Sjögren’s Syndrome Salivary Gland Immunopathology: Increased Laminin Expression Precedes Lymphocytic Infiltration

McArthur, Carole; Daniels, Patrick J.; Kragel, Peter J.; Howard, P; Julian, Linda

doi:10.1006/jaut.1996.0109

Cited by 21 publications

(18 citation statements)

References 18 publications

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“…Biopsies from SS patients showed significant increases in laminin protein and laminin mRNA expression preceding lymphocytic infiltration compared with normal controls. This study suggests that an alteration in basement membrane synthesis is an early event associated with salivary gland pathology in SS prior to the attack by lymphocytes (McArthur et al ., 1997). Interestingly, IFN-␥was shown to up-regulate laminin and MMP-9 expression in the HSG cell line when the cells were treated with IFN-␥in vitro ( Daniels et al ., 1999;Wu et al ., 1997, respectively).…”

Section: (A) Geneticcontrol Of Autoimmunity Innod Mice Andhumanpatientsmentioning

confidence: 66%

Progress in Understanding Autoimmune Exocrinopathy Using the Non-obese Diabetic Mouse: An Update

Cha

Peck

Humphreys‐Beher

2002

Critical Reviews in Oral Biology & Medicine

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Sjögren's Syndrome (SS) is a chronic autoimmune disease characterized by histological and functional alterations of salivary and lacrimal glands that result in a severe dryness of the mouth and the eyes. The etiology of SS has remained undefined despite investigators' significant efforts to identify the mechanisms of initiation. Based on histopathology, several animal models are available-such as MRL/lpr, NZW/NZB, NFS/sld, graft vs. host, transgenic mouse expressing viral surface antigen, and the nonobese diabetic (NOD) mouse-for investigation of the etiology of SS. Biochemical and immunological similarities between human SS and autoimmune exocrinopathy (AEC) in the NOD mouse, including the loss of secretory function, establish the NOD mouse as an appropriate model to unravel the underlying pathophysiology of SS. Recently, several NOD congenic partner strains have been developed to investigate the roles of genetic intervals, cytokines, and autoantibodies in the disease pathogenesis. Studies on NOD-scid suggest that the pathogenesis of SS occurs in two phases: an asymptomatic phase, in which epithelial cells of exocrine tissues undergo dedifferentiation accompanied by elevated apoptosis; and a second phase in which autoaggression is mounted against target organ autoantigens, resulting in the activation of T-and B-cells, and the generation of autoantibodies. The presence of autoantibodies on the cell-surface signaling receptor, the muscarinic 3 receptor, in both SS patients and the NOD mice correlates with the hallmark clinical symptom of secretory dysfunction. Additionally, the NOD mouse model provides an important example of how both Th1 and Th2 cytokines, as well as non-immune genetic loci, are involved in the maintenance of and progression to the overt disease state. Ultimately, analysis of these data provides insight into potentially novel therapeutic interventions.

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Section: (A) Geneticcontrol Of Autoimmunity Innod Mice Andhumanpatientsmentioning

confidence: 66%

Progress in Understanding Autoimmune Exocrinopathy Using the Non-obese Diabetic Mouse: An Update

Cha

Peck

Humphreys‐Beher

2002

Critical Reviews in Oral Biology & Medicine

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“…However, such findings of the biosynthesis of ECM molecules by inflammatory cells have been infrequently recorded, although tenascin production by macrophages [37] and in vitro fibronectin synthesis by activated T lymphocytes have been recorded [36]. The results of immunohistochemistry and in situ hybridization experiments for elevated expression of laminin genes by Macarthur [23,24] may be partially due to this phenomenon but not only by epithelial cells. Our in situ hybridization experiments showed that the mRNA signals were also present in lymphoid cells in the stroma and not only in inflammatory cells within LELs.…”

Section: Discussionmentioning

confidence: 86%

“…Ultrastructurally, Takeda et al [35] could not determine the cells responsible for the hyaline deposits because there were no secretory properties in the constituent cells, but instead they suggested some immune deposits. Since epithelial cells comprise the largest cell population in the LELs, their contribution to the production of the hyaline material in the process of deposition cannot be easily denied, because enhanced expression of laminin in minor salivary gland duct epithelial cells in Sjogren's syndrome has been demonstrated by Macarthur and his colleagues [23,24]. Since we have also demonstrated the presence of mRNA signals for HSPG in myoepithelial cells of normal salivary ducts [20] and the in vitro biosynthesis of four BM molecules and fibronectin by salivary epithelial tumor cells [7], we had expected that epithelial cells would have taken part in the production more significantly.…”

