Targeting Tregs in Juvenile Idiopathic Arthritis and Juvenile Dermatomyositis-Insights From Other Diseases

Abstract

Regulatory T cells (Tregs) are believed to be dysfunctional in autoimmunity. Juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM) result from a loss of normal immune regulation in specific tissues such as joints or muscle and skin, respectively. Here, we discuss recent findings in regard to Treg biology in oligo-/polyarticular JIA and JDM, as well as what we can learn about Treg-related disease mechanism, treatment and biomarkers in JIA/JDM from studies of other diseases. We explore the potential use of Treg immunoregulatory markers and gene signatures as biomarkers for disease course and/or treatment success. Further, we discuss how Tregs are affected by several treatment strategies already employed in the therapy of JIA and JDM and by alternative immunotherapies such as anti-cytokine or co-receptor targeting. Finally, we review recent successes in using Tregs as a treatment target with low-dose IL-2 or cellular immunotherapy. Thus, this mini review will highlight our current understanding and identify open questions in regard to Treg biology, and how recent findings may advance biomarkers and new therapies for JIA and JDM.

Keywords: biomarker; juvenile dermatomyositis; juvenile idiopathic arthritis; regulatory T cells; therapy.

Figure 1

Current and desired disease progression models. (A) Current “Trial-and-error” model: Upon diagnosis the first line of treatment is started, which may lead to remission, or partial remission. Often, a second, third or fourth treatment strategy needs to be implemented when the previous treatments are not effective. Choice of treatments is guided by previous experience, e.g., upon presentation non-steroidal anti-inflammatory drugs with glucocorticoids are used, after a couple of month many patients are switched to methotrexate as first disease modifying therapy, often followed by anti-TNF-α agents with/without methotrexate (4). This disease progression and subsequent staggering of therapy can result in irreversible damage and long-term therapy. (B) Desired personalized/biomarker-driven model: Biomarkers could be used for prediction and aid decisions at the following stages: disease trajectory, selection of treatment, early response to therapy, remission/minimal disease activity and the risk of flare upon withdrawal of therapy, ongoing monitoring of immune activity and risk of flares. Biomarkers might thus contribute to more efficient therapy, pre-empt flares, and minimize short- and long-term effects of flares and reduce long-term damage. Lines represent models of disease progression, with line thickness representing frequency estimates.

Figure 2

Tregs provide challenges and opportunities in JIA/JDM pathogenesis, treatment and monitoring. (A) Tregs are altered in repertoire, phenotype and frequency in JIA/JDM, particularly at the site of inflammation. (B–D) Treatment options to restore the immunoregulatory balance include targeting pro-inflammatory cytokines (B), targeting Tregs to enhance their activity (C) or using Tregs as a cellular therapy (D). (E) Further, changes in Treg gene signatures could aid as biomarkers to measure or predict disease/treatment response.