The Relation of Interleukin 17 (IL-17) and IL-23 to Th1/Th2 Cytokines and Disease Activity in Systemic Lupus Erythematosus

Division of Rheumatology and Clinical Immunology, Department of Medicine, Queen Mary Hospital, Hong Kong.
The Journal of Rheumatology (Impact Factor: 3.19). 10/2010; 37(10):2046-52. DOI: 10.3899/jrheum.100293
Source: PubMed


Interleukin 17 (IL-17) was recently linked to pathogenesis of systemic lupus erythematosus (SLE), but its relation to disease activity has not been well characterized. We examined the relation between serum levels of Th17 (IL-17, IL-23), Th1 (IL-12, interferon-γ), Th2 (IL-10, IL-6, IL-4) cytokines and disease activity in patients with SLE.
Serum cytokines were measured by enzyme linked immunosorbent assays. Disease activity was determined by SLE disease activity index (SLEDAI), anti-dsDNA antibody, and C3 and C4 levels.
Serum levels of IL-17 (p < 0.001), IL-6 (p = 0.006) and IL-10 (p < 0.001) were higher in SLE patients (n = 70) compared to healthy controls (n = 36). Higher serum IL-23 level was found in patients with active disease with cutaneous manifestations (p = 0.004) and serositis (p = 0.04) compared to those without. Serum IL-17 level above the detection limit was more frequently found in patients who had active lupus nephritis (11/23, 47.8%) (p = 0.002), nonrenal active disease (9/15, 60%) (p = 0.001), and inactive lupus (21/32, 65.6%) (p < 0.001) compared to healthy controls (0%). Serum IL-17 levels were otherwise comparable between these 3 groups of patients and were not related to SLEDAI, glomerular filtration rate, activity or chronicity score and ISN/RPS criteria class among patients with active lupus nephritis. There was no significant correlation between serum IL-17/IL-23 and Th1 or Th2 cytokine levels.
SLE patients had higher serum IL-17 levels than healthy controls. Elevated serum IL-23 was found in patients with inflammatory manifestations including cutaneous involvement and serositis. The lack of correlation between Th17, Th1, and Th2 cytokines suggested independent regulatory mechanisms for these cytokines.

