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Regulatory T-cell dysfunction and cutaneous exposure to Staphylococcus aureus underlie eczema in DOCK8 deficiency

Wilkie H, Das M, Pelovitz T, Bainter W, Woods B, Alasharee M, et al.

J Allergy Clin Immunol, 2024 Jul;154(1):143-156.
PMID: 38185418 DOI: 10.1016/j.jaci.2023.12.020

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8)-deficient patients have severe eczema, elevated IgE, and eosinophilia, features of atopic dermatitis (AD).
OBJECTIVE: We sought to understand the mechanisms of eczema in DOCK8 deficiency.
METHODS: Skin biopsy samples were characterized by histology, immunofluorescence microscopy, and gene expression. Skin barrier function was measured by transepidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous sensitization with ovalbumin (OVA) or cutaneous application of Staphylococcus aureus.
RESULTS: Skin lesions of DOCK8-deficient patients exhibited type 2 inflammation, and the patients' skin was colonized by Saureus, as in AD. Unlike in AD, DOCK8-deficient patients had a reduced FOXP3:CD4 ratio in their skin lesions, and their skin barrier function was intrinsically intact. Dock8-/- mice exhibited reduced numbers of cutaneous T regulatory (Treg) cells and a normal skin barrier. Dock8-/- and mice with an inducible Dock8 deletion in Treg cells exhibited increased allergic skin inflammation after epicutaneous sensitization with OVA. DOCK8 was shown to be important for Treg cell stability at sites of allergic inflammation and for the generation, survival, and suppressive activity of inducible Treg cells. Adoptive transfer of wild-type, but not DOCK8-deficient, OVA-specific, inducible Treg cells suppressed allergic inflammation in OVA-sensitized skin of Dock8-/- mice. These mice developed severe allergic skin inflammation and elevated serum IgE levels after topical exposure to Saureus. Both were attenuated after adoptive transfer of WT but not DOCK8-deficient Treg cells.
CONCLUSION: Treg cell dysfunction increases susceptibility to allergic skin inflammation in DOCK8 deficiency and synergizes with cutaneous exposure to Saureus to drive eczema in DOCK8 deficiency.

Matched MeSH terms: Dermatitis, Atopic/immunology
Sensitization to Local Seafood Allergens in Adult Patients with Atopic Dermatitis in Malaysia

Lee HL, Tang MM, Bakhtiar MF, Mohamad Yadzir ZH, Johar A

Int Arch Allergy Immunol, 2021;182(2):153-157.
PMID: 32927463 DOI: 10.1159/000510314

BACKGROUND: Seafood is an important source of nutrition in Asia. However, it was believed to cause or aggravate atopic dermatitis (AD).
OBJECTIVES: We aim to determine relevant seafood sensitization among adults with AD and investigate cross-sensitization to aeroallergens.
METHODS: One hundred thirty-two adults with AD who were subjected to skin prick test (SPT) with 7 common local seafood allergens (anchovy, tuna, mackerel, squid, giant freshwater prawn, shrimp, and crab), house dust mites (HDMs), and cockroach were analyzed retrospectively.
RESULTS: The median age of the study subjects was 32 years (range 17-77 years) with a male to female ratio of 1:3. The mean duration of AD was 16 years. Eighty-two patients (62.2%) had other atopic conditions. Using SCORAD, 44.7% had mild, 42.4% moderate, and 12.9% severe disease. Eighty-six patients (65.2%) self-reported to have seafood allergy, with the main symptoms of transient pruritus and erythema within 2 h of ingestion. SPT revealed 51.5% of the patients were sensitized to at least 1 of the 7 seafood allergens. The relevant sensitization rate was 45.1%. Interestingly, 46% of those without a history of seafood allergy developed at least 1 positive reaction in the SPT. Prawn, shrimp, and crab were the 3 most frequently sensitized allergens. Nearly all patients (98.3%) who were sensitized to crustaceans were also sensitized to HDMs and/or cockroach. There was no significant correlation between a positive SPT to seafood with age, age of onset of AD, duration, and severity of AD, and the presence of other atopic diatheses.
CONCLUSION: The relevant sensitization rate of local seafood among adults with AD was 45.1%.

Matched MeSH terms: Dermatitis, Atopic/immunology*
A systematic review on the off-label use of montelukast in atopic dermatitis treatment

Chin WK, Lee SWH

Int J Clin Pharm, 2018 Oct;40(5):963-976.
PMID: 29777328 DOI: 10.1007/s11096-018-0655-3

