Th17‐ and Treg‐related cytokine and mRNA expression are associated with acute and resolving Kawasaki disease

Guo, Mindy Ming‐Huey; Tseng, W.-N.; Ko, Chun-Han; Pan, Hsiu-Yung; Hsieh, Kai‐Sheng; Kuo, Ho‐Chang

doi:10.1111/all.12558

Cited by 124 publications

(119 citation statements)

References 35 publications

(37 reference statements)

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“…In addition, mIgA also inhibited the production of IL-17A, the signature cytokine of Th17 cells (Figure 1C). The suppressive effect of mIgA was similar to that of therapeutic intravenous immunoglobulin IgG (IVIG) (Figures 1A–C) that is used in the therapy of various autoimmune, inflammatory, and infectious diseases (19–23) and was previously shown to inhibit Th17 responses both in experimental models and in patients with autoimmune diseases (24–29). …”

Section: Resultsmentioning

confidence: 53%

“…Importantly, targeting Th17 responses have given promising results in experimental models of autoimmune diseases and in patients (47). Recent data from ours and others show that beneficial effects of therapeutic IVIG containing IgG from pooled plasma of thousands of healthy donors is associated with inhibition of Th17 responses (24–29, 48–50), indicating that immunoglobulins have regulatory functions on Th17 cells. The data from current report show that in addition to IgG, mIgA also exerts modulatory effects on Th17 responses.…”

Section: Discussionmentioning

confidence: 76%

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Monomeric Immunoglobulin A from Plasma Inhibits Human Th17 Responses In Vitro Independent of FcαRI and DC-SIGN

et al. 2017

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Circulating immunoglobulins including immunoglobulin G (IgG) and IgM play a critical role in the immune homeostasis by modulating functions of immune cells. These functions are mediated in part by natural antibodies. However, despite being second most abundant antibody in the circulation, the immunoregulatory function of IgA is relatively unexplored. As Th17 cells are the key mediators of a variety of autoimmune, inflammatory, and allergic diseases, we investigated the ability of monomeric IgA (mIgA) isolated from pooled plasma of healthy donors to modulate human Th17 cells. We show that mIgA inhibits differentiation and amplification of human Th17 cells and the production of their effector cytokine IL-17A. mIgA also suppresses IFN-γ responses under these experimental conditions. Suppressive effect of mIgA on Th17 responses is associated with reciprocal expansion of FoxP3-positive regulatory T cells. The effect of mIgA on Th17 cells is dependent on F(ab′)2 fragments and independent of FcαRI (CD89) and DC-SIGN. Mechanistically, the modulatory effect of mIgA on Th17 cells implicates suppression of phosphorylation of signal transducer and activator of transcription 3. Furthermore, mIgA binds to CD4+ T cells and recognizes in a dose-dependent manner the receptors for cytokines (IL-6Rα and IL-1RI) that mediate Th17 responses. Our findings thus reveal novel anti-inflammatory functions of IgA and suggest potential therapeutic utility of mIgA in autoimmune and inflammatory diseases that implicate Th17 cells.

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Section: Resultsmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 76%

Monomeric Immunoglobulin A from Plasma Inhibits Human Th17 Responses In Vitro Independent of FcαRI and DC-SIGN

et al. 2017

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“…To date, no studies have been performed on the recently discovered IL-17-producing T cell subset (Th17) in SRMA patients. However, IL-17-producing cells have an important role in the development of several autoimmune diseases in humans such as systemic lupus erythematosus [40], rheumatoid arthritis [41], bronchial allergy [21], inflammatory bowel disease [20], multiple sclerosis [42], and Kawasaki disease [43] and also in experimental models such as collagen-induced arthritis [19] and experimental autoimmune encephalomyelitis (EAE) [22]. The extrapolation of findings in experimental rodent models for human inflammatory diseases is very limited.…”

Section: Discussionmentioning

confidence: 99%

Th17-skewed immune response and cluster of differentiation 40 ligand expression in canine steroid-responsive meningitis-arteritis, a large animal model for neutrophilic meningitis

