Search

For decades, Sjögren's syndrome (SS) and Sjögren's syndrome-like (SS-like) disease in patients and mouse models, respectively, have been intensely investigated in attempts to identify the underlying etiologies, the pathophysiological changes defining disease phenotypes, the nature of the autoimmune responses, and the propensity for developing B cell lymphomas. An emerging question is whether the generation of a multitude of mouse models and the data obtained from their studies is actually important to the understanding of the human disease and potential interventional therapies. In this brief report, we comment on how and why mouse models can stimulate interest in specific lines of research that apparently parallel aspects of human SS. Focusing on two mouse models, NOD and B6· Il14α , we present the possible relevance of mouse models to human SS, highlighting a few selected disease-associated biological processes that have baffled both SS and SS-like investigations for decades. [ABSTRACT FROM AUTHOR]

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease that is estimated to affect 35 million people worldwide. Currently, no effective treatments exist for Sjögren's syndrome, and there is a limited understanding of the physiological mechanisms associated with xerostomia and hyposalivation. The present work revealed that aquaporin 5 expression, a water channel critical for salivary gland fluid secretion, is regulated by bone morphogenetic protein 6. Increased expression of this cytokine is strongly associated with the most common symptom of primary Sjögren's syndrome, the loss of salivary gland function. This finding led us to develop a therapy in the treatment of Sjögren's syndrome by increasing the water permeability of the gland to restore saliva flow. Our study demonstrates that the targeted increase of gland permeability not only resulted in the restoration of secretory gland function but also resolved the hallmark salivary gland inflammation and systemic inflammation associated with disease. Secretory function also increased in the lacrimal gland, suggesting this local therapy could treat the systemic symptoms associated with primary Sjögren's syndrome. [ABSTRACT FROM AUTHOR]

Microengraving is a novel technology that uses an array of microfabricated subnanoliter wells to isolate and characterize secreted proteins from larger number of single cells. This printing technique permits the capture and characterization of secreted antibodies on glass slides. Here, we profiled the antigenic repertoires of B cells reacting against salivary gland tissues in Sjögren’s syndrome (SjS), an autoimmune disease targeting the exocrine glands. Single-cell suspensions of spleen and cervical lymph node cells prepared from normal C57BL/6 and SjS-susceptible (SjSs) C57BL/6.NOD-AecAec2 mice were dispersed into subnanoliter wells (nanowells). Capture slides preincubated with mouse immunoglobulins were used for printing. Detection antibodies included fluorescence conjugated anti-IgG1, salivary gland lysates of C57BL/6 and SjSs mice. Results indicate an increase in the frequency of IgG1-secreting cells in the spleen of SjSs mice compared to C57BL/6 mice. Cells from the lymph node of SjSs mice yield higher instances of IgG1 reactive against salivary gland antigens than cells from the lymph nodes of C57BL/6 mice. These data demonstrate the isotype-specific reactivity of antibodies during the autoimmune process, and further reveals significant differences in the non-autoimmune and autoimmune antibody repertoires. These results support the generation of self-reactive B cell repertoires during the autoimmune process, at the same time, verifying that microengraving of single cells might allow for identification of novel biomarkers in SjS. [ABSTRACT FROM AUTHOR]

