Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: Correlation with disease activity
Introduction
Autoimmune rheumatic diseases (ARDs) encompass a wide variety of diseases in which both innate and adaptive immune responses result in autoimmune-mediated tissue destruction. In total, ARDs affect approximately 5% of the population and result in substantial morbidity, and increased mortality. Among the ARDs, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) for which the natural history in humans is best understood [1], [2].
SLE is a heterogeneous inflammatory chronic autoimmune disorder characterized by the deposition of immune complexes in different organs which may lead to multisystem involvement [3]. It has a progressive as well as relapsing/remitting nature in many patients and present as a mixture of mild skin or musculoskeletal and hematological signs and symptoms. It may also involve more serious central nervous system complications and organ damage [4]. Even though the etiology of SLE is unknown, many predisposing factors have been found, including genetic, environmental, infections, and hormonal factors [3].
The immune malfunction that leads to overt SLE is complex, but the pathological hallmarks of SLE alter immune responses to autoantigens with autoantibody production. It produces an endless source of antibodies with various specificities like [3], [5], [6]. This action is mediated by alterations in the production of some cytokines; complement activation; unrestricted B lymphocyte hyperactivity accompanied by immunoglobulin repertoire changes leading to overproduction of auto-antibodies and impaired cell mediated immunity, which results from both T lymphocyte and antigen presenting cell (APC) abnormalities [3], [7].
CD4+ TH lymphocytes can be divided into TH1 (interferon (IFN-γ), IL-2, and tumor necrosis factor-β (TNF-β) and type 2 (IL-4, IL-5, IL-6, IL-10 and IL-13) subsets on the basis of their cytokine secretion profile [8]. However, human TH1 and TH2 subsets are usually defined according to IFN-γ/IL-4 production because the synthesis of IL-2, IL-6, and IL-10 is not stringently restricted to a single subset [9].
In addition to well characterized TH1 and TH2 lymphocytes, naive CD4+ T-cells can be differentiated into TH17, a distinct subset of TH cells characterized by expression of the transcription factor (related orphan receptor gamma; RORγt) [10]. TH17 cells secrete a profile of potent proinflammatory cytokines, including IL-17, IL-21, IL-22 and potent TNF-α and IL-6 upon certain stimulation [11]. Recent studies indicated that IL-17 aids in coordinating tissue inflammation [10], [11], [12]. It has been hypothesized that TH17-cells, in particular, play a pivotal role in the initiation and development of autoimmunity. Several studies suggested a pathogenic role of TH17-cells in the progression of SLE [8], [13], [14].
Another subpopulation of CD4+ lymphocytes is T-regulatory (Tregs) cells. It is thought to suppress autoreactive effector T cells. At present, human Treg cells can be characterized by a CD4+CD25+ and transcription factor forkhead box P3 (FoxP3+) phenotype (CD4 + CD25 + FoxP3+). A decreased frequency and/or an impaired function of these cells might be involved in the development of autoimmune diseases [10], [14]. Though the concept of the preventive role of Treg cells in autoimmunity is widely accepted, data regarding SLE are inconsistent [10], [15]. Cytokine secretion of Treg that has been reported includes IL-10 and TGF-β [16].
Controversy still exists regarding the contribution of specific TH cell subsets and related cytokines in the pathogenesis of SLE. We hypothesized that measuring circulating cytokines may shed some light on the proposed imbalance between TH cell subsets in SLE. In this context, we conducted this case-control study in order to investigate plasma levels of TH1 (IL-12, IFN-γ), TH2 (IL-4, IL-6, IL-10), TH17 (IL-17, IL-23) and Treg (IL-10 and TGF-β) cytokines. The correlations of these cytokines with the disease activity were also demonstrated.
Section snippets
Study population
Sixty consecutive SLE patients (56 women) who fulfilled the American College of Rheumatology (ACR) criteria for the diagnosis of SLE were included in the present study [17]. Their mean age was 28.58 ± 7.3 years (range 17–49 years); the mean duration of SLE was 4.97 ± 3.4 years (range 0.33–15 years). On the day of blood sampling, disease activity was assessed for all the patients using the SLE disease activity index (SLEDAI) [18]. Based on the disease activity [19], [20], SLE patients were divided into
Patients’ characteristics
Demographic and clinical characteristics of SLE and RA patients were summarized in Table 1, Table 2.
Cytokines secretion profile in relation to SLE and RA diseases
As shown in Fig. 1, SLE patients were found to have significantly higher levels of IL-17 (p < 0.001), IL-6 (p < 0.01), IL-12 (p < 0.001) and IL-10 (p < 0.05) but comparable IL-23 and IL-4 and slight statistically insignificant reduction of TGF-β levels compared to controls. A significant decrease in IFN-γ (p < 0.001) was reported in SLE patients in relation to normal subjects.
Regarding the correlation of
Discussion
The role of cytokines as effectors or predisposing elements in autoimmune rheumatic diseases has received prominent attention. However, results were frequently contradictory and, more importantly, difficult to incorporate into a conceptual. Thus, our study is concerned with the TH1/TH2/TH17/Treg cytokine secretion profile in SLE patients.
In the present study, a significant down regulation of IFN-γ in SLE patients could be attributed to the previously observed reduction in frequency and number
Conclusion
Although our study was limited by small sample size, multiple statistical comparisons and cross-sectional design, it supported a role of imbalance in TH1/TH17, TH1/TH2 as well as Treg/TH17 cells (based on their major cytokines secretion profile) in SLE patients. Larger studies with longitudinal measurement of these cytokines may provide information in regard to their relationship with disease activity and clinical response to treatment. We also believe that further functional studies are
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