Abstract
IntroductionRecently, we reported the development of the C57BL/6.NOD-Aec1Aec2 mouse that carries two genetic intervals derived from the non-obese diabetic (NOD) mouse capable of conferring Sjögren's syndrome (SjS)-like disease in SjS-non-susceptible C57BL/6 mice. In an attempt to define the molecular bases underlying the onset of stomatitis sicca (xerostomia) in this C57BL/6.NOD-Aec1Aec2 mouse model, we have carried out a study using genomic microarray technology.MethodsBy means of oligonucleotide microarrays, gene expression profiles of salivary glands at 4, 8, 12, 16, and 20 weeks of age were generated for C57BL/6.NOD-Aec1Aec2 male mice. Using Linear Models for Microarray Analysis and B-statistics software, 480 genes were identified as being differentially expressed (P < 0.01 and Q < 0.0001) during the development of SjS-like disease in the salivary glands.ResultsThe 480 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 biological functions. By means of pair-wise analysis, temporal changes in transcript expressions provided profiles indicating that many additional genes are differentially expressed at specific time points during the development of disease. Multiple genes reportedly showing an association with autoimmunity and/or SjS, in either humans or mouse models, were found to exhibit differential expressions, both quantitatively and temporally. Selecting various families of genes associated with specific functions (for example, antibody production, complement, and chemokines), we noted that only a limited number of family members showed differential expressions and these correlated with specific phases of disease.ConclusionsTaking advantage of known functions of these genes, investigators can construct interactive gene pathways, leading to modeling of possible underlying events inducing salivary gland dysfunction. Thus, these different approaches to analyzing microarray data permit the 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.
Highlights
We reported the development of the C57BL/6.NOD-Aec1Aec2 mouse that carries two genetic intervals derived from the non-obese diabetic (NOD) mouse capable of conferring Sjögren's syndrome (SjS)-like disease in SjS-non-susceptible C57BL/6 mice
Selecting various families of genes associated with specific functions, we noted that only a limited number of family members showed differential expressions and these correlated with specific phases of disease
Taking advantage of known functions of these genes, investigators can construct interactive gene pathways, leading to modeling of possible underlying events inducing salivary gland dysfunction. These different approaches to analyzing microarray data permit the 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
Summary
We reported the development of the C57BL/6.NOD-Aec1Aec mouse that carries two genetic intervals derived from the non-obese diabetic (NOD) mouse capable of conferring Sjögren's syndrome (SjS)-like disease in SjS-non-susceptible C57BL/6 mice. While there are multiple underlying causes for decreased secretions of saliva, one of the more severe causes of xerostomia sicca, or dry mouth disease, results from an autoimmune disease, referred to as Sjögren's syndrome (SjS), in which the immune system targets initially the salivary and/or lacrimal glands [1,2,3]. In phase 1, aberrant genetic, physiological, and biochemical activities, resulting presumably from retarded salivary gland development and increased acinar cell apoptosis, occur between 6 and 10 weeks of age. In phase 3, an overt clinical disease occurs and is defined by measurable loss of salivary and lacrimal gland secretory function, usually detected after 18 to 20 weeks of age [4,5]. Salivary and lacrimal gland dysfunction in SjS is currently thought to result from a combination of (a) pro-inflammatory cytokine production capable of inducing cellular apoptosis and autoantibodies reactive with the muscarinic acetylcholine and adrenergic receptors and (b) the action of infiltrating T cells (possibly CD4+ TH17 cells) [6], leading to a progressive loss of acinar cell mass
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