Disease-Specific Autoantibodies Induce Trained Immunity in RA Synovial Tissues and Its Gene Signature Correlates with the Response to Clinical Therapy.

Xiaoli Dai,Keqin Zeng,Qiao Zhong,Fang-Yuan Gong,Zheng Gong,Xiao-Ming Gao,Xiaoqiu Dai,Chen Yang,Agnieszka Dobrzyn

doi:10.1155/2020/2109325

Abstract

Much evidence suggests that trained immunity is inappropriately activated in the synovial tissue in rheumatoid arthritis (RA), but the underlying mechanism remains unclear. Here, we describe how RA-specific autoantibody deposits can train human monocytes to exert the hyperactive inflammatory response, particularly via the exacerbated release of tumor necrosis factor α (TNFα). Comparative transcriptomic analysis by plate-bound human IgG (cIgG) or β-glucan indicated that metabolic shift towards glycolysis is a crucial mechanism for trained immunity. Moreover, the cIgG-trained gene signatures were enriched in synovial tissues from patients with ACPA- (anticitrullinated protein antibody-) positive arthralgia and undifferentiated arthritis, and early RA and established RA bore a great resemblance to the myeloid pathotype, suggesting a historical priming event in vivo. Additionally, the expression of the cIgG-trained signatures is higher in the female, older, and ACPA-positive populations, with a predictive role in the clinical response to infliximab. We conclude that RA-specific autoantibodies can train monocytes in the inflamed lesion as early as the asymptomatic stage, which may not merely improve understanding of disease progression but may also suggest therapeutic and/or preventive strategies for autoimmune diseases.

Highlights

The dogma that only adaptive immunity can build immunological memory has recently been challenged by the new concepts of trained immunity or innate immune memory [1, 2]
To test our hypothesis that the presence of rheumatoid arthritis (RA)-specific autoantibodies can train innate immunity, we purified anticitrullinated protein antibodies (ACPA) IgG to investigate the capacity for trained immunity using an in vitro model based on a previous study [4] (Figure 1)
The plate-bound RA autoantibodies stimulated the release of substantial levels of chemokines by monocytes, including CXCL8 and CCL2 (Figures 2(c) and 2(d)), which may provide chemotactic signaling for the infiltration of myeloid lineage cells into the inflamed lesion [33]

Summary

Introduction

The dogma that only adaptive immunity can build immunological memory has recently been challenged by the new concepts of trained immunity or innate immune memory [1, 2]. This notion was first described for exposure to Candida albicans or β-glucans, which can protect the host against reinfection via functional reprogramming of monocytes. Inappropriate activation of trained immunity may cause a series of deleterious consequences via its hyperactivity. A growing body of evidence suggests that this hyperactivity may occur as an early event during the asymptomatic stage of disease, such as hyperuricemia and hyperlipoproteinemia [5, 6]

Methods

Results

Conclusion