Toshiharu Fujiyama

TSLP Directly Interacts with Skin-Homing Th2 Cells Highly Expressing its Receptor to Enhance IL-4 Production in Atopic Dermatitis

Thymic stromal lymphopoietin (TSLP) is overtly expressed on skin lesions of atopic dermatitis (AD), and the initiative role of TSLP-activated DCs in AD has gained much attention in the past few years, while its actions on other immune cells such as T cells have been given less notice. We aimed to clarify whether TSLP receptor (TSLPR) is expressed on certain populations of T cells and whether TSLP possesses the capability to directly interact with T cells from AD patients. Peripheral lymphocytes from 51 AD patients are analyzed by flow cytometry, and ex vivo experiments using peripheral blood and lesional skin-derived T cells were conducted. TSLPR expression was defined to CD4+ T cells, and CD4+CCR4+CXCR3-CCR7-CCR10+CLA+ T cells in AD patients exhibited enhanced TSLPR expression. The frequency of TSLPR+CD4+ T cells correlated with disease activity. CD4+ T cells from AD patients directly interacted with TSLP to produce a higher amount of IL-4 than those from normal subjects, and this action was attenuated with anti-TSLPR antibody. The importance of IL-4 in the induction of TSLPR expression was found in AD T cells. Our findings indicate that T cells from AD patients possess strong potential to directly interact with TSLP to promote Th2 response.

Biochemical, cytological, and immunological mechanisms of rhododendrol-induced leukoderma

Recently, an unexpected outbreak of patients with leukoderma occurred in Japan with the use of brightening/lightening cosmetics containing rhododendrol (RD). Patients developed leukoderma mostly on the skin sites repeatedly applied with RD, but some patients also had vitiligo-like lesions on the non-applied sites. RD is a tyrosinase-competitive inhibiting substance, thereby serving as an inhibitor of melanin synthesis. Upon inhibition of tyrosinase, RD is converted to new products such as tyrosinase-catalyzed hydroxyl-metabolite, which damage melanocytes. The melanocyte cell lysates seem to induce T-cell response. The frequencies of CD8+ T cells in both lesional skin and peripheral blood are significantly higher in the RD leukoderma as well as non-segmental vitiligo patients than in normal controls. In HLA-A*02:01 positive cases, circulating Melan-A-specific cytotoxic T cells can be detected at a high frequency. It is thus suggested that RD-induced leukoderma is induced by not only cytolysis of melanocytes but also subsequent immune reactions toward melanocytes.

Clinical and histopathological differential diagnosis of eosinophilic pustular folliculitis

Eosinophilic pustular folliculitis (EPF) is an inflammatory disease characterized by repeated pruritic follicular papules and pustules arranged in arcuate plaques, and folliculotropic infiltration of eosinophils. The diagnosis of EPF is occasionally difficult and problematic because EPF may share the clinical appearance and histological findings with other diseases. Moreover, EPF has several clinical subtypes, including the classical type, infantile type and immunosuppression‐associated type. Because the therapies of EPF are relatively specific as compared to eczematous disorders, accurate diagnosis is essential for the management of EPF. Clinical differential diagnoses include tinea, acne, rosacea, eczematous dermatitis, granuloma faciale, autoimmune annular erythema, infestations and pustular dermatosis. Histologically, cutaneous diseases with eosinophilic infiltrates can be differentially diagnosed. Follicular mucinosis, mycosis fungoides and other cutaneous T‐cell lymphomas are the most important differential diagnoses both clinically and histopathologically. It should be kept in mind particularly that the initial lesions of cutaneous T‐cell lymphoma resemble EPF.

