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Regulatory T Cells in SLE

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Pathogenesis of Systemic Lupus Erythematosus

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Abstract

Autoimmune diseases such as type 1 diabetes and systemic lupus erythematosus are chronic inflammatory diseases caused by immune system dysfunction. When immune cells such as T cells and B cells recognize self-antigens, this can lead to cellular and tissue destruction. Multiple causes of autoimmune diseases have been suggested, such as genetic predisposition, molecular mimicry, and importantly, a loss in numbers and/or function of regulatory T cells. Regulatory T cells (or Tregs) are a subset of CD4+ T cells essential for functional cellular immunity. They play an important role in preventing the induction of autoimmunity through various mechanisms, including, but not limited to, the secretion of immunosuppressive cytokines such as IL-10 and TGF-β. Their indispensability in protection against autoimmunity can be demonstrated in cases of immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, where loss of Treg function results in severe autoimmunity and even death. Furthermore, a decrease in numbers of functional Tregs and/or loss of Treg function is often been implicated in the pathogenesis of autoimmune diseases. Consequently, there has been increased interest in the use of Tregs in immunotherapy (whether polyclonal or antigen-specific) to treat autoimmune diseases such as systemic lupus erythematosus. Recent studies have shown that antigen-specific Tregs are important for protection against autoimmune disease. In a paradigm shifting study, utilizing the model autoimmune disease, Goodpasture’s, it was found that antigen-specific Tregs dominantly suppressed pro-inflammatory autoreactive conventional T cells and protected from disease. Therefore, there are now efforts to increase the numbers of antigen-specific Tregs to treat autoimmune diseases. One such way is to genetically engineer antigen-specific Tregs. Studies using animal models of disease and Jurkat cell lines have shown potential for the genetic engineering of antigen-specific Tregs for antigen-specific disease suppression. These Tregs can be conferred with antigen specificity through the use of lentiviral vectors containing specific T cell receptor (TCR) sequences. The use of antigen-specific Tregs as therapeutics in autoimmunity could also be applied to systemic lupus erythematosus (SLE), a chronic inflammatory autoimmune disease estimated to affect 1 in 1000 people. SLE is a highly heterogenous disease with a number of target autoantigens such as double-stranded DNA and the Smith (Sm) antigen. Patients present with different disease manifestations, including, but not limited to, lupus nephritis, malar rash, and neuropsychiatric lupus. Amongst the autoantigens, the Sm antigen is most specific for SLE; and, autoreactivity to the Sm antigen is associated with worse prognosis, in particular a strong predisposition to develop lupus nephritis. Furthermore, there is a strong HLA association in anti-Sm + SLE patients, suggesting a dominant T cell directed response in these patients. Current treatments for SLE involve the use of corticosteroids and immunosuppressive agents. However, long-term intake of these medications can lead to severe side effects such as increased risks of infection and drug toxicity. Due to the importance of antigen-specific Tregs in protecting against autoimmune disease, there is now the potential to develop antigen-specific Tregs for use as treatment for SLE.

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  1. Regulatory T Cell Therapy Group, Department of Medicine At Monash Health, School of Clinical Sciences, Monash University, Clayton, VIC, 3168, Australia

    Rachel Cheong & Joshua Ooi

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  1. Department of Medicine, Monash University, Clayton, VIC, Australia

    Alberta Hoi

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Cheong, R., Ooi, J. (2021). Regulatory T Cells in SLE. In: Hoi, A. (eds) Pathogenesis of Systemic Lupus Erythematosus. Springer, Cham. https://doi.org/10.1007/978-3-030-85161-3_9

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