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

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.

Training vs. Tolerance: The Yin/Yang of the Innate Immune System

“…Furthermore, it is well-known that the pathogenesis of rheumatic arthritis as a chronic inflammatory disease affecting predominantly the joints is driven by several innate immune cells (i.e., monocytes, macrophages and dendritic cells) [ 314 , 315 , 316 , 317 ]. A close interplay between trained innate immune cells and the progression of rheumatic arthritis has been postulated, where the augmented inflammatory response by myeloid cells is controlled by epigenetic and metabolic changes mediated by the mTOR/STAT3 pathway [ 318 , 319 , 320 , 321 ]. Likewise, BCG-trained murine macrophages, characterized by an elevated cytokine production, can modulate fibroblast transformation involving T/B cells affecting the severity of systemic sclerosis (SSc) and inflammatory fibrotic disorders [ 322 ].…”

The future clinical implications of trained immunity

“…Rheumatoid arthritis (RA), the most common autoimmune disease, is characterized by circulating autoantibodies and synovitis with progressive cartilage and bone damage. Antiparietal cell antibodies often precede clinical manifestations and were shown to induce TI phenotype in monocytes [89]. The hyperinflammatory status of circulating monocytes was established in several studies, which confirmed an increased cytokine response and hypermetabolic status with increased glycolysis induced by STAT3 [90,91].…”

Glycolysis Rate-Limiting Enzymes: Novel Potential Regulators of Rheumatoid Arthritis Pathogenesis

“…Additionally, IgG immune complexes sensitize human monocytes for overactive inflammation through transcriptomic and epigenetic reprogramming in RA ( 39 ). This suggests that RA specific autoantibodies can train monocytes in inflammatory lesions as early as the asymptomatic stage, when enhanced glycolysis in RA diseased region is already occurring ( 40 ). An alteration of energy metabolism is clear from the initial stages of RA; glucose, the main energy supplier of the body, is preferentially utilized.…”

“…OSM regulates metabolic reprogramming in RA FLSs in conjunction with TNFα, and it boosts mRNA expression of GLUT1, HK-II, PFKFB3, PKM2, and LDH through STAT3 phosphorylation ( 67 ). Many glycolytic pathway enzymes (including HK-III, PFK, PKM2, and ENO) have been shown to be upregulated in plate-bound human IgG-trained monocytes compared to their levels in blank controls ( 40 ). Upon encountering ICOSL+ B cells, activated effector memory TH cells from patients with RA spontaneously differentiate into inflammatory TH subsets.…”

“…CD45-PDPN+ FLS cells from the K/BxN mouse serum transfer model of arthritis and enriched in culture show significantly higher expressions of PKM2 mRNA, GLUT1, LDHA and ENO1 than CD45-PDPN- cells ( 33 ). A comparative transcriptomic analysis has shown PMK2 upregulation in human IgG-trained monocytes compared to its expression in controls ( 40 ). SUMOylation is an important modification with a regulatory role in cellular responses to various types of stress including osmotic, hypoxic and oxidative stress ( 131 ).…”