Pollen grains induce a rapid and biphasic eczematous immune response in atopic eczema patients

Introduction: Eczematous reactions to type I allergy-inducing antigens are documented in a subgroup of patients with atopic eczema. Yet, the underlying immunological mechanisms are not well understood. Material and Methods: To delineate the effect of native pollen grains on human skin of healthy and atopic individuals we performed patch tests (atopy patch test with native pollen grains, PPT). Nickel patch tests (NPT) served as an established model of contact dermatitis. Skin site biopsies were taken 6 - 96 h after allergen application and investigated immunohistochemically. Results: Histology of positive patch tests showed an influx of mononuclear cells (predominantly CD4+, CD25+, CD45RO+). This influx was detected earlier in the PPT reaction than in the immune response to nickel. A biphasic cytokine response could be detected in the PPT: IL-5 dominated in the early, IFN-gamma in the late phase. The NPT was continuously dominated by IFN-gamma. Dendritic cell subpopulations imitated the earlier kinetics of the mononuclear infiltrate. Discussion: Thus, pollen grains induce eczematous reactions in susceptible individuals. This reaction appears clinically and immunohistochemically similar to the contact hypersensitivity reaction to nickel but follows a faster kinetic and a biphasic course: Th2 and IgE in the early (24 h) and Th1 predominance in the late (96 h) phase. Copyright (c) 2007 S. Karger AG, Basel

Keratinocytes regulate the threshold of inflammation by inhibiting T cell effector functions

Whilst the importance of keratinocytes as a first-line defense has been widely investigated, little is known about their interactions with non-resident immune cells. In this study, the impact of human keratinocytes on T cell effector functions was analyzed in an antigen-specific in vitro model of allergic contact dermatitis (ACD) to nickel sulfate. Keratinocytes partially inhibited T cell proliferation and cytokine production. This effect was dependent on the keratinocyte/T cell ratio and was partially reversible by increasing the number of autologous dendritic cells. The inhibition of T cell proliferation by keratinocytes was independent of the T cell subtype and antigen presentation by different professional antigen-presenting cells. Autologous and heterologous keratinocytes showed comparable effects, while the fixation of keratinocytes with paraformaldehyde abrogated the immunosuppressive effect. The separation of keratinocytes and T cells by a transwell chamber, as well as a cell-free keratinocyte supernatant, inhibited T cell effector functions to the same amount as directly co-cultured keratinocytes, thus proving that soluble factor/s account for the observed suppressive effects. In conclusion, keratinocytes critically control the threshold of inflammatory processes in the skin by inhibiting T cell proliferation and cytokine production

Sebum lipids influence macrophage polarization and activation

K

The integration of large-scale public data and network analysis uncovers molecular characteristics of psoriasis

In recent years, a growing interest in the characterization of the molecular basis of psoriasis has been observed. However, despite the availability of a large amount of molecular data, many pathogenic mechanisms of psoriasis are still poorly understood. In this study, we performed an integrated analysis of 23 public transcriptomic datasets encompassing both lesional and uninvolved skin samples from psoriasis patients. We defined comprehensive gene co-expression network models of psoriatic lesions and uninvolved skin. Moreover, we curated and exploited a wide range of functional information from multiple public sources in order to systematically annotate the inferred networks. The integrated analysis of transcriptomics data and co-expression networks highlighted genes that are frequently dysregulated and show aberrant patterns of connectivity in the psoriatic lesion compared with the unaffected skin. Our approach allowed us to also identify plausible, previously unknown, actors in the expression of the psoriasis phenotype. Finally, we characterized communities of co-expressed genes associated with relevant molecular functions and expression signatures of specific immune cell types associated with the psoriasis lesion. Overall, integrating experimental driven results with curated functional information from public repositories represents an efficient approach to empower knowledge generation about psoriasis and may be applicable to other complex diseases.Peer reviewe

Urticaria: Collegium Internationale Allergologicum (CIA) Update 2020.