Freundt-Revilla

Maiolini

Carlson

et al. 2017

J Neuroinflammation

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BackgroundSteroid-responsive meningitis-arteritis (SRMA) is an immune-mediated disorder characterized by neutrophilic pleocytosis and an arteritis particularly in the cervical leptomeninges. Previous studies of the disease have shown increased levels of IL-6 and TGF-ß1 in cerebrospinal fluid (CSF). In the presence of these cytokines, naive CD4+ cells differentiate into Th17 lymphocytes which synthesize interleukin 17 (IL-17). It has been shown that IL-17 plays an active role in autoimmune diseases, it induces and mediates inflammatory responses and has an important role in recruitment of neutrophils. The hypothesis of a Th17-skewed immune response in SRMA should be supported by evaluating IL-17 and CD40L, inducing the vasculitis.MethodsAn enzyme-linked immunosorbent assay (ELISA) was performed to measure IL-17 and CD40L in serum and CSF from a total of 79 dogs. Measurements of patients suffering from SRMA in the acute state (SRMA A) were compared with levels of patients under treatment with steroids (SRMA T), recurrence of the disease (SRMA R), other neurological disorders, and healthy dogs, using the two-part test. Additionally, secretion of IL-17 and interferon gamma (IFN-γ) from the peripheral blood mononuclear cells (PBMCs) was confirmed by an enzyme-linked immunospot (ELISpot) assay.ResultsSignificant higher levels of IL-17 were found in CSF of dogs with SRMA A compared with SRMA T, other neurological disorders and healthy dogs (p < 0.0001). In addition, levels of CD40L in CSF in dogs with SRMA A and SRMA R were significantly higher than in those with SRMA T (p = 0.0004) and healthy controls (p = 0.014). Furthermore, CSF concentrations of IL-17 and CD40L showed a strong positive correlation among each other (rSpear = 0.6601; p < 0.0001) and with the degree of pleocytosis (rSpear = 0.8842; p < 0.0001 and rSpear = 0.6649; p < 0.0001, respectively). IL-17 synthesis from PBMCs in SRMA patients was confirmed; however, IL-17 is mainly intrathecally produced.ConclusionsThese results imply that Th17 cells are inducing the autoimmune response in SRMA and are involved in the severe neutrophilic pleocytosis and disruption of the blood-brain barrier (BBB). CD-40L intrathecal synthesis might be involved in the striking vasculitis. The investigation of the role of IL-17 in SRMA might elucidate important pathomechanism and open new therapeutic strategies.

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“…In patients with acute KD, Tregs were shown to decrease not only in numbers, but in function with a downregulation in Treg key regulatory molecules including FOXP3, GITR, and CTLA-4 [55,56]. Downregulation of these key regulatory molecules in acute phase KD is suggested to be the result of increased expression of miR-31, which directly targets FOXP3 mRNA, and decreased expression of miR-155, which is involved in a signaling pathway promoting FOXP3 expression (Table 3) [55].…”

Section: Kawasaki Diseasementioning

confidence: 99%

Epigenetics and Vasculitis: a Comprehensive Review

Renauer

Coit

Sawalha

2015

Clinic Rev Allerg Immunol

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Vasculitides represent a group of relatively rare systemic inflammatory diseases of the blood vessels. Despite recent progress in understanding the genetic basis and the underlying pathogenic mechanisms in vasculitis, the etiology and pathogenesis of vasculitis remain incompletely understood. Epigenetic dysregulation plays an important role in immune-mediated diseases, and the contribution of epigenetic aberrancies in vasculitis is increasingly being recognized. Histone modifications in the PR3 and MPO gene loci might be mechanistically involved in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Similarly, other studies revealed important epigenetic contribution to other vasculitides, including Kawasaki disease and IgA vasculitis. More recently, genome-wide epigenomic studies have been performed in several vasculitides. A recent genome-wide DNA methylation study uncovered an important role for epigenetic remodeling of cytoskeleton-related genes in the pathogenesis of Behçet's disease and suggested that reversal of some of these DNA methylation changes associates with disease remission. Genome-wide DNA methylation profiling characterized the inflammatory response in temporal artery tissue from patients with giant cell arteritis and showed increased activation of calcineurin/nuclear factor of activated T cells (NFAT) signaling, prompting the suggestion that a specific calcineurin/NFAT inhibitor that is well tolerated and with the added beneficial anti-platelet activity, such as dipyridamole, might be of therapeutic potential in giant cell arteritis. While epigenetic studies in systemic vasculitis are still in their infancy, currently available data clearly indicate that investigating the epigenetic mechanisms underlying these diseases will help to better understand the pathogenesis of vasculitis and provide novel targets for the development of disease biomarkers and new therapies.

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Th17‐ and Treg‐related cytokine and mRNA expression are associated with acute and resolving Kawasaki disease

Cited by 124 publications

References 35 publications

Monomeric Immunoglobulin A from Plasma Inhibits Human Th17 Responses In Vitro Independent of FcαRI and DC-SIGN

Monomeric Immunoglobulin A from Plasma Inhibits Human Th17 Responses In Vitro Independent of FcαRI and DC-SIGN

Th17-skewed immune response and cluster of differentiation 40 ligand expression in canine steroid-responsive meningitis-arteritis, a large animal model for neutrophilic meningitis

Epigenetics and Vasculitis: a Comprehensive Review

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