Proteome analysis of stratum corneum from atopic dermatitis patients by hybrid quadrupole-orbitrap mass spectrometer

may also be anti-inflammatory by reducing nuclear factor kappa B gene expression. Similarly, in addition to their inflammatory role, Langerhans cells are thought to have immunoregulatory functions. Indeed, we see that langerin cells are largely reduced in lesional than in nonlesional AD skin at baseline, and significantly increase on clinical reversal after 12 weeks of CsA treatment (Fig 1, E, and Table E3). In addition to the RDGP, other possible mechanisms for disease recurrence in the same areas need to be considered, including (1) regional differences (increased humidity/friction, transepidermal water loss, pH, and lipids) that allow increased antigen penetration, (2) epigenetic modifications, and (3) microbiome differences. In summary, we have demonstrated that although the CsA RDGP is much smaller than the NB-UVB RDGP, important structural defects and residual inflammation remain and the overall size of the RDGP does not predict relapse kinetics. Given that NB-UVB and CsA have different courses of disease maintenance on discontinuing therapy, some elements in the RDGP of each treatment might explain relevant treatmentand disease-specific mechanisms. Mariya Rozenblit, BA Mayte Suarez-Farinas, PhD Avner Shemer, MD Saakshi Khattri, MD Patricia Gilleaudeau, NP Mary Sullivan-Whalen, NP Xiuzhong Zheng, MSc Hui Xu, MSc Irma Cardinale, MSc James G. Krueger, MD, PhD Emma Guttman-Yassky, MD, PhD

Skin recruitment of monomyeloid precursors involves human herpesvirus‐6 reactivation in drug allergy

In drug‐induced hypersensitivity syndrome (DIHS), latent human herpesvirus (HHV)‐6 is frequently reactivated in association with flaring of symptoms such as fever and hepatitis. We recently demonstrated an emergence of monomyeloid precursors expressing HHV‐6 antigen in the circulation during this clinical course.

Increased frequencies of Th17 cells in drug eruptions

c y d TNF-a and IL-6 [8]. Since LCs are commonly activated under IL-1a and TNF-a condition in case of contact hypersensitivity [9], it is conceivable that activated LCs may be an important factor on the occurrence of vitiligo as the interface of melanocyte-specific adoptive immunity cooperating with cytotoxic T cells and may also induce innate immunity in participation with Th17 cells. Following increased infiltration of CD11c+ myeloid dendritic cells and dermal CD1a+ dendritic cells in vitiligo skin can act as antigen trafficking to draining lymph nodes and can produce proinflammatory cytokines such as IL-6 and TNF-a leading to determine helper T cells polarization [10]. Taken together with the effect of Th17 cellrelated cytokines on surrounding keratinocyte and fibroblast [6], this positive feedback linage of local cytokines is possibly important for transient appearance of indeterminate dendritic cells and subsequent mature melanocyte disappearance. Given this idea on the underlying immunogenic mechanism, early therapeutic intervention of molecular targeting biologics is considerable for the treatment with progressive nonsegmental vitiligo.

Induction of cytotoxic T cells as a novel independent survival factor in malignant melanoma with percutaneous peptide immunization.

BACKGROUND Malignant melanoma (MM) often shows multiple chemo-resistance, leading to poor prognosis of the patients. Therapeutic anti-cancer vaccination may be a feasible way to prolong the survival of patients. We have demonstrated that application of antigenic peptides via the tape-stripped, horny layer-removed skin, known as percutaneous peptide immunization (PPI), induces tumor cell-specific cytotoxic T lymphocytes (CTLs) in rodents and humans. OBJECTIVE To evaluate clinical significance of PPI in advanced MM patients. METHODS We performed PPI in 59 patients undergoing advanced MM with Melan-A, tyrosinase, MAGE-2, MAGE-3 and gp-100 peptides based on HLA typing in individuals. The induction of CTLs was assessed by the tetramer or pentamer flow cytometry in 35 patients. Patients showing positive CTL responses to all antigens were defined as complete responder (n=18), and those showing negative responses to at least one applied antigen were classified as incomplete responder (n=17). The primary endpoint of the study was overall survival (OS). For statistical analysis, log-rank test, univariate and multivariate Cox proportional hazard model were used. RESULTS OS of the complete responders was longer than that of the incomplete responders (median survival time: 55.8 vs 20.3 months, log rank P=0.089). A hazard ratio for the complete responders relative to the incomplete responders was 0.23 (95% confidence interval: 0.06-0.93, P=0.039) in a multivariate Cox proportional hazard model. CONCLUSION The induction of CTLs was a novel independent survival factor, and the induction of peptide-specific CTLs by PPI contributes to the prolonged survival and represents an impact on therapeutic approaches in MM. Unique trial number: UMIN000005706.

