Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity.
ABSTRACT IL-23-dependent IL-17-producing T helper (Th) lymphocytes are associated with autoimmunity. We investigated the immunopathological mechanisms for activation of Th17 cells of patients with systemic lupus erythematosus (SLE). Concentration of cytokines/chemokine in plasma and culture supernatant from SLE patients and healthy controls were measured by ELISA or flow cytometry. Plasma IL-12, IL-17, IL-23 and CXCL10 concentrations and the number of Th17 cells were significantly elevated in SLE patients than control subjects (both p<0.05). Elevated IL-12, IL-17 and CXCL10 concentrations correlated positively and significantly with SLEDAI (all p<0.05). Plasma IL-12 and IL-17 showed significant and positive correlation with plasma Th1 chemokine CXCL10 concentration in SLE patients (all p<0.05). Ex vivo inductions of IL-17 by IL-23 or IL-18 from co-stimulated lymphocytes were significantly higher in SLE patients than controls (all p<0.05). The activated IL-23/IL-17 axis is important for the inflammatory immunity in SLE.
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ABSTRACT: CD4(+) T helper (Th) cells are critical for proper immune cell homeostasis and host defense, but are also major contributors to pathology of autoimmune and inflammatory diseases. Since the discovery of the Th1/Th2 dichotomy, many additional Th subsets were discovered, each with a unique cytokine profile, functional properties, and presumed role in autoimmune tissue pathology. This includes Th1, Th2, Th17, Th22, Th9, and Treg cells which are characterized by specific cytokine profiles. Cytokines produced by these Th subsets play a critical role in immune cell differentiation, effector subset commitment, and in directing the effector response. Cytokines are often categorized into proinflammatory and anti-inflammatory cytokines and linked to Th subsets expressing them. This article reviews the different Th subsets in terms of cytokine profiles, how these cytokines influence and shape the immune response, and their relative roles in promoting pathology in autoimmune and inflammatory diseases. Furthermore, we will discuss whether Th cell pathogenicity can be defined solely based on their cytokine profiles and whether rigid definition of a Th cell subset by its cytokine profile is helpful. Copyright © 2014 Elsevier Ltd. All rights reserved.Cytokine 10/2014; 74(1). DOI:10.1016/j.cyto.2014.09.011 · 2.87 Impact Factor
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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
- BMC Immunology 12/2015; 16(1). DOI:10.1186/s12865-015-0070-7 · 2.25 Impact Factor