IL-17 in skin infections and homeostasis.

Interleukin (IL) 17 is a proinflammatory cytokine belonging to a structurally related group of cytokines known as the IL-17 family. It has been profoundly studied for its contribution to the pathology of autoimmune diseases. However, it also plays an important role in homeostasis and the defense against extracellular bacteria and fungi. IL-17 is important for epithelial barriers, including the skin, where some of its cellular targets reside. Most of the research work on IL-17 has focused on its effects in the skin within the context of autoimmune diseases or sterile inflammation, despite also having impact on other skin conditions. In recent years, studies on the role of IL-17 in the defense against skin pathogens and in the maintenance of skin homeostasis mediated by the microbiota have grown in importance. Here we review and discuss the cumulative evidence regarding the main contribution of IL-17 in the maintenance of skin integrity as well as its protective or pathogenic effects during some skin infections.

Expression of epidermal antimicrobial peptides is increased in tinea pedis.

BACKGROUND: Tinea pedis is often chronic or recurrent, but not all individuals are equally susceptible to this infection. Dermatophytes are able to induce the expression of antimicrobial peptides and proteins (AMPs) in human keratinocytes and certain AMPs can inhibit the growth of dermatophytes. OBJECTIVE: The focus of this study was to analyse the secretion of relevant AMPs, especially RNase 7, human beta-defensin-2 (hBD-2) and the S-100 protein psoriasin (S100A7), in patients with confirmed tinea pedis. METHODS: To verify the diagnosis, skin scales were obtained from all patients (n = 13) and the dermatophytes were identified by potassium hydroxide mount, culture and molecular analysis. To determine the AMP concentrations, the lesional skin area of the foot was rinsed with a buffer that was subsequently analysed by ELISA. The corresponding area of the other unaffected foot as well as defined healthy skin areas of the forearm and forehead and samples from age and gender-matched healthy volunteers served as controls. RESULTS: In tinea pedis patients the AMP concentrations were higher in lesional skin than in non-lesional skin and in healthy skin of controls. In particular, concentrations of hBD-2 and psoriasin were significantly elevated. CONCLUSIONS: The induction of AMPs in tinea pedis might be triggered directly by the dermatophytes; furthermore, attendant inflammation and/or differentiation processes may play a role. Our results indicate that there is no defect in the constitutive expression and induction of the analysed AMPs by dermatophytes in the epidermis of affected patients. However, it is not known why the elevated AMP concentrations fail to efficiently combat dermatophyte growth.

Exogenous factors in the pathogenesis of atopic dermatitis: Irritants and cutaneous infections.

Atopic dermatitis (AD) is a chronic relapsing inflammatory cutaneous disease that is often associated with other atopic symptoms, such as food allergy, allergic rhinitis and asthma, leading to significant morbidity and healthcare costs. The pathogenesis of AD is complicated and multifactorial. Although the aetiology of AD remains incompletely understood, recent studies have provided further insight into AD pathophysiology, demonstrating that the interaction among genetic predisposition, immune dysfunction and environmental provocation factors contributes to its development. However, the increasing prevalence of AD suggests that environmental factors such as irritation and cutaneous infection play a crucial role in triggering and/or aggravating the disease. Of note, AD skin is susceptible to bacterial, fungal and viral infections, and microorganisms may colonize the skin and aggravate AD symptoms. Overall, understanding the mechanisms by which these risk factors affect the cutaneous immunity of patients with AD is of great importance for developing a precision medicine approach for treatment. This review summarizes recent developments in exogenous factors involved in the pathogenesis of AD, with special emphasis on irritants and microbial infections.

Skin and Soft Tissue Infections in Non-Human Immunodeficiency Virus Immunocompromised Hosts.

