Opinion Review
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Med Genet. Jul 20, 2023; 11(3): 28-38
Published online Jul 20, 2023. doi: 10.5496/wjmg.v11.i3.28
Role of IL-2/IL-2 receptor in pathogenesis of autoimmune disorders: Genetic and therapeutic aspects
Sana Rafaqat, Saira Rafaqat
Sana Rafaqat, Department of Biotechnology (Specialized in Human Genetics), Lahore College for Women University, Lahore 54000, Pakistan
Saira Rafaqat, Department of Zoology, Lahore College for Women University, Lahore 54000, Pakistan
Author contributions: All authors contributed equally.
Conflict-of-interest statement: The authors declared no conflict of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Sana Rafaqat, PhD, Research Fellow, Department of Biotechnology, Lahore College for Women University, G8VG+FR6, Jail Road, Near Wapda Flats, Jubilee Town, Lahore 54000, Pakistan. sana.rafaqat44@gmail.com
Received: April 13, 2023
Peer-review started: April 13, 2023
First decision: June 1, 2023
Revised: June 10, 2023
Accepted: June 30, 2023
Article in press: June 30, 2023
Published online: July 20, 2023

Interleukin-2 (IL-2) is an important cytokine that plays a key role in the immune response. The IL-2 receptor (IL-2R) is composed of three subunits, alpha, beta, and gamma, with the alpha subunit having the highest affinity for IL-2. Several studies reported that immune dysregulation of IL-2 may cause tissue injury as well as damage leading to the pathogenesis of various autoimmune diseases such as acute necrotizing vasculitis in systemic lupus erythematosus (SLE), inflammatory synovitis in rheumatoid arthritis (RA), salivary and lacrimal gland dys-function in Sjogren syndrome (SS), obliterative vasculopathy fibrosis in systemic sclerosis (SSc), and inflammatory demyelination in multiple sclerosis (MS). The aim of this review paper was to examine the role of IL-2/IL-2R in various autoimmune disorders, taking into account recent advancements and discoveries, gaps in the current literature, ongoing debates, and potential avenues for future research. The focus of this review is on systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, sjogren syndrome, and multiple sclerosis, which are all linked to the malfunctioning of IL-2/IL-2R. In genetic studies, gene polymorphisms of IL-2 such as IL-2 330/T, IL-2 330/G, and rs2069763 are involved in increasing the risk of SLE. Furthermore, genetic associations of IL-2/IL-2R such as rs791588, rs2281089, rs2104286, rs11594656, and rs35285258 are significantly associated with RA susceptibility. The IL-2 polymorphism including rs2069762A, rs6822844T, rs6835457G, and rs907715T are significant connections with systemic sclerosis. In addition, rs2104286 (IL-2), rs11594656 (IL-2RA), rs35285258 (IL-2RB) gene polymorphism significant increases the risk of multiple sclerosis. In therapeutic approaches, low-dose IL-2 therapy could regulate Tfr and Tfh cells, resulting in a reduction in disease activity in the SLE patients. In addition, elevated sIL-2R levels in the peripheral blood of SLE patients could be linked to an immunoregulatory imbalance, which may contribute to the onset and progression of SLE. Consequently, sIL-2R could potentially be a target for future SLE therapy. Moreover, Low dose-IL2 was well-tolerated, and low levels of Treg and high levels of IL-21 were associated with positive responses to Ld-IL2 suggested to be a safe and effective treatment for RA. Additionally, low-dose IL-2 treatment improves the exocrine glands' ability to secrete saliva in SS-affected mice. Whereas, Basiliximab targets the alpha chain of the IL-2 receptor suggested as a potential treatment for SSc. Also, pre-and post-treatment with Tregs, MDSCs, and IL-2 may have the potential to prevent EAE induction in patients with MS. It is suggested that further studies should be conducted on IL-2 polymorphism in Sjogren syndrome.

Keywords: IL-2, IL-2R, Pathogenesis, Autoimmune diseases, Systemic lupus erythematosus, Rheumatoid arthritis, Systemic sclerosis, Sjogren syndrome, Multiple sclerosis

Core Tip: Immune dysregulation of Interleukin-2 (IL-2) may cause tissue injury and damage leads to pathogenesis of various autoimmune diseases The aim of this review paper was to examine the role of IL-2/IL-2R in various autoimmune disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), multiple sclerosis (MS) and Sjogren Syndrome (SS), which are all linked to malfunctioning of IL-2/IL-2R. IL-2 gene polymorphism is involved in increasing the risk of SLE, RA, SSc, and MS but no data has been available about the genetic role of IL-2 in the pathogenesis of Sjogren syndrome. In therapeutic approaches, a low dose of IL-2 therapy is found to be safe, effective, and well-tolerated in the treatment of SLE, RA, SSc, MS, and SS patients.