“Inflammatory skin march” in atopic dermatitis and psoriasis

Background

Comorbidities of cardiovascular diseases (CVDs), metabolic syndrome and autoimmune diseases with systemic inflammation are recent topics in medicine. Inflammatory skin diseases such as atopic dermatitis and psoriasis are an active source of diverse proinflammatory cytokines and chemokines, which are readily detectable in the circulation and are likely to be involved in developing comorbidities.

Evidence

Both atopic dermatitis and psoriasis are frequently comorbid with CVD, metabolic syndrome and autoimmune diseases, the consequence of which is called “inflammatory skin march”, “psoriatic march” or “march of psoriasis”.

Conclusion

In this review, we summarize the epidemiological evidence and pathogenetic concepts regarding inflammatory skin march in atopic dermatitis and psoriasis.

     

Food allergy in patients suffering from atopic dermatitis – association with concomitant allergic diseases

A few reports demonstrate the relationship between food allergy in atopic dermatitis patients and other allergic diseases and parameters. The objective of this study is to evaluate if some food allergens has the relationship to the occurrence of other atopic diseases and parameters. The following parameters were examined: food allergy to wheat flour, cow milk, egg, peanuts and soy; the occurrence of asthma bronchiale and rhinitis; duration of atopic dermatitis; family history; pollen allergy and onset of atopic dermatitis. The statistical evaluation of the relations among food allergy and monitored parameters was performed. Two hundred and seventy two patients were examined (87 men, 185 women). In general, atopic dermatitis patients with confirmed food allergy suffer significantly more often from rhinitis, asthma bronchiale, persistent eczematic lesions and pollen allergy and have positive data about atopy in their family history. Peanuts, soy and wheat are of great importance.     

Does allergen-specific immunotherapy represent a therapeutic option for patients with atopic dermatitis?

House dust mite (HDM) allergens are perennial indoor allergens, which may play a role as allergic trigger factors in atopic dermatitis (AD). Facilitated by their high enzymatic activity, HDM allergens are capable of penetrating the impaired epidermal skin barrier in patients with AD, gaining access to immune cells. In this way, HDM allergens induce both allergic reactions of the immediate type and allergic reactions of the delayed type, which contribute to impairment of AD. Because allergen reduction achieved by encasing strategies does not always lead to significant improvement of clinical symptoms, specific immunotherapy (SIT) might represent an attractive therapeutic option for long-time treatment of this subgroup of patients with AD. However, systematic studies on the effectiveness of SIT in patients with AD are rare. Furthermore, data on the immunologic changes induced by SIT in patients with AD are not well studied. In this review, we provide an overview of the pathogenic impact of HDM allergens as an example for aeroallergens on the course of AD. In addition, we discuss prophylactic and therapeutic options for the treatment of HDM allergy in patients with AD, including a summary of the current data available on SIT as a potential therapeutic option for patients with AD.     

Risk of COVID-19 and its complications in patients with atopic dermatitis undergoing dupilumab treatment—a population-based cohort study

The risk of coronavirus disease (COVID-19) infection and its complications among patients with atopic dermatitis (AD) treated by dupilumab is yet to be determined. We aimed to assess the risk of SARS-CoV-2 infection, COVID-19-associated hospitalization, and mortality among patients with AD treated by dupilumab. A population-based cohort study was conducted to compare AD patients treated by dupilumab (n?=?238) with those treated by prolonged systemic corticosteroids (≥?3 months; n?=?1,023), phototherapy (n?=?461), and azathioprine or mycophenolate mofetil (MMF; n?=?194) regarding the incidence of COVID-19 and its complications. The incidence rate of COVID-19, COVID-19-associated hospitalization, and mortality among patients treated by dupilumab was 70.1 (95% CI, 40.5–116.4), 5.0 (95% CI, 0.3–24.7), and 0.0 per 1,000 person-year, respectively. The use of dupilumab was not associated with an increased risk of SARS-CoV-2 infection [adjusted HR for dupilumab vs. prolonged systemic corticosteroids: 1.13 (95% CI, 0.61–2.09); dupilumab vs. phototherapy: 0.80 (95% CI, 0.42–1.53); dupilumab vs. azathioprine/MMF: 1.10 (95% CI, 0.45–2.65)]. Dupilumab was associated with a comparable risk of COVID-19-associated hospitalization [adjusted HR for dupilumab vs. prolonged systemic corticosteroids: 0.35 (95% CI, 0.05–2.71); dupilumab vs. phototherapy: 0.43 (95% CI, 0.05–3.98); dupilumab vs. azathioprine/MMF: 0.25 (95% CI, 0.02–2.74)]. When applicable, the risk of mortality was not elevated in patients with AD treated by dupilumab [HR for dupilumab vs. prolonged systemic corticosteroids: 0.04 (95% CI, 0.00–225.20)]. To conclude, dupilumab does not impose an increased risk of SARS-CoV-2 infection or COVID-19 complications in patients with AD. Dupilumab should be continued and considered as a safe drug for moderate-to-severe AD during the pandemic.

