Systems Analysis of Primary SjÖgren'S Syndrome and Malt Lymphoma

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized by xerostomia and xerophthalmia, and patients with pSS exhibit a 40-fold increased risk for lymphoma development. The molecular mechanisms underlying pSS and its progression to mucosal-associated lymphoid tissues (MALT) lymphoma are still largely unknown. Objectives: To conduct systems analysis of pSS and MALT lymphoma in parotid glands (PG) and understand associated genes and pathways. Methods: PG biopsies from control subjects and patients with pSS and MALT lymphoma (n=7 each) were used for comparative analysis. The total RNAs were analyzed with HG133A+2 microarrays and data analysis was performed using SAM. Meanwhile the total proteins from the same PG tissues were isolated for 2-D gel electrophoresis/mass spectrometry. The gel images were analyzed using PDQuest and proteins were identified using LC-MS/MS (LTQ) and SEQUEST database searching. Results: Microarray analysis revealed up-regulation of 2,638 transcripts and down-regulation of 456 transcripts in pSS as compared to control, as well as up-regulation of 2,391 transcripts and down-regulation of 2,078 transcripts in lymphoma as compared to pSS (p<0.05; fold change>2). Proteomic analysis identified 19 proteins up-regulated in pSS compared to control and lymphoma, 17 proteins up-regulated in both pSS and lymphoma as compared to control, and 63 proteins up-regulated in lymphoma compared to both control and pSS. GO analysis suggested that those genes are significantly involved in 16 biological processes, and pathway analysis with KEGG and Biocarta revealed 18 pathways most significantly associated with the diseases. Conclusion: This is the first study on systems analysis of pSS and MALT lymphoma in salivary glands. Integration of the data from concurrent transcriptome and proteome analysis has revealed activated pathways in preparation for model building and specific interventions to critically asses the role of key molecular determinants and biological pathways in SS pathogenesis.

Supported by RO1-DE17593 and UO1- DE016275.