Increased IL‐17‐expressing γδ T cells in seborrhoeic dermatitis‐like lesions of the <i>Mpzl3</i> knockout mice

Wikramanayake, Tongyu C.; Hirt, Penelope A.; Almastadi, Maram; Mitchell, Hunter; Tomic‐Canic, Marjana; Romero, Laura; Garcia, Denisse; Štrbo, Nataša

doi:10.1111/exd.13798

Cited by 16 publications

(13 citation statements)

References 17 publications

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“…In 2018, Wikramanayake et al demonstrated increased levels of IL‐17 expressing γδ T cells in Mpzl3 knockout mice. This was the first time IL‐17 had been shown to be increased in SD . Th17 activity might be increased in SD at baseline, which could be worsened further with IL‐4 blockade .…”

Section: Future Directionsmentioning

confidence: 57%

“…Recently, it was shown by Wikramanayake et al that Mpzl3 knockout mice, which have an SD‐like phenotype, had increased levels of IL‐17 expressing γδ T cells. This is the first time that Il‐17 has been implicated in SD . There also seems to be a disruption in structural epidermal biomarkers such as keratins 1, 10 and 11 as well as ceramides and sphingoid lipids, which are important for the integrity of the skin barrier .…”

Section: Major Advances In Immunology and Molecular Biologymentioning

confidence: 86%

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An update on the microbiology, immunology and genetics of seborrheic dermatitis

Aðalsteinsson

Kaushik

Muzumdar

et al. 2020

Experimental Dermatology

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The underlying mechanism of seborrheic dermatitis (SD) is poorly understood but major scientific progress has been made in recent years related to microbiology, immunology and genetics. In light of this, the major goal of this article was to summarize the most recent articles on SD, specifically related to underlying pathophysiology. SD results from Malassezia hydrolysation of free fatty acids with activation of the immune system by the way of pattern recognition receptors, inflammasome, IL-1β and NF-kB. M. restricta and M. globosa are likely the most virulent subspecies, producing large quantities of irritating oleic acids, leading to IL-8 and IL-17 activation. IL-17 and IL-4 might play a big role in pathogenesis, but this needs to be further studied using novel biologics. No clear genetic predisposition has been established; however, recent studies implicated certain increased-risk human leucocyte antigen (HLA) alleles, such as A*32, DQB1*05 and DRB1*01 as well as possible associations with psoriasis and atopic dermatitis (AD) through the LCE3 gene cluster while SD, and SD-like syndromes, shares genetic mutations that appear to impair the ability of the immune system to restrict Malassezia growth, partially due to complement system dysfunction. A paucity of studies exists looking at the relationship between SD and systemic disease. In HIV, SD is thought to be secondary to a combination of immune dysregulation and disruption in skin microbiota with unhindered Malassezia proliferation. In Parkinson's disease, SD is most likely secondary to parasympathetic hyperactivity with increased sebum production as well as facial immobility which leads to sebum accumulation. K E Y W O R D Sinflammasome, Malassezia, sebaceous glands, seborrheic dermatitis, systemic disease While the order of events is unclear regarding the pathophysiology of SD, it is agreed upon by most sources that the three main prerequisites are as follows: Malassezia colonization, lipid secretion by sebaceous glands and an underlying immune system susceptibility. [1,5,7,38] The pathogenesis can be categorized into five different phases.

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Section: Future Directionsmentioning

confidence: 57%

Section: Major Advances In Immunology and Molecular Biologymentioning

confidence: 86%

An update on the microbiology, immunology and genetics of seborrheic dermatitis

Aðalsteinsson

Kaushik

Muzumdar

et al. 2020

Experimental Dermatology

View full text Add to dashboard Cite

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“…Mice carrying various mutant alleles of the Mpzl3 gene— rc , ruf and the knockout alleles—would facilitate in‐depth molecular analysis of the pleiotropic functions controlled by MPZL3. The Mpzl3 knockout mice, in particular, with their early‐onset SD‐like skin phenotype and 100% penetrance, offers an excellent in vivo model system to investigate the inflammatory mediators in the development of SD‐like skin inflammation, especially the subtype that involves the ZNF750/MPZL3 pathway. For example, this model already has permitted to reveal an important role for IL‐17 positive γδ T cells in SD, which were not known to play a role in its pathogenesis .…”

