Naomi Nakamura

Toll-Like Receptor 3 Increases Allergic and Irritant Contact Dermatitis

There is increasing recognition of the role of Toll-like receptor 3 (TLR3) in noninfectious inflammatory diseases, but the function of TLR3 in inflammatory skin diseases is unclear. We investigated the functions of TLR3 in allergic and irritant contact dermatitis (ICD). The contact hypersensitivity (CHS) response was lower in Toll-like receptor 3 knockout (Tlr3 KO) mice, and was greater in TLR3 transgenic (Tg) mice than in wild-type (WT) mice after challenge with 2,4,6-trinitro-1-chlorobenzene. Adoptive transfer of immunized lymph node cells from Tlr3 KO mice induced CHS in WT recipients. In contrast, adoptive transfer of those from WT mice did not fully induce CHS in Tlr3 KO recipients. The ICD reaction following croton oil application was lower in Tlr3 KO mice, and was greater in TLR3 Tg mice than in WT mice. Maturation, migration, and antigen presentation of dendritic cells and proliferation of lymphocytes between WT mice and Tlr3 KO mice were comparable. These results show that TLR3 enhances antigen-independent skin inflammation in the elicitation phase of allergic contact dermatitis and in ICD.

Cutaneous and laryngeal squamous cell carcinoma in mixed epidermolysis bullosa, kindler syndrome.

Kindler syndrome is a rare autosomal recessive genodermatosis characterized by trauma-induced acral blisters in infancy and childhood, photosensitivity, and progressive poikiloderma. Other clinical features include chronic erosive gingivitis, dysphagia, esophageal and urethral strictures, ectropion, and an increased risk of mucocutaneous squamous cell carcinoma. We describe a patient with Kindler syndrome associated with squamous cell carcinoma of the skin and larynx. He had squamous cell carcinoma on his left knee with simultaneous unresectable laryngeal carcinoma at the age of 43 years. The squamous cell carcinoma on his knee was excised and the laryngeal carcinoma was treated with radiation therapy. Although pathophysiology of Kindler syndrome and its frequency of association with cancer are still not fully elucidated, we speculate that long-term erosion and regeneration of mucosal and cutaneous surfaces may have induced squamous cell carcinoma on the patient’s knee and larynx.

Platelets Regulate the Migration of Keratinocytes via Podoplanin/CLEC-2 Signaling during Cutaneous Wound Healing in Mice

Podoplanin is an endogenous ligand for C-type lectin-like receptor 2 (CLEC-2), which is expressed on platelets. Recent evidence indicates that this specific marker of lymphatic endothelial cells is also expressed by keratinocytes at the edge of wounds. However, whether podoplanin or platelets play a role in keratinocyte activity during wound healing remains unknown. We evaluated the effect of podoplanin expression levels on keratinocyte motility using cultured primary normal human epidermal keratinocytes (NHEKs). Down-regulation of podoplanin in NHEKs via transfection with podoplanin siRNA inhibited their migration, indicating that podoplanin plays a mandatory role in this process. In addition, down-regulation of podoplanin was correlated with up-regulation of E-cadherin, suggesting that podoplanin-mediated stimulation of keratinocyte migration is associated with a loss of E-cadherin. Both the addition of platelets and treatment with CLEC-2 inhibited the migration of NHEKs. The down-regulation of RhoA activity and the up-regulation of E-cadherin in keratinocytes were also induced by CLEC-2. In conclusion, these results suggest that podoplanin/CLEC-2 signaling regulates keratinocyte migration via modulating E-cadherin expression through RhoA signaling. Altering the regulation of keratinocyte migration by podoplanin might be a novel therapeutic approach to improve wound healing.

Contact sensitivity in patients with recalcitrant atopic dermatitis

Patients with atopic dermatitis are usually responsive to conventional treatment such as topical steroids; however, they are sometimes refractory to the treatment. The influence of contact sensitivities on the course of patients with recalcitrant atopic dermatitis is not known. The aim of this study was to investigate whether contact sensitivities affect the course of patients with recalcitrant atopic dermatitis. We evaluated 45 patients with atopic dermatitis who had failed conventional therapy. Patch testing was performed with the Japanese standard series, metal series and/or suspected items. A total of 15 patients had a positive patch test reaction to at least one allergen. The most common allergens were nickel, topical drugs and rubber accelerators. Avoidance of products or food containing allergic substances greatly or partially improved skin symptoms in nine patients. These results suggest that contact allergens and metals may be critical factors causing eczematous lesions in patients with recalcitrant atopic dermatitis.

