Low-dose Interleukin-2: Biology and therapeutic prospects in rheumatoid arthritis

Wu, Ruihe; Li, Na; Zhao, Xiangcong; Ding, Tingting; Xue, Hongwei; Gao, Chong; Li, Xiaofeng; Wang, Caihong

doi:10.1016/j.autrev.2020.102645

Cited by 50 publications

(39 citation statements)

References 153 publications

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“…However, the relations between the serum IL-2 levels and Tfr-like and Tfh-like cells have not been examined in detail. IL-2 is reported to inhibit the differentiation of Tfh cells via a mechanism that may involve the activation or inhibition of the STAT pathway and expression of Bcl-6/Blimp-1 ( 31 , 50 , 51 ). However, the effects of IL-2 on Tfr cells are not yet fully understood.…”

Section: Discussionmentioning

confidence: 99%

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Altered Distribution of Circulating T Follicular Helper-Like Cell Subsets in Rheumatoid Arthritis Patients

Wang

et al. 2021

Front. Med.

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Objective: Recent studies on follicular regulatory T (Tfr) and follicular helper T (Tfh) cells suggest that they may participate in the pathogenesis of rheumatoid arthritis (RA). Here, we examine Tfr-like and Tfh-like cells and their subsets in RA and assess the correlations between these subsets with B cells and cytokines related to the pathogenesis of RA and their clinical significance.Methods: The study population consisted of 18 healthy controls and 47 RA patients (17 new onset, 57.00 ± 11.73 years; 30 treated RA patients, 57.56 ± 1.97 years). Disease activity scores in 28 joints were calculated. The positive rates of rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) were 82.9 and 89.4%, respectively. Cell subsets were analyzed using flow cytometry, and serum cytokine levels were measured using cytometric bead array.Results: Tfh-like and PD-1+ Tfh-like cells were elevated, and the distribution of Tfh-like cell subsets was altered with increased Tfh17-like and Tfh1/17-like cells in RA patients. The receiver operating characteristics curves for Tfh-like, Tfh17-like, Tfh1/17-like, and PD-1+ Tfh-like cells indicate improved RA diagnostic potential. RA patients had decreased regulatory T (Treg), Tfr-like, and memory Tfr-like (mTfr-like) cells and increased Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios. Tfh-like cells and their subsets, including Tfh1-like, Tfh2-like, Tfh1/17-like, and PD-1+ Tfh-like cells, were positively correlated with B cells. Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios were positively correlated with B cells in new-onset RA. Interleukin (IL)-2, IL-4, IL-17, interferon-γ, and tumor necrosis factor-α were positively correlated with Tfr-like and mTfr-like cells. IL-2 and IL-10 were positively correlated with Tfh-like and Tfh2-like cells. IL-4 was positively correlated with Tfh-like cells.Conclusions: Tfh-like and PD-1+ Tfh-like cells are increased, whereas Treg, Tfr-like, and mTfr-like cells are decreased in RA, leading to an imbalance in Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios. Tfh-like cells and a portion of their subsets as well as Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios are closely related to B cells. Dysfunction of cell subsets leads to abnormal levels of cytokines involved in the pathogenesis of RA. The altered distributions of Tfh-like cell subsets, especially Tfh1/17-like cells, represent potential therapeutic targets for treatment of RA.

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Section: Discussionmentioning

confidence: 99%

“…However, these results actually reconfirm the role of IL-2 as a pleiotropic cytokine. Maintaining the balance between the efficacy and pleiotropic functions of IL-2 is always a difficult problem in its use to treat disease ( 51 ). There may be some type of balance and feedback mechanism between IL-2 and Tfr-like and Tfh-like cells.…”

Section: Discussionmentioning

confidence: 99%

Altered Distribution of Circulating T Follicular Helper-Like Cell Subsets in Rheumatoid Arthritis Patients

Wang

et al. 2021

Front. Med.

