Abstract
The nonobese diabetic (NOD) Nss1 and Idd5 loci have been associated with sialadenitis development in mice. In this study the NOD Nss1 and Idd5 loci were backcrossed onto the healthy control strain B10.Q by using the speed congenic breeding strategy, resulting in three congenic strains: B10.Q.Nss1, B10.Q.Nss1/Idd5 heterozygous and B10.Q.Nss1/Idd5 homozygous. We investigated the effects of the Nss1 and Idd5 loci on sialadenitis and gene expression in NOD congenic mice. One submandibular salivary gland from each mouse was used for histological analysis of sialadenitis, whereas the contralateral salivary gland was used for gene expression profiling with the Applied Biosystems Mouse Genome Survey chip v.1.0. The results were validated using quantitative reverse transcriptase PCR. The NOD Nss1 and Idd5 loci had clear influence on the onset and progression of sialadenitis in congenic mice. Double congenic mice exhibited the most severe phenotype. We successfully identified several genes that are located in the NOD congenic regions to be differentially expressed between the congenic strains and the control strain. Several of these were found to be co-regulated, such as Stat1, complement component C1q genes and Tlr12. Also, a vast contingency of interferon-regulated genes (such as Ltb, Irf7 and Irf8) and cytokine and chemokine genes (such as Ccr7 and Ccl19) were differentially expressed between the congenic strains and the control strain. Over-representation of inflammatory signalling pathways was observed among the differentially expressed genes. We have found that the introgression of the NOD loci Nss1 and Idd5 on a healthy background caused sialadenitis in NOD congenic mouse strains, and we propose that genes within these loci are important factors in the pathogenesis. Furthermore, gene expression profiling has revealed several differentially expressed genes within and outside the NOD loci that are similar to genes found to be differentially expressed in patients with Sjögren's syndrome, and as such are interesting candidates for investigation to enhance our understanding of disease mechanisms and to develop future therapies.
Highlights
Primary Sjögren's syndrome is an autoimmune disease (AID) hallmarked by ocular and oral dryness, known as keratoconjunctivitis sicca and xerostomia, respectively
We have found that the introgression of the nonobese diabetic (NOD) loci Nss1 and Idd5 on a healthy background caused sialadenitis in NOD congenic mouse strains, and we propose that genes within these loci are important factors in the pathogenesis
The significance analysis of microarrays (SAM) algorithm was run on the comparisons and gene lists were created based on a false discovery rate (FDR) of less than 10% for the standard analysis gene list and FDR less than 20% for the alternative analysis gene list
Summary
Primary Sjögren's syndrome (pSS) is an autoimmune disease (AID) hallmarked by ocular and oral dryness, known as keratoconjunctivitis sicca and xerostomia, respectively. Sjögren's syndrome can occur alone or secondary to other autoimmune connective tissue diseases, such as rheumatoid arthritis and systemic lupus erythematosus [1]. The genetic contribution to AID = autoimmune disease; CCL = CC chemokine ligand; CCR = CC chemokine receptor; FDR = false discovery rate; MHC = major histocompatibility complex; NOD = nonobese diabetic; PCR = polymerase chain reaction; pSS = primary Sjögren's syndrome; QPCR = quantitative reverse transcriptase PCR; SAM = significance analysis of microarrays; SG = salivary gland; SOCS = suppressor of cytokine signalling; SRI = Sialadenitis Ratio Index; SS = Sjögren's syndrome. There is substantial body of evidence supporting an association of SS with the major histocompatibility complex (MHC) class II region [5,6], but the association with formation of anti-Ro/La antibodies is stronger than that with the disease itself for the alleles DRB1*03 and DQB1*02 [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