Skin and soft tissue infections among the non-human immunodeficiency virus infected immunosuppressed population are a serious and growing concern. Many pathogens can cause cutaneous infections in these patients owing to the highly varied and profound immune deficits. Although patients can be infected by typical organisms, the diversity and antimicrobial-resistant nature of the organisms causing these infections result in significant morbidity and mortality. The diagnostic approach to these infections in immunocompromised hosts can differ dramatically depending on the potential causative organisms. An understanding of new immunosuppressive treatments and evolving antimicrobial resistance patterns are required to optimally manage these difficult cases.

Potential Synergistic Action of Bioactive Compounds from Plant Extracts against Skin Infecting Microorganisms.

The skin is an important organ that acts as a physical barrier to the outer environment. It is rich in immune cells such as keratinocytes, Langerhans cells, mast cells, and T cells, which provide the first line of defense mechanisms against numerous pathogens by activating both the innate and adaptive response. Cutaneous immunological processes may be stimulated or suppressed by numerous plant extracts via their immunomodulatory properties. Several plants are rich in bioactive molecules; many of these exert antimicrobial, antiviral, and antifungal effects. The present study describes the impact of plant extracts on the modulation of skin immunity, and their antimicrobial effects against selected skin invaders. Plant products remain valuable counterparts to modern pharmaceuticals and may be used to alleviate numerous skin disorders, including infected wounds, herpes, and tineas.

A 27-year-old man with recurrent sinopulmonary and cutaneous infections.

The increasing availability of genetic testing for modern immunologists in the evaluation of immune diseases could provide a definite diagnosis in elusive cases. A 27-year-old white male patient presented to the clinic with recurrent sinopulmonary and cutaneous infections since childhood. The patient's mother had seronegative polyarthritis, and one of two sisters of the patient had chronic sinopulmonary infections. Serum immunoglobulins, immunoglobulin G (IgG) subclasses, lymphocyte subset markers, mannose-binding lectin, mitogen and antigen stimulation, bacteriophage study, and Streptococcus pneumoniae titers to 23 serotypes were all normal. B-cell phenotyping revealed a decrease in both nonswitched memory B cells (CD19+CD27+IgD+) and switched memory B-cells (CD19+CD27+IgD-). Genetic testing and the improvement of clinical symptoms after IgG replacement led to the final diagnosis.

Cutaneous protothecosis in kidney transplant recipient

Abstract Protothecosis is a rare condition caused by the aclorophylated algae of the genus Prototheca. In humans, protothecosis, caused mainly by P. wickerhamii, manifests itself in three forms: cutaneous, articular and systemic. It can occur in both immunocompetent and immunosuppressed individuals, being much more common in the latter. We present a new case of protothecosis in Brazil in a kidney transplant recipient.

Cutaneous protothecosis in kidney transplant recipient.

Protothecosis is a rare condition caused by the aclorophylated algae of the genus Prototheca. In humans, protothecosis, caused mainly by P. wickerhamii, manifests itself in three forms: cutaneous, articular and systemic. It can occur in both immunocompetent and immunosuppressed individuals, being much more common in the latter. We present a new case of protothecosis in Brazil in a kidney transplant recipient.

Skin barrier immunity and ageing.

The skin is the outermost layer of the body with an extensive surface area of approximately 1·8 m2 , and is the first line of defence against a multitude of external pathogens and environmental insults. The skin also has important homeostatic functions such as reducing water loss and contributing to thermoregulation of the body. The structure of the skin and its cellular composition work in harmony to prevent infections and to deal with physical and chemical challenges from the outside world. In this review, we discuss how the structural cells such as keratinocytes, fibroblasts and adipocytes contribute to barrier immunity. We also discuss specialized immune cells that are resident in steady-state skin including mononuclear phagocytes, such as Langerhans cells, dermal macrophages and dermal dendritic cells in addition to the resident memory T cells. Ageing results in an increased incidence of cancer and skin infections. As we age, the skin structure changes with thinning of the epidermis and dermis, increased water loss, and fragmentation of collagen and elastin. In addition, the skin immune composition is altered with reduced Langerhans cells, decreased antigen-specific immunity and increased regulatory populations such as Foxp3+ regulatory T cells. Together, these alterations result in decreased barrier immunity in the elderly, explaining in part their increased susceptiblity to cancer and infections.