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“…Naive CD4 + T cells can differentiate into different cells types under antigen presenting cell (APC) stimulation. An imbalance in the function and/or the number of these cells will lead to the abnormal cellular and humoral immunity (7,8). Abnormal humoral immunity often leads to excessive activation of autoantigenic T and B cells, resulting in the abnormal production of antibodies, such as rheumatoid factor (RF) and anti-cycle citrullinated peptide (anti-CCP) antibodies, and the deposition of immune complexes in synovial tissue, resulting in persistent synovitis and joint destruction (4,9,10).…”

Section: Introductionmentioning

confidence: 99%

Function and Role of Regulatory T Cells in Rheumatoid Arthritis

et al. 2021

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Rheumatoid arthritis (RA) is a systemic and heterogeneous autoimmune disease with symmetrical polyarthritis as its critical clinical manifestation. The basic cause of autoimmune diseases is the loss of tolerance to self or harmless antigens. The loss or functional deficiency of key immune cells, regulatory T (Treg) cells, has been confirmed in human autoimmune diseases. The pathogenesis of RA is complex, and the dysfunction of Tregs is one of the proposed mechanisms underlying the breakdown of self-tolerance leading to the progression of RA. Treg cells are a vital component of peripheral immune tolerance, and the transcription factor Foxp3 plays a major immunosuppressive role. Clinical treatment for RA mainly utilizes drugs to alleviate the progression of disease and relieve disease activity, and the ideal treatment strategy should be to re-induce self-tolerance before obvious tissue injury. Treg cells are one of the ideal options. This review will introduce the classification, mechanism of action, and characteristics of Treg cells in RA, which provides insights into clinical RA treatment.

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“…Imbalance between effector and regulatory cells supported by Tfh dysregulation is one of the key mechanisms leading to a breakdown in immune tolerance in auto-immune diseases. Since IL-2 could promote the maintenance of regulatory T cells (Treg), some studies based on IL-2 therapy for the treatment of auto-immune disease or cGVHD have been published [ 82 – 84 ]. In SLE patients, the lack of IL-2 and the imbalance between Tfh and Treg cells could be restored after low dose IL-2 treatment [ 85 , 86 ].…”

Section: Targeting Tfh In Systemic Sclerosis: Perspectives From Other Auto-immune Diseases and Gvhd Modelsmentioning

confidence: 99%

TFH cells in systemic sclerosis

et al. 2021

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Systemic sclerosis is an autoimmune disease characterized by excessive dermal fibrosis with progression to internal organs, vascular impairment and immune dysregulation evidenced by the infiltration of inflammatory cells in affected tissues and the production of auto antibodies. While the pathogenesis remains unclear, several data highlight that T and B cells deregulation is implicated in the disease pathogenesis. Over the last decade, aberrant responses of circulating T follicular helper cells, a subset of CD4 T cells which are able to localise predominantly in the B cell follicles through a high level of chemokine receptor CXCR5 expression are described in pathogenesis of several autoimmune diseases and chronic graft-versus-host-disease. In the present review, we summarized the observed alteration of number and frequency of circulating T follicular helper cells in systemic sclerosis. We described their role in aberrant B cell activation and differentiation though interleukine-21 secretion. We also clarified T follicular helper-like cells involvement in fibrogenesis in both human and mouse model. Finally, because T follicular helper cells are involved in both fibrosis and autoimmune abnormalities in systemic sclerosis patients, we presented the different strategies could be used to target T follicular helper cells in systemic sclerosis, the therapeutic trials currently being carried out and the future perspectives from other auto-immune diseases and graft-versus-host-disease models.

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Low-dose Interleukin-2: Biology and therapeutic prospects in rheumatoid arthritis

Cited by 50 publications

References 153 publications

Altered Distribution of Circulating T Follicular Helper-Like Cell Subsets in Rheumatoid Arthritis Patients

Altered Distribution of Circulating T Follicular Helper-Like Cell Subsets in Rheumatoid Arthritis Patients

Function and Role of Regulatory T Cells in Rheumatoid Arthritis

TFH cells in systemic sclerosis

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