THU0459 RNA Sequencing Reveals Over-Expression of IGG4 and IGE MRNAS and Activated TH2-Related, Treg-Related, and Other Cytokine Pathways in the Blood of IGG4-Related and Mikulicz's Disease Patients
Authors: B.W. Higgs, Y. Liu, J. Guo, C. Morehouse, Y. Sebastian, W. Zhu, L. Richman, Y. Yao, Z. Li
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> IgG4-related disease (IgG4RD) is a spectrum of systemic indications characterized by fibrosclerosis in various organs, tissue infiltrating IgG4+ plasma cells, and sometimes elevation of IgG4 in the serum. Mikulicz9s disease (MD) is one of multiple IgG4RDs with single organ involvement including lachrymal, parotid, and submandibular glands. The pathogenesis of these diseases has been linked to infection and autoimmunity with a predominance of Th2- and Treg-cell cytokines driving increased levels of eosinophils, IgG4, and IgE, ultimately leading to cell infiltration and organ damage. To date, less is known about the molecular differences between IgG4RD and MD, as well as transcriptome-wide mediators of disease. <h3>Objectives</h3> We evaluated most altered molecular pathways in the blood of IgG4RD and MD patients. <h3>Methods</h3> Blood was procured from 13 MD (ages 32-65; 7 Male), 9 IgG4RD (ages 48-80; 9 Male), and 10 healthy control (ages 30-57; 7 Male) Chinese subjects and RNA was sequenced with Illumina HiSeq. Seven MD and 5 IgG4RD patients were treated with ≤20mg prednisone with one other glucocorticoid-sparing agent. In IgG4RD, 342 and 683 genes were over- and under-expressed, respectively and 35 and 33 genes were over- and under-expressed in MD (q&lt;0.01; fold&gt;2). Gene signatures were identified from ex vivo stimulation experiments with whole blood. All comparisons were relative to controls unless stated. <h3>Results</h3> IgG4 was the most over-expressed mRNA in both MD and IgG4RD (fold&gt;32; q<sub>IgG4RD</sub>=0.001, q<sub>MD</sub>=0.002), with IgE mRNA among the top 10 most over-expressed (fold&gt;8; q<sub>IgG4RD</sub>=0.0003, q<sub>MD</sub>=0.01) and both correlated with each other (r=0.85) and IL-5R mRNA (r<sub>IgG4</sub>=0.80; r<sub>IgE</sub>=0.64), which was suppressed in patients treated with prednisone compared to those not (p<sub>IgG4RD</sub>=0.008; p<sub>MD</sub>=0.0001). The same mRNA suppression of IgG4 and IgE was seen in MD patients on prednisone compared to those not (p<sub>IgG4</sub>=0.002 and p<sub>IgG4RD</sub>=0.004; p<sub>IgG4RD</sub>=0.03; p<sub>MD</sub>=0.03). <h3>Conclusions</h3> Our study shows the increase of IgG4 and IgE mRNAs, the activation of Th2, Treg, and other inflammatory cytokine pathways in both diseases compared to controls. A reduced B cell signature in the blood of IgG4RD and MD patients suggests infiltration to disease sites. Prednisone treatment suppresses IgG4 and IgE mRNAs in MD, IL-5R mRNA in both diseases, and activates IL-10 pathways in both diseases compared to treatment naïve patients. Further studies need to be conducted to confirm these observations and correlate them with clinical activity. <h3>Disclosure of Interest</h3> : B. Higgs Shareholder of: Astra Zeneca, Employee of: MedImmune, Y. Liu: None declared, J. Guo: None declared, C. Morehouse Shareholder of: Astra Zeneca, Employee of: MedImmune, Y. Sebastian Shareholder of: Astra Zeneca, Employee of: MedImmune, W. Zhu Shareholder of: Astra Zeneca, Employee of: MedImmune, L. Richman Shareholder of: Astra Zeneca, Employee of: MedImmune, Y. Yao Shareholder of: Astra Zeneca, Employee of: MedImmune, Z. Li: None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2255