Intravital imaging of skin infections.

Intravital imaging of cutaneous immune responses has revealed intricate links between the skin's structural properties, the immune cells that reside therein, and the carefully orchestrated migratory dynamics that enable rapid sensing and subsequent elimination of skin pathogens. In particular, the development of 2-photon intravital microscopy (2P-IVM), which enables the excitation of fluorescent molecules within deep tissue with minimal light scattering and tissue damage, has proven an invaluable tool in the characterization of different cell subset's roles in skin infection. The ability to visualize cells, tissue structures, pathogens and track migratory dynamics at designated times following infection, or during inflammatory responses has been crucial in defining how immune responses in the skin are coordinated, either locally or in concert with circulating immune cells. Skin pathogens affect millions of people worldwide, and skin infections leading to cutaneous pathology have a considerable impact on the quality of life and longevity of people affected. In contrast, pathogens that infect the skin to later cause systemic illness, such as malaria parasites and a variety of arthropod-borne viruses, or infection in distant anatomical sites are a significant cause of morbidity and mortality worldwide. Here, we review recent advances and seminal studies that employed intravital imaging to characterize key immune response mechanisms in the context of viral, bacterial and parasitic skin infections, and provide insights on skin pathogens of global significance that would benefit from such investigative approaches.

Added value of inflammatory markers to vital signs to predict mortality in patients suspected of severe infection.

OBJECTIVE: To evaluate the added value of inflammatory markers to vital signs to predict mortality in patients suspected of severe infection. METHODS: This study was conducted at an acute care hospital (471-bed capacity). Consecutive adult patients suspected of severe infection who presented to either ambulatory care or the emergency department from April 2015 to March 2017 were retrospectively evaluated. A prognostic model for predicting 30-day in-hospital mortality based on previously established vital signs (systolic blood pressure, respiratory rate, and mental status) was compared with an extended model that also included four inflammatory markers (C-reactive protein, neutrophil-lymphocyte ratio, mean platelet volume, and red cell distribution width). Measures of interest were model fit, discrimination, and the net percentage of correctly reclassified individuals at the pre-specified threshold of 10% risk. RESULTS: Of the 1015 patients included, 66 (6.5%) died. The extended model including inflammatory markers performed significantly better than the vital sign model (likelihood ratio test: p < 0.001), and the c-index increased from 0.69 (range 0.67-0.70) to 0.76 (range 0.75-0.77) (p = 0.01). All included markers except C-reactive protein showed significant contribution to the model improvement. Among those who died, 9.1% (95% CI -2.8-21.8) were correctly reclassified by the extended model at the 10% threshold. CONCLUSIONS: The inflammatory markers except C-reactive protein showed added predictive value to vital signs. Future studies should focus on developing and validating prediction models for use in individualized predictions including both vital signs and the significant markers.

Predictors of hospital readmission in United States adults with psoriasis.

BACKGROUND: Previous studies showed a large inpatient burden of psoriasis in the United States. Less is known about the hospital readmission for psoriasis. OBJECTIVES: To determine the patterns and predictors of hospital readmission rates for psoriasis. METHODS: We analyzed data from the 2012-2014 Nationwide Readmissions Database, a representative sample of hospital readmissions in the United States. RESULTS: Among 2606 admissions for psoriasis, 216 had ≥1 readmissions for psoriasis (prevalence [95% confidence interval]: 8.3% [6.6%-10.0%]) and 918 for all-causes (35.2% [32.2%-38.3%]). The mean annual cost of first readmission for any reason was $3,500,141, with $8,357,961 for subsequent readmissions. In multivariable regression models, readmission for psoriasis was associated with ≥6 day-long index hospitalization (adjusted hazard ratio [95% confidence interval]: 1.82 [1.06-3.12]), teaching hospital (1.93 [1.13-3.31]), comorbid skin infection (2.13 [1.11-4.08]), and hospitalization in the autumn (4.51 [2.54-8.00]), but inversely associated with other infections (0.49 [0.26-0.92]). Readmissions for psoriasis increased from 2012 to 2014 (1.93 [1.26-2.93]). LIMITATIONS: No data on psoriasis characteristics. CONCLUSION: Inpatients with psoriasis had high rates of readmission overall but low rates of readmission for psoriasis per se. A subset of psoriasis patients was hospitalized repeatedly and responsible for most inpatients costs. Future interventions are needed to lower readmission rates among psoriasis patients.