Section: Conclusion and Translational Perspectivesmentioning

confidence: 99%

Seborrheic dermatitis—Looking beyond Malassezia

Wikramanayake

Borda

Miteva

et al. 2019

Experimental Dermatology

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Seborrhoeic Dermatitis (SD) is a very common chronic and/or relapsing inflammatory skin disorder whose pathophysiology remains poorly understood. Yeast of the genus Malassezia has long been regarded as a main predisposing factor, even though causal relationship has not been firmly established. Additional predisposing factors have been described, including sebaceous activity, host immunity (especially HIV infection), epidermal barrier integrity, skin microbiota, endocrine and neurologic factors, and environmental influences. Genetic studies in humans and mouse models—with particularly interesting insights from examining the Mpzl3 knockout mice and their SD‐like skin phenotype, and patients carrying a ZNF750 mutation—highlight defects in host immunity, epidermal barrier and sebaceous activity. After synthesizing key evidence from the literature, we propose that intrinsic host factors, such as changes in the amount or composition of sebum and/or defective epidermal barrier, rather than Malassezia, may form the basis of SD pathobiology. We argue that these intrinsic changes provide favourable conditions for the commensal Malassezia to over‐colonize and elicit host inflammatory response. Aberrant host immune activity or failure to clear skin microbes may bypass the initial epidermal or sebaceous abnormalities. We delineate specific future clinical investigations, complemented by studies in suitable SD animal models, that dissect the roles of different epidermal compartments and immune components as well as their crosstalk and interactions with the skin microbiota during the process of SD. This research perspective beyond the conventional Malassezia‐centric view of SD pathogenesis is expected to enable the development of better therapeutic interventions for the management of recurrent SD.

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“…Support for the contribution of Malassezia-induced IL-17 to disease pathogenesis is further provided by the observation that Malassezia-specific Th17 cells are enriched in AD patients (Balaji et al, 2011;. Beyond AD, a link between the IL-23/IL-17 immune axis and Malassezia-associated disorders has also been proposed in seborrheic dermatitis (Wikramanayake et al, 2018) and dandruff (Ehm et al, 2017). Besides the prominent IL-17 profile, Malassezia-responsive T cells in humans also produce IFN-γ (Balaji et al, 2011;Bacher et al, 2019;, whereby the reason underlying the discrepancy between the two host species remains unclear.…”

Section: Malassezia-induced Immunity and Immunopathology In The Skinmentioning

confidence: 97%

Host Immunity to Malassezia in Health and Disease

Sparber

Ruchti

LeibundGut‐Landmann

2020

Front. Cell. Infect. Microbiol.

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The microbiota plays an integral role in shaping physical and functional aspects of the skin. While a healthy microbiota contributes to the maintenance of immune homeostasis, dysbiosis can result in the development of diverse skin pathologies. This dichotomous feature of the skin microbiota holds true not only for bacteria, but also for fungi that colonize the skin. As such, the yeast Malassezia, which is by far the most abundant component of the skin mycobiota, is associated with a variety of skin disorders, of which some can be chronic and severe and have a significant impact on the quality of life of those affected. Understanding the causative relationship between Malassezia and the development of such skin disorders requires in-depth knowledge of the mechanism by which the immune system interacts with and responds to the fungus. In this review, we will discuss recent advances in our understanding of the immune response to Malassezia and how the implicated cells and cytokine pathways prevent uncontrolled fungal growth to maintain commensalism in the mammalian skin. We also review how the antifungal response is currently thought to affect the development and severity of inflammatory disorders of the skin and at distant sites.

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Increased IL‐17‐expressing γδ T cells in seborrhoeic dermatitis‐like lesions of the Mpzl3 knockout mice

Cited by 16 publications

References 17 publications

An update on the microbiology, immunology and genetics of seborrheic dermatitis

An update on the microbiology, immunology and genetics of seborrheic dermatitis

Seborrheic dermatitis—Looking beyond Malassezia

Host Immunity to Malassezia in Health and Disease

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