Background Atopic dermatitis (AD) is the most common form of eczema. As leukotriene mediators are involved in the inflammatory phase of atopic dermatitis, montelukast has been suggested as a possible therapy. Aim of the review To evaluate the safety and efficacy of montelukast off-label use for the treatment atopic dermatitis. Method A search was performed from database inception until March 2018 in six electronic databases for randomized-controlled-trials examining the use of montelukast for AD. Results Among 301 articles screened, 11 studies met the inclusion criteria and were included in the review. The study populations consist of paediatric and adult subjects with moderate-to-severe AD. Montelukast use was shown to improve symptoms such as pruritus in four studies. Another 2 studies reported that montelukast could improve symptoms similar to the standard regimen of topical steroid and oral antihistamine. However, five studies reported that montelukast had no effects in symptoms alleviation. The use of montelukast was associated with a similar safety profile to placebo and well-tolerated with minimal adverse effects. Conclusion There is limited evidence to suggest that the off-label use of montelukast is effective in treating moderate-to-severe AD. Further research with larger study populations employing standardized endpoint measuring instrument is warranted to further investigate the off-label use of montelukast in AD treatment. Until then, the use of conventional treatments including optimal daily skin hydration should remain the mainstay in the management of atopic dermatitis. In fact, for moderate-to-severe condition, steroid sparing immune-suppressants should still be used clinically until more effective and safer alternative is discovered.

Matched MeSH terms: Dermatitis, Atopic/immunology
The detection of house dust mite Dermatophagoides farinae, Der f 2 and Zen-1 allergen-specific immunoglobulin E antibodies in dogs with atopic Dermatitis in Malaysia

Chan WY, Selvarajah GT, Ajat M, Suzuki R, Tsukui T

Vet Immunol Immunopathol, 2019 Jun;212:43-49.
PMID: 31213251 DOI: 10.1016/j.vetimm.2019.05.002

Canine atopic dermatitis (AD) is a chronic, inflammatory and pruritic allergic skin disease in dogs. House dust mites such as Dermatophagoides farinae are one of the known causative agents for the induction of canine AD worldwide. D. farinae protein Der f 2 is known as an important allergen involved in canine AD and recently, Zen-1 has also been identified as an allergenic protein. There is limited information on the prevalence and role of allergen sensitization to crude D. farinae extract (CDF), Der f 2 and Zen-1 among dogs diagnosed with AD in Malaysia. The aim of this study was to determine the proportion of CDF-, Der f 2- and Zen-1-specific reactive sera among dogs diagnosed with AD in Malaysia using an enzyme-linked immunosorbent assay (ELISA). Serum samples were collected from dogs diagnosed with AD from several veterinary clinics in Malaysia. The canine case records were retrieved and information on signalment, dermatological and non-dermatological histories, clinical presentation, food allergies, and exclusion of ectoparasitic, microbial and fungal skin infections were obtained through a survey form. All serum samples were evaluated to quantify the CDF-, Der f 2- and Zen-1-specific immunoglobulin E (IgE) levels. A total of 24.6%, 48.4% and 29.8% of dogs diagnosed with AD were positive for CDF-, Der f 2- and Zen-1-specific IgE, respectively. These results suggest that CDF-, Der f 2- and Zen-1 are important allergens that can contribute to AD in dogs in Malaysia, and serological testing can be performed to provide additional treatment options involving specific immunotherapies.

Matched MeSH terms: Dermatitis, Atopic/immunology
Phytomedicines are Efficient Complementary Therapies for the Treatment of Atopic Dermatitis: A Review of Mechanistic Insight and Recent Updates

Tumpang MA, Ramli NA, Hussain Z

Curr Drug Targets, 2018;19(6):674-700.
PMID: 28914203 DOI: 10.2174/1389450118666170913162147

BACKGROUND: Phytomedicines have been well-accepted alternative complementary therapies for the treatment of a wide range of acute and chronic skin inflammatory diseases including chronic herpes, prurigo, psoriasis, and atopic dermatitis (AD). A plethora of in vitro and in vivo studies have evidenced the therapeutic viability of phytomedicines, polyherbal formulations, plant-based materials and their decoctions for the treatment of mild-to-severe AD.
OBJECTIVE: This review was aimed to summarize and critically discuss the convincing evidence for the therapeutic effectiveness of phytomedicines for the treatment of AD and explore their anti-AD efficacy.
RESULTS: The critical analysis of a wide algorithm of herbal medicines revealed that their remarkable anti-AD efficacy is attributed to their potential of reducing erythema intensity, oedema, inflammation, transepidermal water loss (TEWL) and a remarkable suppression of mRNA expression of ADassociated inflammatory biomarkers including histamine, immunoglobulin (Ig)-E, prostaglandins, mast cells infiltration and production of cytokines and chemokines in the serum and skin biopsies.
CONCLUSION: In conclusion, herbal medicines hold great promise as complementary and alternative therapies for the treatment of mild-to-moderate AD when used as monotherapy and for the treatment of moderate-to-severe AD when used in conjunction with other pharmacological agents.