Protective and pathogenic roles of resident memory T cells in human skin disorders.

The human skin is populated by recirculating T cells and skin-sessile resident memory T cells (TRM). Skin TRM are constructed during immune responses against antigens that the host immune system encounters in the skin. TRM persist in the same sites for a long time and play important protective roles in skin immune responses in collaboration with other skin-composing cells such as dendritic cells and keratinocytes. These TRM with strong effector functions possibly also engender skin inflammatory disorders. Since human skin T cells, especially TRM, are phenotypically distinct from T cells in the blood circulation, T cells residing in the skin should be directly investigated, without presuming from the activities of blood T cells, in order to understand the functional characteristics of skin T cells in skin disorders. This review summarizes the features of human skin TRM and reviews the immunopathological involvement of TRM in human skin disorders such as infectious disease, inflammatory skin disease, and malignant skin tumors.

Connecting the Dots: From Skin Barrier Dysfunction to Allergic Sensitization, and the Role of Moisturizers in Repairing the Skin Barrier

The skin is one of the largest immunologic organs in the body and a continuous target for allergic and immunologic responses. Impairment of the skin barrier increases the likelihood of external antigens and pathogens entering and creating inflammation, which can potentially lead to skin infections, allergies, and chronic inflammatory diseases such as atopic and contact dermatitis. Functionally, the skin barrier can be divided into four different levels. From outermost to innermost, these highly interdependent levels are the microbiome, chemical, physical, and immune levels. The objective of this review is to provide an update on current knowledge about the relationship between skin barrier function and how dysfunction at each level of the skin barrier can lead to allergic sensitization, contact dermatitis, and the atopic march, and examine how to best repair and maintain this barrier through the use of moisturizers. J Drugs Dermatol. 2019;18(6):581-586.

The relationship between Toxocara species seropositivity and allergic skin disorders: a systematic review and meta-analysis.

We performed a systematic review and meta-analysis on observational studies to evaluate the possible associations between Toxocara species seropositivity and allergic skin disorders (ASDs). We searched the MEDLINE, ScienceDirect, Scopus, Web of Science and Google Scholar databases to 15 May 2018 to identify the relevant studies. We used a random effects meta-analysis model to generate the pooled odds ratio (OR) and 95% confidence intervals (CIs). Fifteen studies, including eight studies with a case-control design (735 patients and 1342 controls) and seven studies with a cross-sectional design (a total of 4804 participants, 1302 individuals with ASDs and 3502 without ASDs), were included in the meta-analysis. We found an increased risk for ASDs in individuals with Toxocara seropositivity (OR 1.75 [95% CI 1.16 to 2.64]). Subanalysis showed that Toxocara seropositivity was significantly associated with urticaria (OR 2.97 [95% CI 1.53 to 5.76]), however, it was not significantly associated with atopy (OR 1.08 [95% CI 0.55 to 2.15]) and eczema (OR 1.62 [95% CI 0.95 to 2.78]). Moreover, the pooled ORs were 2.34 (95% CI 1.32 to 4.15) and 1.27 (95% CI 0.69 to 2.35) for case-control and cross-sectional studies, respectively. The results of our study support hypotheses regarding the existence of a positive relationship between Toxocara infection and allergic disorders, although this association should be further investigated by longitudinal and mechanism studies.