Abstract: Recently, we reported development of the C57BL/6.NOD-Aec1Aec2 mouse carrying two genetic intervals derived from the NOD mouse. These two genetic regions confer Sjögren''s syndrome (SjS)-like disease in SjS-non-susceptible C57BL/6 mice. In an attempt to define the molecular bases underlying onset of dacryoadenitis and subsequently keratoconjunctivitis sicca (or xerophthalmia) in the C57BL/6.NOD-Aec1Aec2 mouse model, we have carried out a study utilizing microarray technology. Using oligonucleotide microarrays, gene expression profiles of lacrimal glands at 4, 8, 12, 16 and 20weeks of age were generated for C57BL/6.NOD-Aec1Aec2 male mice. Analyses using Linear Models for Microarray Analysis package and B-statistics, 552 genes were identified as being differentially expressed (adjusted p-value <0.01 and B <1.5) during the development of SjS-like disease. These 552 genes could be arranged into four clusters, with each cluster defining a unique pattern of temporal expression, while the individual genes within each cluster could be grouped according to related function. Using a pair-wise analysis, temporal changes in gene expressions provided profiles indicating that individual genes were differentially expressed at specific time points during development of SjS. In addition, multiple genes that have been reported to show, either in humans or mouse models, an association with autoimmunity and/or SjS, e.g., ApoE, Baff, Clu, Ctla4, Fas/Fasl, Irf5, Lyzs, Nfkb, Socs3, Stat4, Tap2, Tgfβ1, Tnfa, and Vcam1 were also found to exhibit differential expressions, both quantitatively and temporally. Selecting a few families of genes, e.g., cystatins, cathepsins, metalloproteinases, lipocalins, complement, kallikreins, carbonic anhydrases and tumor necrosis factors, it was noted that only a limited number of family members showed differential expressions, suggesting a restricted glandular expression. Utilizing these genes, pathways of inter-reactive genes have been constructed for apoptosis and fatty acid homeostasis, leading to modeling of possible underlying events inducing disease. Thus, these different approaches to analyze microarray data permit identification of multiple sets of genes of interest whose expressions and expression profiles may correlate with molecular mechanisms, signaling pathways and/or immunological processes involved in the development and onset of SjS in this mouse model, thereby providing new insight into the underlying cause or regulation of this disease. [Copyright &y& Elsevier]

The article investigates the role of Th17/interleukin-23 (IL-23) system in Sjögren's syndrome (SS). C57BL/6.NOD-Aec1Aec2 mice were used in the experiment. Results showed that the Th17/IL-23 system is up-regulated in the mice model and SS patients. It cautions that a connection between up-regulated IL-17/IL-23 expression and specific SS clinical manifestations has not been identified yet.

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltrates in the salivary and lachrymal glands resulting in oral and ocular dryness. There are no clinically approved therapies to slow the progression of SS. Immune cells possess receptors for the neurotransmitter GABA (GABA-Rs) and their activation has immunoregulatory actions. We tested whether GABA administration has potential for amelioration of SS in NOD.B10-H2b and C57BL/6.NOD-Aec1Aec2 mice, two spontaneous SS models. Oral GABA treatment was initiated (1) after the development of sialadenitis but before the onset of overt symptoms, or (2) after the appearance of overt symptoms. When assessed weeks later, GABA-treated mice had greater saliva and tear production, as well as quicker times to salvia flow, in both SS mouse models. This was especially evident when GABA treatment was initiated after the onset of overt disease. This preservation of exocrine function was not accompanied by significant changes in the number or area of lymphocytic foci in the salivary or lachrymal glands of GABA-treated mice and we discuss the possible reasons for these observations. Given that GABA-treatment preserved saliva and tear production which are the most salient symptoms of SS and is safe for consumption, it may provide a new approach to help ameliorate SS. [ABSTRACT FROM AUTHOR]

The C57BL/6.NOD-Aec1Aec2 mouse is considered a highly appropriate model of Sjögren's Syndrome (SS), a human systemic autoimmune disease characterized primarily as the loss of lacrimal and salivary gland functions. This mouse model, as well as other mouse models of SS, have shown that B lymphocytes are essential for the development and onset of observed clinical manifestations. More recently, studies carried out in the C57BL/6.IL14α transgenic mouse have indicated that the marginal zone B (MZB) cell population is responsible for development of SS disease, reflecting recent observations that MZB cells are present in the salivary glands of SS patients and most likely initiate the subsequent loss of exocrine functions. Although MZB cells are difficult to study in vivo and in vitro, we have carried out an ex vivo investigation that uses temporal global RNA transcriptomic analyses to profile differentially expressed genes known to be associated with cell migration. Results indicate a temporal upregulation of specific chemokine, chemokine receptor, and Rho-GTPase genes in the salivary glands of C57BL/6.NOD-Aec1Aec2 mice that correlate with the early appearance of periductal lymphocyte infiltrations. Using the power of transcriptomic analyses to better define the genetic profile of lymphocytic emigration into the salivary glands of SS mice, new insights into the underlying mechanisms of SS disease development and onset begin to come into focus, thereby establishing a foundation for further in-depth and novel investigations of the covert and early overt phases of SS disease at the cellular level. [ABSTRACT FROM AUTHOR]