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

Abstract

Lacrimal glands (LGs) of male non-obese diabetic (NOD) mice display many features of human LGs in patients afflicted with the autoimmune disease Sjögren's syndrome (SS), including the loss of secretory functions and a lymphocytic infiltration into the glands by 4 months of age. So far, research has mainly focused on the intracellular events that are involved in initiating LG dysfunction; however, the impact of SS on extracellular matrix (ECM) structures of the diseased LGs has not yet been determined. In this study we identified and compared LG ECM formation and integrity of age-matched male healthy (BALB/c) and diseased (NOD) mice. LG tissues were examined using routine histological, biochemical, immunohistochemical and gene expression analysis. Multiphoton imaging and second-harmonic generation (SHG) microscopy permitted the non-invasive analysis of major LG ECM structures including collagen- and elastin-containing fibers. Biochemical testing demonstrated a significant loss of collagen, glycosaminoglycans and desmosine in NOD LGs when compared to healthy BALB/c LGs. Immunohistochemical staining and gene expression analysis confirmed this disease-related alteration of LG ECM structures. Furthermore, laser-induced autofluorescence and SHG microscopy revealed dramatic changes in the structural organization of most collagenous and elastic fibers of the diseased LG tissues that were more pronounced than those displayed by histological analysis. Our results clearly show an enhanced degradation of ECM proteins accompanied by the severe disorganization and deformation of ECM structures of diseased LG tissues. These new insights into the involvement of ECM degradation in SS may lead to novel therapies for patients suffering from dry eye disease.

Sjögren’s Syndrome-Like Ocular Surface Disease in Thrombospondin-1 Deficient Mice

“…Moreover recently enhanced degradation of extracellular matrix proteins, reported in the lacrimal glands of nonobese diabetic mice, was implicated in the pathogenesis of dry eye disease in Sjö gren's syndrome. 45 Our results, together with these reports, suggest that an extracellular matrix protein such as TSP-1 is likely to be important in maintaining the functional integrity of lacrimal glands and its absence results in increased cell death in the tissue that incites inflammatory infiltrates and autoimmune response causing further damage with an eventual functional loss, which in turn leads to ocular surface disease of dry eye. Thus our study strongly implicates TSP-1 deficiency in the pathogenesis of an autoimmune disease like Sjö gren's syndrome.…”

Two‐photon microscopy of deep intravital tissues and its merits in clinical research

“…7). In combination with the immunohistochemical and histological approaches, diseased lacrimal glands extracellular matrix (ECM) structures including collagen-and elastin-containing fibres in Sjögren's syndrome were examined using the in-tandem detection of 2-photon excitation imaging (Schenke-Layland et al, 2008). It was concluded that the nonlinear optical results were more pronounced than those delineated by histological analysis.…”

Texture analysis applied to second harmonic generation image data for ovarian cancer classification

“…7,[10][11][12] It would then be advantageous to further develop collagen specific microscopic imaging modalities such as second harmonic generation (SHG) imaging microscopy 13 for this purpose. SHG microscopy has already emerged as a highly sensitive/ specific probe of collagen architecture changes in several diseases, including many cancers, 10,11,[14][15][16][17][18] connective tissue disorders, 19,20 and fibroses. 21,22 All these diseases are characterized by changes in alterations of collagen density, fibrillar organization, collagen isoform distribution, and combinations thereof.…”