IL-6 Promotes IgG4-related Disease by Inducing Fibroblast-dependent Tfh Cell and B Cell Differentiation Factors

Zongfei Ji¹, Rongyi Chen ², Xiaomeng Cui ², Lili Ma ², Xiufang Kong ³, Lingying Ma ², Ying Sun ², Xiaomin Dai ², Zhuojun Zhang ², Huiyong Chen ² and Lindi Jiang ², ¹Department of Rheumatology, Zhongshan hospital, Fudan University, Shanghai, China (People's Republic), ²Zhongshan hospital, Fudan University, Shanghai, China (People's Republic), ³University of Michigan & Fudan University, Ann Arbor, MI

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: IgG4 Related Disease and fibroblasts, IL-6

Session Information

Date: Monday, November 11, 2019

Title: Vasculitis – Non-ANCA-Associated & Related Disorders Poster III: Behçet’s Disease & Other Vasculitides

Session Type: Poster Session (Monday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Considering the unsatisfied effect of conventional therapy, to investigate the pathogenesis of IgG4-related disease (IgG4-RD) is crucial to explore novel treatment strategies. This study aims to clarify the pathogenesis of interleukin 6 (IL-6) in IgG4-RD through the induction of fibroblast-dependent Tfh cell and B cell differentiation factors and find the new therapeutic target.

Methods: The IL-6 expression in the serum and tissues of patients with IgG4-RD and healthy controls were detected by ELISA, immunohistochemistry, and immunofluorescence, respectively. Human aorta adventitial fibroblasts (AAFs) were cultured and stimulated with IL-6/IL-6 receptor (IL-6R). The effect of IL-6/IL-6R on AAFs was determined by CCK-8 and Luminex assays.

Results: The level of serum IL-6 was elevated in active IgG4-RD patients and was positively correlated with IgG4-RD reactive index (RI). The expression of IL-6 in the tissue of IgG4-RD patients was also significantly higher than that in the normal tissue. IL-6-producing fibroblasts were found to co-localize with IgG4⁺ plasma cells in the tissue of IgG4-related retroperitoneal fibrosis (IgG4-RF). Co-localization of α-SMA and B cell differentiation cytokines (i.e., B cell activating factor (BAFF)), α-SMA and T follicular helper (Tfh) cell differentiation cytokines (e.g., IL-7, IL-12, and IL-23) were present in the local lesions. IL-6/IL-6R significantly promoted the production of BAFF, IL-7, IL-12, and IL-23 in AAFs in a dose-dependent manner. This effect was blocked by JAK1, JAK2, STAT3, and Akt inhibitors, respectively.

Conclusion: IL-6 promotes IgG4-RD by inducing fibroblast-dependent Tfh and B cell differentiation factors via the JAK2/STAT3, JAK1/STAT3, and JAK2/Akt pathways. Thus, IL-6 and JAK1/2 inhibitors may be therapeutic targets for IgG4-RD.

IL-6 promotes IgG4-related disease by promoting the production of B cell differentiation cytokine -BAFF-, and Tfh cell differentiation cytokines -IL-7, IL-12, and IL-23- in fibroblast.

The level of serum IL-6 was elevated in active IgG4-RD patients. The expression of IL-6 in the tissue of IgG4-RD patients was also significantly higher than that in the normal tissue. *p < 0.05; **p < 0.01

The secretion of cytokines -IL-7, BAFF, IL-12 p70, and IL-23- in the supernatant following stimulation with IL-6/IL-6R -50 ng/mL- with or without different inhibitors. **p < 0.01 versus control group; #p < 0.05 versus IL-6/IL-6R group.

Disclosure: Z. Ji, None; R. Chen, None; X. Cui, None; L. Ma, None; X. Kong, None; L. Ma, None; Y. Sun, None; X. Dai, None; Z. Zhang, None; H. Chen, None; L. Jiang, None.

To cite this abstract in AMA style:

Ji Z, Chen R, Cui X, Ma L, Kong X, Ma L, Sun Y, Dai X, Zhang Z, Chen H, Jiang L. IL-6 Promotes IgG4-related Disease by Inducing Fibroblast-dependent Tfh Cell and B Cell Differentiation Factors [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/il-6-promotes-igg4-related-disease-by-inducing-fibroblast-dependent-tfh-cell-and-b-cell-differentiation-factors/. Accessed .

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