Bilirubin oxidation derived from oxidative stress is associated with disease severity of atopic dermatitis in adults.

BACKGROUND: Bilirubin is an essential antioxidant. Its oxidative metabolites, biopyrrins, are sensitive urinary markers of oxidative stress. Multiple studies suggest that oxidative stress affects the pathogenesis of skin diseases such as atopic dermatitis (AD). AIM: To examine oxidative stress-induced bilirubin oxidation and its association with AD pathogenesis in adults. METHODS: In total, 11 patients with AD and 7 healthy controls (HCs) were enrolled. Bilirubin oxidation profiles in the combined urine of the patients and that of the HCs were examined using high-performance liquid chromatography (HPLC) and fast atom bombardment mass spectrometry. The concentrations of urinary biopyrrins and serum biomarkers for AD disease severity, such as IgE and thymus and activation-regulated chemokine (TARC)/CCL17, were measured by ELISA to determine correlations between urinary biopyrrins and serum biomarkers. Local bilirubin oxidation in AD skin lesions was assessed by immunohistochemical analyses using two antibodies against bilirubin. RESULTS: Levels of dipyrrole-monopyrrole-aldehyde, a novel urinary biopyrrin, were higher in patients with AD than in HCs, and increased with disease severity based on the SCORing Atopic Dermatitis (SCORAD) objective scoring system. Additionally, urinary biopyrrin levels correlated significantly with serum IgE and TARC/CCL17 levels. Furthermore, immunohistochemical analyses revealed that biopyrrins were strongly expressed in both infiltrating and resident cells in AD lesions. However, bilirubin was expressed at low levels in the lesions, suggesting that bilirubin oxidation is augmented in AD lesions. CONCLUSIONS: Bilirubin oxidation derived from oxidative stress in the skin lesions can be associated with disease severity of AD.

Close association between metal allergy and nail lichen planus: detection of causative metals in nail lesions.

BACKGROUND: Lichen planus (LP) is a common skin disorder of unknown aetiology that affects the skin, mucous membranes and nails. Although metal allergies have been implicated in the development of oral LP (OLP), the contribution of these allergies to nail LP (NLP) has yet to be studied in detail. OBJECTIVE: To elucidate the link between metal allergy and NLP. METHODS: We retrospectively analysed 115 LP patients with respect to the contribution of metals to either NLP or OLP. We also attempted to detect the specific metals involved in these nail lesions. RESULTS: Of the 79 patients that received a metal patch test (PT), 24 (30%) were positive for at least one of the metal compounds tested. Notably, the prevalence of positive reactions to metals in the NLP patients was significantly higher as compared with the OLP patients (59% vs. 27%, P < 0.05). Among the 10 PT-positive patients with NLP, improvement of the skin lesions was seen in six of the patients after removal of dental materials containing causative metals or systemic disodium cromoglycate therapy. On the other hand, only 3 of 16 PT-positive patients with OLP exhibited improvement after the removal of dental materials. Causative metals in the dental fillings/braces were detected in the involved nail tissues. CONCLUSION: This study suggests that metal allergies are more closely associated with NLP vs. OLP, and that deposited metals in the nail apparatus contribute to the development of lichenoid tissue reactions in the nail bed and matrix.

Congenital insensitivity to pain with anhidrosis: a case with preserved itch sensation to histamine and partial pain sensation.

Congenital insensitivity to pain with anhidrosis is a rare autosomal recessive hereditary disorder that is characterized by having both sensory neuropathy and anhidrosis. A 6-year-old Japanese boy presented with recurrent fever, lack of sweating, occult bone fractures and impaired pain sensation without mental retardation. Genetic analyses revealed compound heterozygous mutations in the NTRK1 gene that encodes TrkA, which is a receptor for nerve growth factor. While there were no apparent changes in the patient's dermal eccrine glands, the quantitative sudomotor axon reflex test with acetylcholine chloride revealed a complete loss of both the axon reflex-mediated and the directly activated sweat responses. On the other hand, the histamine prick test induced a normal weal response surrounded by a flare phenomenon. Notably, the patient felt both an itch sensation after histamine and a burning sensation after topical capsaicin application. Consistent with these findings, PGP9.5+ nerve fibre innervation of the papillary dermis was observed, although the fibres were completely absent around the eccrine glands. These findings suggest that there was a partial preservation of the nerve endings that express the H(1) receptor and/or TRPV1 in the upper dermis, even though there were mutations of the NTRK1 gene in this case.

Basophil recruitment and activation in inflammatory skin diseases.

BACKGROUND: Basophils are blood leukocytes constituting less than 1% of leukocytes. They share morphological and functional similarities with mast cells, but recent studies indicate that basophils play non-redundant roles via the release of several cytokines and lipid mediators, as well as functioning as antigen presenting cells. However, basophil infiltration into the tissues in human skin diseases remains to be addressed. METHODS: The infiltration of basophils in 24 skin diseases (136 samples) was immunohistochemically analyzed using basophil-specific BB1 antibody. In addition, activation of blood basophils was examined by assessing CD203c expression with flow cytometry. RESULTS: Basophils were detected in skin lesions of atopic dermatitis, prurigo, urticaria, bullous pemphigoid, drug eruptions, eosinophilic pustular folliculitis, insect bites, scabies, Henoch-Schönlein purpura and dermatomyositis. While cell densities in urticaria, bullous pemphigoid and eosinophilic pustular folliculitis were prominent, much lower numbers of basophils were seen in lesional skin of atopic dermatitis. Basophils were entirely absent in psoriasis vulgaris, mastocytosis, tumoral lesions, systemic sclerosis, and systemic lupus erythematosus. Levels of CD203c expression on blood basophils from prurigo and urticaria patients were higher than those from healthy donors. CONCLUSIONS: Basophils infiltrate into skin lesions more commonly than previously thought, and thus they may play important roles in a variety of inflammatory skin diseases.

Gene silencing of STAT6 with siRNA ameliorates contact hypersensitivity and allergic rhinitis.

BACKGROUND: Silencing of genes using small interfering RNA (siRNA) is a recently developed strategy to regulate the synthesis of target molecules. Signal transducer and activator of transcription 6 (STAT6) is a nuclear transcription factor that mediates Th2-type immunity. METHODS: To elucidate the therapeutic potential of using siRNA to inhibit STAT6 in allergic reactions, we determined the nucleotide sequences of siRNA specific for STAT6. RESULTS: The selected sequences of STAT6 siRNA specifically inhibited the generation of STAT6 synthesis in dermal fibroblasts and eotaxin (CCL11) production in response to IL-4/TNF-α in vitro. Local administration of STAT6 siRNA in vivo alleviated contact hypersensitivity responses to chemical haptens. This was accompanied by reduced local production of IL-4, IL-13, eotaxin (CCL11), TARC (CCL17) and MDC (CCL22). Similarly, consecutive intranasal instillation of STAT6 siRNA markedly inhibited inflammatory cellular infiltration of mucosal tissues in allergic rhinitis responses in association with reduced IL-4 and IL-5 production from regional lymph node cells. Immediate responses, such as sneezing and nasal rubbing behaviors, were also improved by STAT6 siRNA. CONCLUSIONS: Local administration of STAT6 siRNA is thus a promising therapeutic strategy for both Th2-mediated cutaneous diseases and allergic rhinitis.