Study in focus 1: Dendritic cells drive profibrotic inflammation and aberrant T-cell polarization in systemic sclerosis

Systemic sclerosis (SSc) is a complex multifaceted autoimmune disease, characterized by obliterative vasculopathy and fibrosis of the skin and internal organs. Here, dendritic cells (DCs) are an essential component of the inflammatory infiltrate in skin lesions. Notably, an increased number of plasmacytoid DCs are found in both the skin and systemic circulation of these patients.

The authors examined how monocyte-derived DCs respond to cytokines and the extent to which they can activate Th17 cells in patients with limited and diffuse cutaneous SSc and healthy controls. The study also analyzed T cell subpopulations to determine the role of DCs in promoting fibrosis in SSC and demonstrated the significant function of DCs in fibrosis by assisting TH17 cell proliferation, as well as the generation of cytokines related to Th17. In addition to supporting abnormal T cell polarization, DCs also enhance the development of Th17 cells, leading to a self-reinforcing cycle. Researchers have found increased levels of IL-33 in the blood, skin, and organs of SSc patients with late-stage disease and those with ILD, which is linked to the extent of skin involvement and ILD progression. Therefore, it is proposed that the change in functionality of DCs results in improper T cell polarization and profibrotic inflammation, contributing to the variations in the clinical presentation of SSc.

Study in focus 2: Low-dose interleukin-2 therapy, a promising targeted therapeutic approach for systemic lupus erythematosus (SLE)

Among a number of innate and adaptive immune system cells, auto-reactive effector T cells (Teff) are particularly implicated in the initiation, maintenance, and progression of the pathogenic processes in SLE. Despite a sound understanding of immunopathogenesis, many potential treatment methods have failed in clinical trials. Low-dose interleukin-2 (IL-2) therapy is a novel and potentially effective treatment for SLE. As regulatory T cells (Treg) are dependent on IL-2 for growth and maintenance, IL-2 deficiency significantly leads to immunological dysregulation and tolerance breach in SLE. The immunological pathology in SLE is directly impacted by low-dose IL-2 therapy’s capacity to restore Treg function, making it a targeted therapeutic approach.

The authors have discussed the pathophysiological explanations for this potential therapy along with the clinical progress and significant advances in translational research. They described both past and recent clinical studies which have repeatedly demonstrated that it is well tolerated and effective at expanding the Treg population in a targeted manner, and reduces disease activity in SLE patients. Its favourable safety profile gives an option for combining with other immunosuppressants, including biologics, as it may have synergistic and complementary immunomodulatory effects without increasing the risk of infections. In numerous inflammatory and autoimmune diseases, randomized clinical studies utilizing either normal IL-2 or IL-2 mutants are being conducted. Ongoing clinical investigations of thistherapeutic idea in SLE are thus justified.

References:

1. Choreño-Parra JA, et al. Dendritic cells drive profibrotic inflammation and aberrant T-cell polarization in systemic sclerosis. Rheumatology (Oxford). 2023; 62(4) : 1687 – 1698.
2. Akbarzadeh R, et al. Low-dose interleukin-2 therapy: a promising targeted therapeutic approach for systemic lupus erythematosus. Curr Opin Rheumatol. 2023; 35(2) : 98 – 106.