High-throughput RNA sequencing reveals distinct gene signatures in active IgG4-related disease

Brandon W Higgs,Yan Du,Lingli Dong,Yinong Sebastian,Pan Wei,Zhan-Guo Li,Hong Hua,Guangyan Yu,Jianping Guo,Yihong Yao,Mengru Liu,Yi Wang,Chris Morehouse,Limin Ren,Wei Zhu,Zhengang Wang,Yanying Liu

doi:10.1038/s41598-017-17602-9

Abstract

We aimed to characterize the molecular differences and effects from prednisone treatment among IgG4-related disease with salivary gland lesions (RD-SG), without SG lesions (RD-nonSG), and IgG4-related retroperitoneal fibrosis (RF). RNA sequencing was conducted on blood from 25 RD-SG, 11 RD-nonSG, 3 RF and 10 control subjects. Among these, 8 RD-nonSG and 12 RD-SG patients were subjected to treatment with prednisone and/or glucocorticoid-sparing agents. Six RD patients had a longitudinal time point. The mRNA levels of IgG4 and IgE, genes specific for Th2 cells, eosinophils, and neutrophils were over-expressed in RD-SG and RD-nonSG. A B-cell signature was suppressed in patients group versus controls, while Th1, Th2, Treg, and eosinophil gene signatures were increased in patients without treatment. Interestingly, Tfh genes and B cell signature were decreased at flare disease state. Prednisone treatment led to increased neutrophil, but decreased Treg signatures. Serum IgG4 levels correlated with the eosinophil and neutrophil gene signatures in RD-SG patients, and with a B cell signature in only RD-nonSG patients. IgG4, IgE, and cell-specific signatures are regulated in patients, suggesting the imbalance of immune and inflammatory cells in IgG4-related disease. Prednisone treatment selectively modulates Treg, eosinophil, and neutrophil signatures.

Highlights

We aimed to characterize the molecular differences and effects from prednisone treatment among IgG4-related disease with salivary gland lesions (RD-SG), without SG lesions (RD-nonSG), and IgG4related retroperitoneal fibrosis (RF)
We demonstrate that prednisone suppresses the levels of these genes in the blood in RD-SG, but not RD-nonSG patients
Among the 25 RD-SG patients, 17 of them in this study only have sialadenitis and dacryoadenitis involvement, which may explain the homogeneity of dramatic reduction in both IgG4 and IgE levels in the blood from prednisone treatment

Summary

Introduction

We aimed to characterize the molecular differences and effects from prednisone treatment among IgG4-related disease with salivary gland lesions (RD-SG), without SG lesions (RD-nonSG), and IgG4related retroperitoneal fibrosis (RF). IgG4-related disease (IgG4-RD) is a systemic disorder involving a spectrum of multiple indications, distinguished by often elevated levels of serum IgG4, infiltration of IgG4+ plasma cells into target tissues, and diffuse swelling, mass formation, or fibrosis of affected organs[1]. Active involvement of Th2- (IL-4, IL-5, and IL-21), T follicular helper cell (Tfh)- (BCL-6 and CXCR5) and T-reg- (IL-10, FOXP3, CCL18, and TGF-β1) related transcripts in patients with IgG4-RD was observed. These data showed how elevated levels of such cytokines and chemokines can induce IgG4 plasma cell infiltration, high IgG4 levels in the periphery, and impact tissue fibrosis in the LSG of IgG4-RD patients[19]. No studies to date have assessed the differences in molecular pathways or cell populations among IgG4-related disease with salivary gland lesions (RD-SG), without SG lesions (RD-nonSG), and IgG4-related retroperitoneal fibrosis (RF), in the peripheral blood, as well as the effects of corticosteroids on these signaling pathways

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