This update on chronic urticaria (CU) focuses on the prevalence and pathogenesis of chronic spontaneous urticaria (CSU), the expanding spectrum of patient-reported outcome measures (PROMs) for assessing CU disease activity, impact, and control, as well as future treatment options for CU. This update is needed, as several recently reported findings have led to significant advances in these areas. Some of these key discoveries were first presented at past meetings of the Collegium Internationale Allergologicum (CIA). New evidence shows that the prevalence of CSU is geographically heterogeneous, high in all age groups, and increasing. Several recent reports have helped to better characterize two endotypes of CSU: type I autoimmune (or autoallergic) CSU, driven by IgE to autoallergens, and type IIb autoimmune CSU, which is due to mast cell (MC)-targeted autoantibodies. The aim of treatment in CU is complete disease control with absence of signs and symptoms as well as normalization of quality of life (QoL). This is best monitored by the use of an expanding set of PROMs, to which the Angioedema Control Test, the Cholinergic Urticaria Quality of Life Questionnaire, and the Cholinergic Urticaria Activity Score have recently been added. Current treatment approaches for CU under development include drugs that inhibit the effects of signals that drive MC activation and accumulation, drugs that inhibit intracellular pathways of MC activation and degranulation, and drugs that silence MCs by binding to inhibitory receptors. The understanding, knowledge, and management of CU are rapidly increasing. The aim of this review is to provide physicians who treat CU patients with an update on where we stand and where we will go. Many questions and unmet needs remain to be addressed, such as the development of routine diagnostic tests for type I and type IIb autoimmune CSU, the global dissemination and consistent use of PROMs to assess disease activity, impact, and control, and the development of more effective and well-tolerated long-term treatments for all forms of CU

Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22

Chronic mucocutaneous candidiasis (CMC) constitutes a selective inability to clear infection with the yeast Candida, resulting in persistent debilitating inflammation of skin, nails, and mucous membranes. The underlying defect is unknown. Only recently, IL-17-producing T cells have been reported to be involved in clearing Candida infections. In order to characterize T cellular immune response to Candida, we analyzed T-cell cytokine secretion to Candida antigen and mitogenic stimuli in CMC patients, immunocompetent patients suffering from acute Candida infection, and healthy volunteers. Peripheral blood mononuclear cells (PBMCs) from CMC patients produced significantly lower amounts of IL-17 and IL-22 mRNA and protein when stimulated with Candida albicans or mitogen in vitro compared with that in matched healthy individuals. Additionally, PBMCs from immunocompetent Candida-infected patients secreted more IL-17 and IL-22 than those of both CMC patients and healthy, non-infected controls. Flow cytometry revealed a decreased number of CCR6+ IL-17-producing T cells in CMC patients, whereas the amount of CCR6+/CCR4+ cells was not altered. Levels of differentiating cytokines for human Th17 cells, IL-1β and IL-6, tended to be higher in CMC patients. The inability to clear C. albicans in CMC patients could be due to a defect in the immune response of IL-17-producing T cells

Spatial transcriptomics reveals altered lipid metabolism and inflammation-related gene expression of sebaceous glands in psoriasis and atopic dermatitis

Sebaceous glands drive acne, however, their role in other inflammatory skin diseases remains unclear. To shed light on their potential contribution to disease development, we investigated the spatial transcriptome of sebaceous glands in psoriasis and atopic dermatitis patients across lesional and non-lesional human skin samples. Both atopic dermatitis and psoriasis sebaceous glands expressed genes encoding key proteins for lipid metabolism and transport such as ALOX15B, APOC1, FABP7, FADS1/2, FASN, PPARG, and RARRES1. Also, inflammation-related SAA1 was identified as a common spatially variable gene. In atopic dermatitis, genes mainly related to lipid metabolism (e.g. ACAD8, FADS6, or EBP) as well as disease-specific genes, i.e., Th2 inflammation-related lipid-regulating HSD3B1 were differentially expressed. On the contrary, in psoriasis, more inflammation-related spatially variable genes (e.g. SERPINF1, FKBP5, IFIT1/3, DDX58) were identified. Other psoriasis-specific enriched pathways included lipid metabolism (e.g. ACOT4, S1PR3), keratinization (e.g. LCE5A, KRT5/7/16), neutrophil degranulation, and antimicrobial peptides (e.g. LTF, DEFB4A, S100A7-9). In conclusion, our results show that sebaceous glands contribute to skin homeostasis with a cell type-specific lipid metabolism, which is influenced by the inflammatory microenvironment. These findings further support that sebaceous glands are not bystanders in inflammatory skin diseases, but can actively and differentially modulate inflammation in a disease-specific manner

Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity