The Relation of Interleukin 17 (IL-17) and IL-23 to Th1/Th2 Cytokines and Disease Activity in Systemic Lupus Erythematosus
ABSTRACT 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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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.03/2011; 2011(2090-1984):810649. DOI:10.1155/2011/810649
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ABSTRACT: Objective. The Hygiene Hypothesis suggests that parasitic helminths (worms) protect against development of autoimmune disease as a serendipitous side-effect of worm-derived immunomodulators that concomitantly promote parasite survival and limit host pathology. We therefore investigated whether ES-62, a phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, protects against kidney damage, in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE).Methods. MRL/Lpr mice progressively produce high levels of autoantibodies and the resultant deposition of immune-complexes drives kidney pathology. The effects of ES-62 on disease progression were assessed by measurement of proteinuria and kidney histology, as well as by determination of anti-nuclear antibody (ANA) and cytokine levels and flow cytometric analysis of relevant cellular populations.Results. ES-62 restores the disrupted effector:regulatory B cell balance in MRL/Lpr mice, acting to inhibit plasmablast differentiation with consequent reduction in ANA production and immune complex and C3a deposition in the kidneys. Moreover, by reducing IL-22 production, ES-62 may desensitise downstream effector mechanisms of kidney pathogenesis. Highlighting the therapeutic importance of resetting B cell responses, adoptive transfer of purified splenic B cells from ES-62-treated MRL/Lpr mice mimics the protection afforded by the helminth product. Mechanistically, this reflects downregulation of MyD88 expression by B cells and also kidney cells, resulting in inhibition of pathogenic crosstalk amongst TLR-, C3a- and immune complex-mediated effector mechanisms.Conclusion. This study provides the first demonstration of protection against pathology by a parasitic worm-derived immunomodulator in a model of SLE and suggests therapeutic potential for drugs based on ES-62 mechanism of action. This article is protected by copyright. All rights reserved.12/2014; 67(4). DOI:10.1002/art.39004
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ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic autoimmune systemic disease that mainly affects women of reproductive age. Emerging data from recent molecular studies show us that estrogen hormone plays a central role in the development of this disease. By acting via its cognate receptors ERα and ERβ expressed on immune cells, estrogen can modulate immune function in both the innate and adaptive immune responses. Interestingly, estrogen may also evoke autoimmune responses after binding to B lymphocytes leading to the generation of high-affinity autoantibodies and proinflammatory cytokines (so-called estrogen-induced autoimmunity). Unfortunately, reproductive function of young female patients with this disease is commonly compromised by different pathophysiologic processes. First, ovarian reserve is diminished even in the presence of mild disease suggesting a direct impact of the disease itself on ovarian function possibly due to ovarian involvement in the form of autoimmune oophoritis. Second, SLE patients with severe manifestations of the disease are treated with alkylating chemotherapy agent cyclophosphamide. Cyclophosphamide and other drugs of alkylating category have the highest gonadotoxicity. Therefore, SLE patients exposed to cyclophosphamide have a much higher risk of developing infertility and premature ovarian failure than do the counterparts who are treated with other less toxic treatments. Third, the functions of the hypothalamic pituitary ovarian axis are perturbed by chronic inflammatory state. And finally adverse pregnancy outcomes are more commonly observed in SLE patients such as fetal loss, preterm birth, intrauterine fetal growth restriction, preeclampsia-eclampsia, and fetal congenital heart block. We aimed in this review article to provide the readers an update on how estrogen hormone closely interacts with and induces lupus-prone changes in the immune system. We also discuss ovarian function and other reproductive outcomes in SLE patients and the current strategies to preserve their fertility in the light of the most recent evidence-based findings of the clinical trials and molecular studies.Obstetrical and Gynecological Survey 03/2015; 70(3):196-210. DOI:10.1097/OGX.0000000000000160 · 2.36 Impact Factor