Emamian, Eshrat Sadat2010-07-152010-07-152010-05https://hdl.handle.net/11299/92013University of Minnesota Ph.D. dissertation. May 2010. Major: Oral Biology. Advisor: Kathy L. Moser, PHD. 1 computer file (PDF); vi, 105 pages. Ill. (some col.)Sjögren’s syndrome (SS) is a common autoimmune disorder characterized by lymphocytic infiltration into exocrine glands. Disruption of target organ function, such as salivary and lacrimal glands may lead to irreversible manifestations such as severe dry eyes and mouth. A complex genetic architecture combined with the influence of environmental factors is thought to contribute to the etiology of SS; however, the pathophysiological basis of SS is poorly understood. To identify important molecular pathways involved in SS and define biomarkers for clinical features of the disease, we have used high-density oligonucleotide microarrays to compare global gene expression profiles in peripheral blood samples of SS patients and controls. We first analyzed mononuclear cells of 21 SS patients and 23 controls and identified a prominent pattern of over-expressed genes that are inducible by interferons (IFNs). We then repeated the analysis in whole blood of a second independent dataset of 17 SS patients and 22 controls and observed the same pattern with respect to IFN inducible genes. Furthermore, we observed that gene expression of IFN-inducible genes was positively correlated with titers of anti-Ro/SSA (P<0.001) and anti-La/SSB (P<0.001) autoantibodies and negatively correlated to salivary flow or tear production. Additional inflammatory and immune-related pathways with altered expression patterns in SS cases included B and T cell receptor, IGF-1, GM-CSF, PPARα/RXRα, and PI3/AKT signaling. Our results strongly support innate and adaptive immune processes in the pathogenesis of SS and provide numerous candidate disease markers for further study. We also compared gene expression profiles between patients with SS and systemic lupus erythematosus (SLE). Systemic manifestations in SS patients are common and may include clinical and serological overlap with other autoimmune disease features such as SLE. The pathophysiology of common and distinct features of SS and SLE are poorly understood. In this section of the study, we have directly compared gene expression profiles in whole blood of SS patients and SLE patients to determine which genes are differentially expressed in both phenotypes, and which genes distinguish the two patient groups. Approximately 22,000 RNA transcripts were interrogated using the Affymetrix U133A GeneChip®. Differentially expressed genes were defined using t-tests with nominal significance of p<0.001 and average fold change of >1.5. Our gene expression datasets included 35 Caucasian female SLE patients, 36 Caucasian female SS patients, and 62 Caucasian female controls. We compared each group of SS (n=36) and SLE (n=35) patients separately to the 62 controls. A total of 349 genes were differentially expressed in SS patients and 625 genes were differentially expressed in SLE patients. Of these two gene lists, 95 genes overlapped and were differentially expressed in both SS and SLE patients, the majority of which are IFN-inducible. Among the non-overlapping genes, ribosomal proteins were highly overexpressed in SLE patients but underexpressed in SS patients relative to controls. These results show that SS and SLE patients have identifiable gene expression signatures that are either common or distinct between the two patient populations. Characterization of these profiles has significant potential to facilitate development of improved diagnostic approaches and targeted therapies.en-USInterferonMicroarray technologySjogren's SyndromeOral BiologyThesis or Dissertation