Matched MeSH terms: Dermatitis, Atopic/immunology
Fulltext Topical Lyogel Containing Corticosteroid Decreases IgE Expression and Enhances the Therapeutic Efficacy Against Atopic Eczema

Ng SF, Anuwi NA, Tengku-Ahmad TN

AAPS PharmSciTech, 2015 Jun;16(3):656-63.
PMID: 25511806 DOI: 10.1208/s12249-014-0248-y

Hydrocortisone cream intended for atopic eczema often produces unwanted side effects after long-term use. These side effects are essentially due to repeated percutaneous administration of the medication for skin dermatitis, as atopic eczema is a relapsing disorder. Hence, there is a need to develop a new hydrocortisone formulation that will deliver the drug more effectively and require a reduced dosing frequency; therefore, the side effects could be minimized. In this study, a hydroxypropyl methylcellulose (HPMC) lyogel system based on 80% organic and 20% aqueous solvents containing 1% hydrocortisone was formulated. The hydrocortisone lyogel physicochemical characteristics, rheological properties, stability profile, and in vitro Franz cell drug release properties, as well as the in vivo therapeutic efficacies and dermal irritancy in Balb/c mice were investigated. The HPMC lyogel appeared clear and soft and was easy to rub on the skin. The lyogel also showed a higher drug release profile compared with commercial hydrocortisone cream. Similar to the cream, HPMC lyogels exhibited pseudoplastic behavior. From the mouse model, the hydrocortisone lyogel showed higher inflammatory suppressive effects than the cream. However, it did not reduce the transepidermal water loss as effectively as the control did. The dermal irritancy testing revealed that the hydrocortisone lyogel caused minimal irritation. In conclusion, HPMC lyogel is a promising vehicle to deliver hydrocortisone topically, as it showed a higher drug release in vitro as well as enhanced therapeutic efficacy in resolving eczematous inflammatory reaction compared with commercial cream.

Matched MeSH terms: Dermatitis, Atopic/immunology
Fulltext Downregulation of immunological mediators in 2,4-dinitrofluorobenzene-induced atopic dermatitis-like skin lesions by hydrocortisone-loaded chitosan nanoparticles

Hussain Z, Katas H, Mohd Amin MC, Kumolosasi E, Sahudin S

Int J Nanomedicine, 2014;9:5143-56.
PMID: 25395851 DOI: 10.2147/IJN.S71543

Atopic dermatitis is a chronic, noncontiguous, and exudative disorder accompanied by perivascular infiltration of immune mediators, including T-helper (Type 1 helper/Type 2 helper) cells, mast cells, and immunoglobulin E. The current study explores the immunomodulatory and histological effects of nanoparticle (NP)-based transcutaneous delivery of hydrocortisone (HC).

Matched MeSH terms: Dermatitis, Atopic/immunology*
Artesunate attenuates 2, 4-dinitrochlorobenzene-induced atopic dermatitis by down-regulating Th17 cell responses in BALB/c mice

Bai XY, Liu P, Chai YW, Wang Y, Ren SH, Li YY, et al.

Eur J Pharmacol, 2020 May 05;874:173020.
PMID: 32087254 DOI: 10.1016/j.ejphar.2020.173020

Steroidal agent is a standard clinical treatment of atopic dermatitis; however, have serious side effects. Artesunate is reported to exhibit anti-inflammatory properties although its effect on atopic eczema remains unknown. We investigated the therapeutic effects and possible mechanism of systemic artesunate on DNCB-induced atopic dermatitis in a BALB/c mouse model. To ascertain artesunate (5 and 10 mg/kg) efficacy, skin dermatitis severity and ear, spleen, and lymph node weight were evaluated. Skin tissue mRNA and protein expression and serum cytokine levels were examined. Artesunate significantly improved atopic dermatitis symptoms, decreasing the dermatitis score, ear weight difference, spleen weight, and lymph node weight compared with those following DNCB treatment. Artesunate reduced ear and skin epidermal thickness and mast cell infiltration, as determined using hematoxylin-eosin and toluidine blue staining, respectively. The basal level of IgE (287.67 ± 70.41 ng/ml) and TNF-α (19.94 ± 3.98 pg/ml) were Significantly elevated by DNCB (IgE: 1273.23 ± 176.53 ng/ml; TNF-α: 57.53 ± 3.87 pg/ml), while markedly been suppressed in the treatment group (AS-L: IgE: 1100.25 ± 135.32 ng/ml; TNF-α: 38.47 ± 3.26 pg/ml; AS-H: IgE: 459.46 ± 74.75 ng/ml; TNF-α: 24.38 ± 3.85 pg/ml). Among Th17 cell-related factors, DNCB treatment increased mRNA expression of IL-6, IL-17, IL-23, STAT3, and ROR-γt, but reduced TGF-β and SOCS 3; While artesunate reverse these changes. Compared with the model group, artesunate promoted SOCS3 protein and significantly inhibited ROR-γt protein and STAT3 phosphorylation. Thus, artesunate attenuates DNCB-induced atopic dermatitis by inhibiting the release of inflammatory cytokines and downregulating Th17 cell responses in atopic dermatitis mice.

Matched MeSH terms: Dermatitis, Atopic/immunology