     

Association of CD14 and TLR4 with LPS-stimulated human normal skin fibroblasts in immunophenotype changes and secretion of TGF-β1 and IFN-γ

Objectives: We attempted to explore the association of CD14 and TLR4 with LPS-stimulated human normal skin fibroblasts in immunophenotype changes and secretion of TGF-β1 and IFN-γ, and to expand the current knowledge of the mechanisms that underlie LPS-induced scar formation. Methods: We randomized the human normal skin fibroblasts cultured in vitro into four groups. The expression profile of immune phenotypes was determined by immunohistochemical staining. Ultrastructure of cells was observed by use of transmission electron microscopy. Secretion status of TGF-β1 and IFN-γ was inspected using ELISA assay. Results: Compared with group A, the expressions of α-SMA and α1 (I) procollagen in groups B, C, D were lower, and it in group D were the lowest in all groups. The cells in group A were diversification under the electron microscope, and the ratio of the nuclear to plasma of the fibroblasts was large, with unregular nuclear membrane, more Golgi apparatus, rough endoplasmic reticulum, and microfilament and canaliculus appeared. The ultrastructure of the fibroblasts in group B, C, D was spindle and the nuclear was large, with regular nuclear membrane, more Golgi apparatus, rough endoplasmic reticulum. ELISA assay indicated that the secretion of TGF-β1 markedly lowered in groups B, C, D in comparison to group A, with the most marked decline observed in group D. Interestingly, we found significantly increased IFN-γ secretion in groups B, C, D (P < 0.05), with the latter group showing the most notable increase (P < 0.01). Conclusion: These data suggest that both combined and isolated use of CD14 and TLR4 significantly reduce α-SMA expression levels, the number of α1 (I) pro-collagen positive cells, and TGF-β secretion, while substantially increased IFN-γ secretion. The reduction and increase are especially notable when pretreating with CD14 and TLR4 combined. Here we thus draw a conclusion that both CD14 and TLR4 are associated with the immunophenotype changes and secretion of TGF-β1 and IFN-γ in LPS-stimulated human normal skin fibroblasts.     

What plays a role in the severity of atopic dermatitis in children?

Background/aim Determining the characteristics and risk factors of severe disease is extremely important to combat atopic dermatitis (AD), which has recently shown increasing prevalence. In this study, we aimed to investigate the clinical characteristics of pediatric patients with AD and identifying the factors associated with the severity of the disease.Materials and methods A total of 304 pediatric patients diagnosed with atopic dermatitis were included in the study. The patients’ age at admission, age at onset of symptoms, the presence of atopy history in their family, eosinophil levels obtained from blood counts were recorded, together with the data of cigarette exposure, and area of residence. Disease severity was determined according to the SCORAD index. Epidermal prick tests (EPT) were applied to all patients.Results There was a negative correlation between the SCORAD score and both age at admission (r = 0.277, p < 0.001) and age at onset of the symptoms (r = –0.474, p < 0.001). Food sensitization rates were higher in individuals with moderate-severe disease (90.7% vs. 23.1%; p < 0.001) and patients with food allergy (FA) had significantly higher SCORAD scores [33 (IQR: 22–44) vs. 14 (IQR: 12–16); p < 0.001]. SCORAD scores of the individuals living in rural areas were higher than the ones living in urban [22 (IQR: 15–39.5) vs. 15 (IQR: 12–22); p < 0.001]. Familial atopy history was more common in patients with moderate-severe disease (66.5% vs. 17.5%; p < 0.001). The SCORAD scores were higher in patients exposed to passive smoking [21 (IQR:14.75–38) vs. 13 (IQR: 12–16); p < 0.001]. The eosinophil count found to be positively correlated with SCORAD scores (r = 0.531, p < 0.001).Conclusion Our findings show that early-onset, food sensitivity, living in rural areas, having familial atopy history and passive cigarette smoke exposure play a role in severe AD. Since it is remarkably correlated with SCORAD scores, eosinophil count can be used as a marker to assess the severity of AD in children.     

Expression density of receptors to IL-1β in atopic dermatitis

Interleukin 1 (IL-1 β) and the system for regulation of its biological effects play an important role in the development and behavior of inflammatory processes in atopic dermatitis. Notably, cells that are actively involved in the pathological process have altered expression of cytokine receptors. However, standard evaluation of cells by flow cytometry measures only the percentage of cells expressing the appropriate marker, which is not enough for a full assessment of these changes. The aim of this study was to investigate changes in the expression of IL-1β cytokine receptors in patients with atopic dermatitis by both percentage of cells with receptors in various subsets and the absolute number of membrane-bound receptors themselves. It was found that an increase or decrease in the percentage of cells expressing the receptors in subsets of immune cells in patients with atopic dermatitis was not associated with a change in the number of receptors on the cell surface. Moreover, the changes in the percentage of cells and the number of receptors may occur in different directions, as shown for IL-1R2 expression on B cells and IL-1R1 expression for monocytes. Changes in the parameters of IL-1β receptor expressions are associated with disease severity index SCORAD in atopic dermatitis. These findings underline the importance of studying the density of cytokine receptor expression in the pathology.     