Section: Discussionmentioning

confidence: 97%

Vascular endothelial cell participation in formation of lymphoepithelial lesions (epi-myoepithelial islands) in lymphoepithelial sialadenitis (benign lymphoepithelial lesion)

et al. 2003

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Lymphoepithelial lesions (LELs, or epi-myoepithelial islands) in lymphoepithelial sialadenitis (LESA, or benign lymphoepithelial lesion) of the salivary gland are known to be mainly composed of duct epithelial cells. However, other constituent cells are poorly characterized. Formalin-fixed paraffin sections obtained from six surgical specimens of LESA were examined using immunohistochemistry for cytoskeletal proteins, inflammatory cells, vascular endothelial cells, and extracellular matrix (ECM) molecules as well as by in situ hybridization for ECM molecules. In addition to keratin-immunopositive (+) duct-like epithelial cells, there were CD31/CD34+ vascular endothelial cells-which were either scattered in a singular fashion, in formed sheets, or in tubular structures-, CD20+ B lymphocytes, CD45RO+ T lymphocytes, and CD68 macrophages in the LELs. ECM molecules, such as heparan sulfate proteoglycan and tenascin, were immunolocalized in hyaline materials in the LELs. Their mRNAs were demonstrated mainly in endothelial cells and, to a lesser extent, in lympho-monocytic cells around hyaline materials, but were not as evident in epithelial constituent cells of LELs. The results indicate that endothelial cells as well as inflammatory cells are important constituents of the LELs, and the hyaline ECM cores mainly result from the intra-LEL angiogenesis by endothelial cells with the assistance of inflammatory cells. This intra-LEL vasculature seems to support regeneration and proliferation of salivary epithelial remnant cells.

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“…Biopsies from patients show signifi- cant increases in laminin protein and steady state concentrations of mRNA preceding lymphocytic infiltration compared to normal control tissue [43]. This suggests that altered basement membrane expression is an early event associated with salivary gland pathology in Sjögren's syndrome prior to the arrival of lymphocytes.…”

Section: Altered Ecm Observed In Autoimmune Exocrine Tissue Pathologymentioning

confidence: 80%

Abnormal Organogenesis in Salivary Gland Development May Initiate Adult Onset of Autoimmune Exocrinopathy

Cha¹,

Blockland

Versnel

et al. 2001

Exp Clin Immunogenet

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Objectives: Salivary gland organogenesis was evaluated in NOD mice, an animal model for autoimmune exocrinopathy, to determine when disease onset is first present in the target tissues. Methods: Submandibular glands were removed for histological, immunohistochemical and biochemical evaluation from neonatal NOD and congenic strains as well as healthy control C57BL/6 mice. Results: Histomorphological analyses of neonatal submandibular glands, the primary target for autoimmune exocrinopathy at 1 day postpartum, revealed delayed morphological differentiation during organogenesis in autoimmune-susceptible NOD mice when compared to nonsusceptible C57BL/6 mice. Acinar cell proliferation was reduced, while expression of Fas, FasL and bcl-2 were increased. Acinar cell proliferation was reduced, while expression, of Fas, FasL and bcl-2 were increased. Throughout the preweaning period (21 days) submandibular glands from NOD and NOD congenic strains aberrantly expressed an increased matrix metalloproteinase (MMP)-2 and MMP-9 activity. Substitution of two susceptibility alleles (Idd3 and Idd5) in NOD mice resulted in an hierarchical and additive reversal of delayed organogenesis, elevated MMP-9 activity, and aberrant expression of parotid secretory protein. Discussion: NOD-derived mice whose submandibular glands showed normal organogenesis did not progress to develop autoimmune exocrinopathy. Altered organogenesis of target tissue may therefore provide a cellular microenvironment capable of activating autoimmunity.

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Sjögren’s Syndrome Salivary Gland Immunopathology: Increased Laminin Expression Precedes Lymphocytic Infiltration

Cited by 21 publications

References 18 publications

Progress in Understanding Autoimmune Exocrinopathy Using the Non-obese Diabetic Mouse: An Update

Progress in Understanding Autoimmune Exocrinopathy Using the Non-obese Diabetic Mouse: An Update

Vascular endothelial cell participation in formation of lymphoepithelial lesions (epi-myoepithelial islands) in lymphoepithelial sialadenitis (benign lymphoepithelial lesion)

Abnormal Organogenesis in Salivary Gland Development May Initiate Adult Onset of Autoimmune Exocrinopathy

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