Interstitial granulomatous dermatitis? An unusual presentation in the mucosa and periungual skin.

Interstitial granulomatous dermatitis (IGD) is a reactive phenomenon accompanying disorders including autoimmune disease, lymphoproliferative disorders and drug reactions. Histologically, IGD shows a granulomatous infiltrate surrounding piecemeal fragmentation of collagen in the diffuse interstitium. IGD presents with linear cords, papules and plaques mainly on the trunk and extremities. Herein, we report a case with peculiar clinical features that were histopathologically consistent with IGD. A 74‐year‐old man presented with periungual painful erythema, nail deformity of all fingers and labial, penile and anal erosive erythema. Histopathological examination of the lesions showed interface dermatitis and a diffuse interstitial granulomatous infiltrate mainly composed of CD68‐positive histiocytes and lymphocytes. Degenerative collagen bundles were also observed in granulomas. C‐reactive protein and the white blood cell count were elevated, but further examinations did not reveal systemic inflammatory disorders such as autoimmune disease, lymphoproliferative disorder, inflammatory bowel disease or drug hypersensitivity. The lesions were successfully treated with oral and topical steroids.

Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1‐keratin 5–specific transgenic mice

Our genomewide association study documented an association between cold medicine‐related Stevens‐Johnson syndrome/toxic epidermal necrolysis (CM‐SJS/TEN) and Ikaros Family Zinc Finger 1 (IKZF1). Few studies examined biological and pathological functions of IKZF1 in mucosal immunity. We hypothesized that IKZF1 contributes to the mucocutaneous inflammation.

The role of toll-like receptor 3 in chronic contact hypersensitivity induced by repeated elicitation

BACKGROUND Accumulating evidence suggests that Toll-like receptor (TLR)-3 signaling is involved in non-infectious immune and inflammatory reactions as well as in viral infections. The skin of patients with atopic dermatitis (AD) is often infected with virus and bacteria, leading to the aggravation of atopic symptoms. These findings suggest TLR3 signaling may be involved in the pathogenesis of AD, but the exact role of TLR3 in AD remains to be defined. OBJECTIVE The purpose of this study was to investigate the role of TLR3 in chronic contact hypersensitivity reactions induced by repeated elicitation, resembling the features of AD. METHODS Wild-type (WT) and Toll-like receptor 3 knockout (Tlr3 KO) mice were sensitized, and chronic contact hypersensitivity reactions were elicited in their ear skin via repeated application of a hapten, 2,4,6-trinitro-1-chlorobenzene (TNCB) or oxazolone. RESULTS The Tlr3 KO mice exhibited less ear swelling, less leukocyte infiltration into the skin, and lower serum total IgE levels than WT mice after hapten challenge. The Tlr3 KO mice also displayed lower expression levels of inflammatory cytokines (interleukin (IL)-33, IL-4, IL-10, and interferon-ɤ in their TNCB-treated ear skin than WT mice. CONCLUSION These results showed that TLR3 deficiency suppressed the development of chronic contact hypersensitivity reactions, suggesting that TLR3 signaling may participate in the pathogenesis of AD.

Myxofibrosarcoma arising from a chronic burn scar.

the relief of the patient’s severe stabbing pain, which despite the previous use of a wide spectrum of therapeutic regimens had never been successfully controlled. Thus, we initiated a monotherapeutic trial with oral doxazosin (Cardura; Pfizer, Athens, Greece), a specific antagonist of a-1 adrenergic receptors at a dose of 1 mg/day (gradually increasing to 2 mg/day), which is widely used in the treatment of hypertension and urinary retention. The pain completely resolved approximately 24 h after the onset of treatment and pain attacks were no longer triggered. The patient has presently completed an 8-month follow up without any recurrence of her symptoms or occurrence of any side-effects. Our findings, taken together with those of Batchelor et al., suggest that a-1 adrenergic receptors may be of paramount importance in the pathogenesis of leiomyoma-associated pain. Additionally, they indicate that oral doxazosin may represent a safe and extremely effective approach to the management of pain associated with multiple cutaneous leiomyomas. Nevertheless, long-term clinical trials are now warranted to fully elucidate its analgesic efficacy and safety in this disorder. CONFLICT OF INTEREST: None declared.