, Tear Film, and Dry Eye Syndromes ◽

10.1007/978-1-4615-2417-5_32 ◽

1994 ◽

pp. 185-188 ◽

Cited By ~ 2

Author(s):

Masafumi Ono ◽

Kenichi Yoshino ◽

Kazuo Tsubota ◽

Ichiro Saito

Keyword(s):

Sjögren’S Syndrome ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Lacrimal Glands ◽

Sjögren‘S Syndrome

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Mesenchymal Stem Cells Extract (MSCsE)-Based Therapy Alleviates Xerostomia and Keratoconjunctivitis Sicca in Sjogren’s Syndrome-Like Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20194750 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4750 ◽

Cited By ~ 4

Author(s):

Ghada Abughanam ◽

Osama A. Elkashty ◽

Younan Liu ◽

Mohammed O. Bakkar ◽

Simon D. Tran

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Sjögren’S Syndrome ◽

Sjögren's Syndrome ◽

Nod Mice ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Peripheral Tolerance ◽

Lacrimal Glands ◽

Sjögren‘S Syndrome

Sjogren’s syndrome (SS) is an autoimmune disease that manifests primarily in salivary and lacrimal glands leading to dry mouth and eyes. Unfortunately, there is no cure for SS due to its complex etiopathogenesis. Mesenchymal stem cells (MSCs) were successfully tested for SS, but some risks and limitations remained for their clinical use. This study combined cell- and biologic-based therapies by utilizing the MSCs extract (MSCsE) to treat SS-like disease in NOD mice. We found that MSCsE and MSCs therapies were successful and comparable in preserving salivary and lacrimal glands function in NOD mice when compared to control group. Cells positive for AQP5, AQP4, α-SMA, CK5, and c-Kit were preserved. Gene expression of AQP5, EGF, FGF2, BMP7, LYZ1 and IL-10 were upregulated, and downregulated for TNF-α, TGF-β1, MMP2, CASP3, and IL-1β. The proliferation rate of the glands and serum levels of EGF were also higher. Cornea integrity and epithelial thickness were maintained due to tear flow rate preservation. Peripheral tolerance was re-established, as indicated by lower lymphocytic infiltration and anti-SS-A antibodies, less BAFF secretion, higher serum IL-10 levels and FoxP3+ Treg cells, and selective inhibition of B220+ B cells. These promising results opened new venues for a safer and more convenient combined biologic- and cell-based therapy.

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