Genetic, environmental and hormonal factors act on various elements of the innate and adaptive immune responses. The T-cell response to antigen is aberrant in terms of early and late signalling events and results in misbalanced production of cytokines including decreased interleukin (IL)-2 and increased IL-17. Distinct molecular events account for the opposite production of these two cytokines.¹

IL-17-producing T cells also through distinct pathways acquire increased ability to invade tissues and contribute to the inflammatory response. IL-23 is crucial for the development of various autoimmune diseases by promoting Th17 cell-mediated tissue inflammation. A human monoclonal antibody that binds to the p40 subunit, which is shared by IL-23 and IL-12 provided early efficacy in patients with lupus.² IL-23 alters the function of kidney resident cells and causes their demise.³

Most Treg cells develop in the thymus, while some can develop in the periphery from naïve CD4+ T cells. The main contributor to the differentiation, survival and function of Treg cells is IL-2. People and mice lacking elements of the pathway that controls Treg cell development, i.e. IL-2, IL-2 receptor or FoXP3 invariably develop autoimmune disease. Metabolically Treg cells can switch between fatty acid and pyruvate oxidation or glycolysis. The effect of low-dose IL-2 has been studied in systemic lupus erythematosus (SLE) and several studies have shown biological (Treg cell induction) as well as clinical response. Other forms of IL-2 formulations with enhanced or specified receptor-binding capacities such as muteins or complexes with antibodies are in development. Restoration of immune tolerance by expanding and activating Treg cells is now extensively used as a novel approach to treat autoimmune diseases and native IL-2 is the first-in-class molecule. It needs to be studied in bigger trials how IL-2 can add to the current therapeutic landscape in curbing a pro-inflammatory state either as monotherapy in mild disease or in combination with immunosuppressives in active disease.^{4 5}

References

1. Tsokos GC. Autoimmunity and organ damage in systemic lupus erythematosus. Nat Immunol 2020 Jun;21(6):605–614.

2. van Vollenhoven RF, et al. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet 2018 Oct 13;392(10155):1330–1339.

3. Li H, et al. IL-23 reshapes kidney resident cell metabolism and promotes local kidney inflammation. J Clin Invest 2021 Jun 15;131(12):e142428.

4. Kolios AGA, et al. Interleukin-2 and regulatory T cells in rheumatic diseases. Nat Rev Rheumatol 2021 Dec;17(12):749–766.

5. Sharabi A, et al. Regulatory T cells in the treatment of disease. Nat Rev Drug Discov 2018 Nov;17(11):823–844.

Learning Objectives

• Explain the role of cytokine in autoimmune diseases, specifically SLE

• Describe the role of Treg cells in restoration of immune tolerance

• Discuss IL–2 as a therapeutic target for the treatment of autoimmune diseases