Effect of amino acid substitutions in the human IFN-γR2 on IFN-γ responsiveness

Patients with interferon-γ receptor (IFN-γR) null mutations have severe infections with poorly pathogenic Mycobacteria. The IFN-γR complex involves two IFN-γR1 and two IFN-γR2 chains, in which several amino acid substitutions, some linked to disease and some apparently naturally occurring, have been described. We developed a model system to study functional effects of genetic variations in IFN-γR2. We retrovirally transduced wild-type IFN-γR2 and IFN-γR2 carrying presently known amino acid substitutions in various human cell lines, and next determined the IFN-γR2 expression pattern as well as IFN-γ responsiveness. We determined that the T58R, Q64R, E147K and K182E variants of IFN-γR2 are fully functional, although the Q64R variant may be expressed higher on the cell membrane. The R114C, T168N and G227R variants were identified in patients that had disseminated infections with non-tuberculous Mycobacteria. Of these genetic variants, T168N was confirmed to be completely non-functional, whereas the novel variant G227R, and the previously reported R114C, were partial functional. The impaired IFN-γ responsiveness of R114C and G227R is mainly due to reduced receptor function, although expression on the cell membrane is reduced as well. We conclude that the T58R, Q64R, E147K and K182E variants are polymorphisms, whereas the R114C, T168N and G227R constitute mutations associated with disease.     

Overexpression of phospholipase Cε in keratinocytes upregulates cytokine expression and causes dermatitis with acanthosis and T-cell infiltration

Phospholipase Cε (PLCε) is an effector of Ras and Rap small GTPases. We showed previously using PLCε-deficient mice that PLCε plays a critical role in activation of cytokine production in non-immune skin cells in a variety of inflammatory reactions. For further investigation of its role in inflammation, we created transgenic mice overexpressing PLCε in epidermal keratinocytes. The resulting transgenic mice spontaneously developed skin inflammation as characterized by formation of adherent silvery scales, excessive growth of keratinocytes, and aberrant infiltration of immune cells such as T cells and DC. Development of the skin symptoms correlated well with increased expression of factors implicated in human inflammatory skin diseases, such as IL-23, in keratinocytes, and with the accumulation of CD4(+) T cells producing IL-22, a potent inducer of keratinocyte proliferation. Intradermal injection of a blocking antibody against IL-23 as well as treatment with the immunosuppressant FK506 reversed these skin phenotypes, which was accompanied by suppression of the IL-22-producing T-cell infiltration. These results reveal a crucial role of PLCε in the development of skin inflammation and suggest a mechanism in which PLCε induces the production of cytokines including IL-23 from keratinocytes, leading to the activation of IL-22-producing T cells.     

Dengue virus infection of human skin fibroblasts in vitro production of IFN-β, IL-6 and GM-CSF

Summary Dengue virus is transmitted to humans by the bite of infected mosquitos. In our efforts to understand the pathogenesis of dengue virus infection, we examined whether skin fibroblasts can be infected in vitro with dengue viruses. Fibroblasts could be infected with dengue viruses, yellow fever virus and West Nile virus. Dengue virus antigen-positive cells were detected as early as 4h and the percentage of dengue virus antigen-positive cells reached maximum levels by 24h after infection. High titers of infectious dengue virus were also detected in the culture supernatants at 20h after infection. Dengue virus-infected fibroblasts produced interferon- (IFN-), and the IFN- protected uninfected fibroblasts from dengue virus infection. Dengue virus-infected fibroblasts also produced interleukin 6 (IL-6) and granulocyte macrophage colony stimulation factor (GM-CSF).These results suggest that skin fibroblasts may be one of the cell types which first support dengue virus and other flavivirus infections in vivo after introduction by the bite of infected mosquito, and that production of IFN-, IL-6, and GM-CSF by these virus-infected fibroblasts may be important host immune responses to control flavivirus infections.     

Shikonin inhibits IFN-γ-induced K17 over-expression of HaCaT cells by interfering with STAT3 signaling

Objectives: We hypothesized that interferon-γ (IFN-γ) induces K17 over-expression in HaCaT cells by activating STAT3 and that Sh might inhibit the over-expression through interference of STAT3 signaling. Methods: In vitro culture of HaCaT cells treated with IFN-γ and measurement of K17 protein by enzyme linked immunosorbent assay. Results: The level of K17 protein (one kind of keratin protein) in the supernatant induced by IFN-γ was significantly reduced by Shikonin at various concentrations. Interference of STAT3 suppressed the effect of IFN-γ on K17 expression at both mRNA and protein levels. The over-expression of K17 in IFN-γ-induced HaCaT cells was significantly suppressed by 2 µg/L Shikonin. Interfering with STAT3 signaling with 2 µg/L Shikonin resulted in an intermediate level of IFN-γ-induced K17 protein in HaCaT cells. Conclusions: These data demonstrate that IFN-γ induces K17 protein over-expression of HaCaT cells by activating STAT3 and Shikonin may inhibit the over-expression partly through interference of STAT3.