Preferential infiltration of interleukin-4-producing CXCR4+ T cells in the lesional muscle but not skin of patients with dermatomyositis.

Dermatomyositis (DM) and polymyositis (PM) are collectively termed autoimmune myopathy. To investigate the difference between muscle‐ and skin‐infiltrating T cells and to address their role for myopathy, we characterized T cells that were directly expanded from the tissues. Enrolled into this study were 25 patients with DM and three patients with PM. Muscle and skin biopsied specimens were immersed in cRPMI medium supplemented with interleukin (IL)‐2 and anti‐CD3/CD28 antibody‐conjugated microbeads. The expanded cells were subjected to flow cytometry to examine their phenotypes. We analysed the cytokine concentration in the culture supernatants from the expanded T cells and the frequencies of cytokine‐bearing cells by intracellular staining. There was non‐biased in‐vitro expansion of tissue‐infiltrating CD4+ and CD8+ T cells from the muscle and skin specimens. The majority of expanded T cells were chemokine receptor (CCR) type 7–CD45RO+ effecter memory cells with various T cell receptor (TCR) Vβs. The skin‐derived but not muscle‐derived T cells expressed cutaneous lymphocyte antigen (CLA) and CCR10 and secreted large amounts of IL‐17A, suggesting that T helper type 17 (Th17) cells may have a crucial role in the development of skin lesions. Notably, the frequency of IL‐4‐producing chemokine (C‐X‐C motif) receptor (CXCR)4+ Th2 cells was significantly higher in the muscle‐derived cells and correlated inversely with the serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) levels. stromal‐derived factor (SDF)‐1/CXCL12, a ligand for CXCR4, was expressed at a high level in the vascular endothelial cells between muscular fasciculi. Our study suggests that T cell populations in the muscle and skin are different, and the Th2 cell infiltrate in the muscle is associated with the low severity of myositis in DM.

Histiocytoid Sweet’s syndrome associated with t(9;22)(q34;q11)-positive chronic myelogenous leukemia: immature granulocytic origin of histiocytic cells

and functional analysis of a chimeric protein COL1A1PDGFB generated by the translocation t(17;22)(q22;q13.1) in dermatofibrosarcoma protuberans (DP). Oncogene 2001; 20: 2965–2975. 6 Bague S, Folpe AL. Dermatofibrosarcoma protuberans presenting as a subcutaneous mass: a clinicopathological study of 15 cases with exclusive or near-exclusive subcutaneous involvement. Am J Dermatopathol 2008; 30: 327–332.

CD8+ Sézary syndrome with interleukin-22 production modulated by bacterial sepsis

22. 6 Lee JB, Liu Y, Hashimoto T. Cicatricial pemphigoid sera specifically react with the most C-terminal portion of BP180. J Dermatol Sci 2003; 32:59–64. 7 Hisamatsu Y, Amagai M, Garrod DR et al. The detection of IgG and IgA autoantibodies to desmocollins 1–3 by enzyme-linked immunosorbent assays using baculovirus-expressed proteins, in atypical pemphigus but not in typical pemphigus. Br J Dermatol 2004; 151:73–83. 8 Muller R, Heber B, Hashimoto T et al. Autoantibodies against desmocollins in European patients with pemphigus. Clin Exp Dermatol 2009; 34:898–903.