Infectious events and associated risk factors in mycosis fungoides/Sézary syndrome: a retrospective cohort study.

BACKGROUND: Infections are one of the major causes of death in patients with advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS). However, few recent data are available on the characteristics and risk factors of these infectious events. OBJECTIVES: To describe infectious events occurring in a cohort of patients with MF/SS, and to identify associated clinical and biological risk factors. METHODS: A retrospective cohort study was performed to investigate infectious events and associated factors in patients diagnosed with MF (stage IB and beyond) or SS followed from May 2011 to May 2016 at the University Hospital of Bordeaux, France. RESULTS: Seventy-one patients with complete follow-up were included. Eighty infectious events were recorded in 40 patients, including 28 skin and soft tissue infections and 25 cases of pneumonia. Opportunistic infections, which are usually associated with depleted cell-mediated immunity, were scarce (9%). In multivariate analysis, cardiac, renal or lung comorbidities [odds ratio (OR) 7·2, 95% confidence interval (CI) 3·3-15·9; P = 0·002], SS (OR 8·8, 95% CI 7·7-10·2; P = 0·037) and lymphocyte count < 0·5 × 109 cells L-1 (OR 6·4, 95% CI 1·5-27·4; P = 0·004) were significantly associated with a higher risk of infection. CONCLUSIONS: Opportunistic germs were rarely recorded, but their incidence was probably prevented by adequate prophylaxis (ongoing in 28% of patients). As in patients living with AIDS, pneumonias were frequent. On the other hand, bacterial cutaneous infections represent a specific pattern in patients with MF/SS. Patients with chronic organ failure, lymphocytopenia and SS should be considered as being at high risk for infectious events. Pneumococcal vaccination should be systematically recommended, and prophylaxis with co-trimoxazole and valaciclovir when the CD4 count is < 0·2 × 109 cells L-1 .

The endocannabinoid system of the skin. A potential approach for the treatment of skin disorders.

The skin is the largest organ of the body and has a complex and very active structure that contributes to homeostasis and provides the first line defense against injury and infection. In the past few years it has become evident that the endocannabinoid system (ECS) plays a relevant role in healthy and diseased skin. Specifically, we review how the dysregulation of ECS has been associated to dermatological disorders such as atopic dermatitis, psoriasis, scleroderma and skin cancer. Therefore, the druggability of the ECS could open new research avenues for the treatment of the pathologies mentioned. Numerous studies have reported that phytocannabinoids and their biological analogues modulate a complex network pharmacology involved in the modulation of ECS, focusing on classical cannabinoid receptors, transient receptor potential channels (TRPs), and peroxisome proliferator-activated receptors (PPARs). The combined targeting of several end-points seems critical to provide better chances of therapeutically success, in sharp contrast to the one-disease-one-target dogma that permeates current drug discovery campaigns.

[Cutaneous manifestations in primary immunodeficiency diseases]. / Az elsodleges immunhiány-betegségek bormanifesztációi.

Primary immunodeficiency diseases (PIDs) are inherited, genetic disorders. The majority of PIDs are diagnosed in infancy or early childhood, but manifestation in adulthood may also occur. Frequent, recurrent and prolonged infections, which respond poorly to treatment may be heralding signs. PID patients may have increased suspectibility to infections, that mostly affect the sino-pulmonary and intestinal tracts and the skin. PIDs are also frequently associated with autoimmune and inflammatory disorders. Cutaneous manifestations affect 40% to 70% of patients with diagnosed PID. Bacterial and fungal infections of the skin, recurrent pyogen abscesses are common complications. Severe atopy, eczema and erythroderma occurring early in childhood should raise awareness of PID. Cutaneous granulomas, pigment changes and dysplasia of skin, hair, and nails can also be seen frequently in some of these conditions. Here we overview the most frequent dermatological diseases occuring in patients with PID. Orv Hetil. 2018; 159(23): 937-947.