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    • "Moreover, IL-23Rþ cells, including both CD4þ and CD8þ lymphocytes, are expanded in lupus patients, and the increase of IL-23Rþ and IL-17þ cells correlates with clinical disease activity[27]. Evidence that expression of specific cytokines may correlate with tissue tropism of disease comes from the observation that IL-23 is elevated in patients with inflammatory manifestations such as skin disease and serositis[28]. IL-22 and IL-22-producing T cells have also been noted to be elevated in lupus patients with skin rather than renal involvement[29]. "
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    ABSTRACT: Interleukin (IL)-23 and the related cytokine IL-17 play vital roles in immune-mediated inflammatory pathology. In the years since its discovery, IL-23 has been implicated as a central pathogenic factor in multiple rheumatic conditions and has been shown to act via a wide range of immune cells including type 17 T-helper (Th17) cells and innate-like immune cells. We review here the pivotal role of these cytokines and IL-23-responsive cells in both the bona fide autoimmune rheumatic diseases rheumatoid arthritis and systemic lupus erythematosus, as well as the spondyloarthropathies which more closely resemble the auto-inflammatory conditions. IL-23 and related cytokines have been found to be up-regulated in rheumatoid arthritis, systemic lupus erythematosus and spondyloarthropathy, and preclinical models suggest that they play important pathological roles in these conditions. It is anticipated that agents which target the IL-23 pathway will have profound roles in modifying the natural history of these diseases and in preventing the structural damage which occurs secondary to such chronic inflammation. This is especially relevant in the case of spondyloarthropathy in which case prevention of the novel bone formation is a particular challenge. It is also potentially pertinent for patients with rheumatoid arthritis, particularly those who do not respond to other biological therapies.
    Full-text · Article · Jan 2015 · Current Opinion in Rheumatology
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    • "The IL-21/IL-21R pathway seems to play an important role in the homeostasis of T-cells, in particular in the differentiation of naïve T-cells towards Th17 cells. These cells have been identified to be key mediators in autoimmune diseases such as SLE [13-15]. Additionally, Th17 cells have been shown to be a source of IL-21 [16]. "
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    ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease accompanied by a disturbed T-cell balance skewed towards effector T-cells, in particular Th17-cells. The novel cytokine interleukin-21 (IL-21) is suggested to be crucial for triggering T-cell responses towards IL-17 producing cells. Thus, we aimed to investigate the ability of T-cells to produce IL-21 and IL-17 in SLE patients. Peripheral blood of 34 SLE patients and 18 healthy controls (HC) was stimulated with phorbol myristate acetate (PMA) and calcium ionophore (Ca-Io). Percentages of IL-21- and IL-17A expressing T-cells were analysed by flow cytometry. The expression levels of the transcription factors B-cell lymphoma-6 (BCL-6) and factors retinoid-related orphan receptor (ROR-γt) were assessed in T-cells by real-time RT-PCR and flow cytometry. Additionally, IL-21 receptor (IL-21R) expression on B- and T-cells of patients and HC was analyzed. Significantly increased percentages of IL-21 expressing CD4+ T-cells and CD8+ T-cells were found in SLE patients as compared to HC. The percentages of IL-21+ CD4+ T-cells and CD8+ T-cells correlated significantly with the percentages of IL-17A+ CD4+ T-cells and CD8+ T-cells, respectively. The relative expression of BCL-6 and ROR-γt did not differ between SLE patients and HC. IL-21R expression occurred mainly on B-cells and was not different comparing SLE patients and HC. This study demonstrates an increased proportion of IL-21+ T-cells in SLE patients correlating with the proportion of IL-17+ T-cells. This suggests a pivotal role of IL-21 in the pathogenesis of SLE.
    Full-text · Article · Sep 2011 · Arthritis research & therapy
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    • "They provide immediate immunological protection by producing antimicrobial and acute phase response proteins against a variety of pathogens, specifically Propionibacterium acnes, Citrobacter rodentium, Klebsiella pneumoniae, Bacteroides spp., Staphylococcus aureus [23], acid-fast Mycobacterium tuberculosis, and fungi infection such as Candida albicans [18] [24]. Most importantly, having the potential to upregulate the expression of specifics matrix metalloproteinases (MMPs) such as MMP-1, MMP-3, MMP-9, MMP-13, IL-17A, and IL- 17F have been shown to be tissue-damaging cytokines and are intimately involved in autoimmune diseases, for example, Crohn's disease [25] [26], EAE [4], collagen-induced arthritis (CIA) [5], Sjögren's syndrome (SjS) [27] [28] and SLE which will be later discussed [29] [30] [31] [32] [33] [34]. However, a recent study by Ishigame et al. [23] suggested that there are differential roles for IL-17A and IL-17F in autoimmune responses, in which IL-17F played a minimal role in the pathogenesis of delayed-type and contact hypersensitivities, EAE, CIA, and arthritis in animal models. "
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    ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a multifaceted range of symptoms affecting almost every organ system. The prototypical pathology of SLE involves the production of antinuclear antibodies and the deposition of immune complexes in basement membranes throughout the body where they induce inflammatory responses. The genetic and environmental etiologies of this process are being intensively sought, and recently, T H 17 cells have been implicated in the pathogenesis of SLE. T H 17 cells are CD4+ memory T cells that behave as both helper and effector cell populations functioning through their signature IL-17 cytokines. Their differentiation is distinct to either the T H 1 or T H 2 cell lineage, but strongly influences development of adaptive responses, including autoimmunity. This paper details the biological functions and regulation of T H 17 cells, followed by an update of their expanding role in SLE.
    Full-text · Article · Mar 2011
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