Staphylococcal α-Toxin Induces a Higher T Cell Proliferation and Interleukin-31 in Atopic Dermatitis

Niebuhr, Margarete; Mamerow, Diana; Heratizadeh, Annice; Satzger, Imke; Werfel, Thomas

doi:10.1159/000323905

Cited by 45 publications

(37 citation statements)

References 25 publications

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“…This is supported by the fact that the IL-31RA is upregulated by S. aureus a-toxin and staphylococcal enterotoxin B in monocytes (91), suggesting a role in innate immunity. Furthermore, PBMCs of patients with AD secrete significantly more IL-31 compared with those of healthy controls upon stimulation with a-toxin and staphylococcal enterotoxin B (26,92). This regulation seems to be specific, and IL31 RNA is not upregulated in response to herpes simplex or influenza virus infection (30).…”

Section: Discussionmentioning

confidence: 98%

Control of the Physical and Antimicrobial Skin Barrier by an IL-31–IL-1 Signaling Network

Hänel

Pfaff

Cornelissen

et al. 2016

The Journal of Immunology

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Atopic dermatitis, a chronic inflammatory skin disease with increasing prevalence, is closely associated with skin barrier defects. A cytokine related to disease severity and inhibition of keratinocyte differentiation is IL-31. To identify its molecular targets, IL-31–dependent gene expression was determined in three-dimensional organotypic skin models. IL-31–regulated genes are involved in the formation of an intact physical skin barrier. Many of these genes were poorly induced during differentiation as a consequence of IL-31 treatment, resulting in increased penetrability to allergens and irritants. Furthermore, studies employing cell-sorted skin equivalents in SCID/NOD mice demonstrated enhanced transepidermal water loss following s.c. administration of IL-31. We identified the IL-1 cytokine network as a downstream effector of IL-31 signaling. Anakinra, an IL-1R antagonist, blocked the IL-31 effects on skin differentiation. In addition to the effects on the physical barrier, IL-31 stimulated the expression of antimicrobial peptides, thereby inhibiting bacterial growth on the three-dimensional organotypic skin models. This was evident already at low doses of IL-31, insufficient to interfere with the physical barrier. Together, these findings demonstrate that IL-31 affects keratinocyte differentiation in multiple ways and that the IL-1 cytokine network is a major downstream effector of IL-31 signaling in deregulating the physical skin barrier. Moreover, by interfering with IL-31, a currently evaluated drug target, we will have to consider that low doses of IL-31 promote the antimicrobial barrier, and thus a complete inhibition of IL-31 signaling may be undesirable.

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Section: Discussionmentioning

confidence: 98%

Control of the Physical and Antimicrobial Skin Barrier by an IL-31–IL-1 Signaling Network

Hänel

Pfaff

Cornelissen

et al. 2016

The Journal of Immunology

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“…[37][38][39] We did not evaluate the a-toxin specific T-cell responses, which is a limitation of this study, and instead focused on evaluating the functionality of the anti-rAT antibodies generated by vaccination. Good seroresponse rates to the rAT vaccine were observed, with higher neutralizing antibody titers noted at the 50 mg rAT dose as compared to the 25 rAT mg dose in both monovalent and bivalent doses.…”

Section: Discussionmentioning

confidence: 99%

Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults

Landrum

Lalani

Niknian³

et al. 2017

Human Vaccines & Immunotherapeutics

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We conducted a randomized, double-blind, placebo-controlled dose-escalation study in healthy adults to evaluate the safety and immunogenicity of recombinant Staphylococcus aureus candidate vaccine antigens, recombinant a-toxoid (rAT) and a sub-unit of Panton-Valentine leukocidin (rLukS-PV). 176 subjects were enrolled and randomized within 1 of 11 treatment cohorts: monovalent rAT or rLukS-PV dosages of 10, 25, 50, and 100 mg; bivalent rAT:rLukS dosages of 10:10, 25:25, and 50:50 mg; and alum or saline placebo. All subjects were assessed at Days 0, 7, 14, 28, and 84. Subjects in the 50:50 mg bivalent cohort received a second injection on Day 84 and were assessed on Days 98 and 112. Incidence and severity of reactogenicity and adverse events (AEs) were compared. Geometric mean serum concentrations (GMC) and neutralizing activity of anti-rAT and anti-rLukS-PV IgG were assessed. Reactogenicity incidence was significantly higher in vaccine than placebo recipients (77% versus 55%, respectively; p D 0.006). However, 77% of reactogenicity events were mild and 19% were moderate in severity. The AE incidence and severity were similar between the cohorts. All monovalent and bivalent rAT dosages resulted in a significant increase in the anti-rAT IgG and anti-rLukS-PV GMCs between day 0 and 28 compared with placebo, and persisted through Day 84. Exploratory subgroup analyses suggested a higher GMC and neutralizing antibody titers for the 50 mg monovalent or bivalent rAT and rLukS-PV dose as compared to the other doses. No booster effect was observed after administration of the second dose. We conclude that the rAT and rLukS-PV vaccine formulations were well-tolerated and had a favorable immunogenicity profile, producing antibody with neutralizing activity through day 84. There was no benefit observed with a booster dose of the vaccine.

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“…SEB is a superantigen; it is capable of activating T cells directly to trigger skewed immune response (18). On the other hand, SEB can also act as an immune adjuvant to promote immune responses such as the induction of the hypersensitivity (5,6).…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin E3 Ligase A20 Facilitates Processing Microbial Product in Nasal Epithelial Cells

Geng

et al. 2012

Journal of Biological Chemistry

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Staphylococcal α-Toxin Induces a Higher T Cell Proliferation and Interleukin-31 in Atopic Dermatitis

Cited by 45 publications

References 25 publications

Control of the Physical and Antimicrobial Skin Barrier by an IL-31–IL-1 Signaling Network

Control of the Physical and Antimicrobial Skin Barrier by an IL-31–IL-1 Signaling Network

Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults

Ubiquitin E3 Ligase A20 Facilitates Processing Microbial Product in Nasal Epithelial Cells

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