Anti-neutrophil cytoplasmic antibody-(ANCA)-associated vasculitis (AAV) is a life-threatening group of autoimmune systematic diseases that includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) [1, 2]. The pathological characteristic of AAV is necrotizing small vasculitis mediated by the production of the ANCAs. And these antibodies including c-ANCA targeting to proteinase 3 (PR3) and p-ANCA targeting to myeloperoxidase (MPO)[3–5], which can affect small blood vessels and cause systemic autoimmune inflammatory response leading to multiple organ injuries especially the kidneys, lungs and peripheral nerve. Therefore, it is particularly critical to achieve the early diagnosis and treat the disease. However, the pathogenesis of AAV remains unclear by now.
ANCAs, produced by B cells to target and attack the primary granule constituents of neutrophils and the lysosomes of monocytes , have been considered to be the initiator of AAV. However, the ANCA titer is not related to AAV disease activity or predictive of recurrence [7, 8]. Particularly, there are some patients whose clinical features and pathology are consistent with AAV but ANCA testing are negative, can still be diagnosed as AAV [5, 6]. Therefore, there may be other important factors involved in AAV. Recent years, it has been a rising area to study the role of T lymphocytes in AAV. T cells play an important regulatory role in helping B cells to synthesize high-affinity antibodies to exert humoral immune response, and the insufficient regulation of T cells can lead to the deficiency of adaptive immune and promote the autoimmune inflammatory response [9, 10]. And in animal models, T cells were observed to infiltrate into kidney and other tissues in patients with AAV .Thus, T cells may be involved in the development of AAV.
CD4 + T cell subsets, which are critical regulators of the adaptive immune response, are implicated in the pathogenesis of autoimmune diseases. Naïve CD4 + T cells can differentiate into several distinct subsets including T-helper (Th)1, Th2, Th17 and regulatory T (Treg) cells .After the in-depth study of CD4 + T cell subsets, it is found that Th17 and Treg cells can exert opposite effects. Th17 cells have the ability to produce many pro-inflammatory cytokines and stimulate specific B cells to produce autoantibodies, and the increased level of Th17 cells can promote the overproduction of pro-inflammatory cytokines and autoantibodies resulting in systemic inflammation and autoimmune response finally[13, 14]. By contrast, with the presentation of the novel concept of immune tolerance, CD4 + CD25 + Foxp3 + Treg cell has gradually become a field of interest attracted a lot of attention. It has been confirmed that Treg cells are important for suppressing excessive immune responses and maintaining immune tolerance by inhibiting the stimulatory capacity of antigen-presenting cells and producing anti-inflammatory cytokines [15–17]. The reduced levels of peripheral blood Treg cells have been reported in some autoimmune disease, which has been considered to be the more important factor leading to the breakdown of immune tolerance and the development of autoimmune diseases [18, 19]. Thus, the imbalance of Th17 and Treg cells has been confirmed to be the main force in the development of autoimmune diseases [20–22]. However, the effect of Th17 and Treg cells exerted in the development of AAV has not been well defined now.
Interleukin (IL)-2, a T cell growth factor, has the unique ability to promote the development, proliferation and differentiation of T cells after combining with IL-2 receptors (IL-2Rs),which consists of IL-2Rα (also known as CD25), IL-2Rβ (also known as CD122), and IL-2Rγ (also known as CD132). Thus, IL-2Rs can be divided into low affinity receptor (only IL-2Rα), intermediate affinity receptors (containing IL-2Rβ and IL-2Rγ) and high affinity receptors (containing IL-2Rα, IL-2Rβ and IL-2Rγ) [23–25],which have different affinities for binding to IL-2. In these three categories, intermediate affinity receptor is present mostly on CD8 + T cells and NK cells, which has a low affinity for IL-2 and requires high-dose IL-2 to bind to it, while high affinity receptor is expressed on the activated lymphocyte such as Treg cells, which has a high affinity for IL-2 (dissociation constant (Kd) ≈ 10− 11 M) and can be easily activated by low-dose IL-2 . It has been confirmed that IL-2 has pleiotropic function act and the dose of IL-2 may be a driver of the imbalance between autoimmunity and immune tolerance, which means that IL-2 can act as a pro-inflammatory factor to promote autoimmune inflammatory response under the high-dose IL-2 on the one hand, and act as an anti-inflammatory factor to maintain immune tolerance under the low-dose IL-2 on the other hand [23, 24]. The therapies targeted the recovery of the number or function of Treg cells have become a hot topic in clinical trials [19, 27] and the effect of low-dose IL-2 has essential role in the proliferation, differentiation and function of Treg cells [27–29], which is a significant impact on immunology research. A single and open clinical trial have showed that low-dose IL-2 had a broad therapeutic potential to treat 11 autoimmune diseases effectively and safely by expanding and activating Treg cells, and which also has been confirmed in other autoimmune diseases [31–34].And we have demonstrated that low-dose IL-2 has potential therapeutic prospects in alleviating the disease activity of rheumatoid arthritis by expanding the number of Treg cells to restore the balance of Th17/Treg in the peripheral blood.But the effect of low-dose IL-2 therapy in AAV is still unknown, which needs further exploration.
Our study assessed the absolute number of CD4 + T cell subsets in patients with AAV and HCs by flow cytometry and analyzed the relationship between the cells and disease activity indicators to explore the role of Treg cells in the progression of AAV. And we compared the changes of CD4 + T cell subsets before and after the low-dose IL-2 therapy to evaluate the effect of it on CD4 + T cell subsets. In addition, we also compared the changes of disease activity before and after the low-dose IL-2 therapy to evaluate its efficacy on AAV.