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ABSTRACTIntroduction: Approximately, 30.4–66.0% of cutaneous melanomas possess a mutation in the BRAF gene that activates downstream signaling through the mitogen-activated protein (MAP) kinase pathway; this provides an attractive target for the treatment of advanced melanoma. Although BRAF inhibitors rapidly suppress melanoma growth, median progression-free survival remains unsatisfactory. Recent clinical trials have investigated drugs that can optimally enhance and prolong the anti-melanoma effects of BRAF inhibitors.Area covered: This review discusses the development of BRAF inhibitor-based combination therapies for BRAF-mutant advanced melanoma.Expert opinion: Future strategies for the treatment of advanced melanoma include novel combination therapies using BRAF/MEK inhibitors and immune checkpoints inhibitors or histone deacetylase inhibitors. These combination therapies might enhance antitumor responses against melanoma, prolonging survival in advanced melanoma patients. Further clinical studies are needed to optimize these novel combination therapies.

Identification of predictive biomarkers is crucial for formulating preventive interventions and halting the progression of atopic march. Although controversial, the use of accessible markers to predict or detect early onset of atopic diseases is highly desirable. Therefore, this study aimed to investigate whether corneal squamous cell carcinoma antigen-1 (SCCA1) collected from infants can predict the development of atopic dermatitis and food allergy.

Precise skin phenotypic data are indispensable in accurately diagnosing atopic dermatitis (AD). Therefore, this study examined the interobserver concordance for AD and non-AD diagnoses between two dermatologists. AD prevalence determined by the self-reported physician diagnoses and the diagnoses determined from the United Kingdom (UK) diagnostic criteria were compared with the diagnoses made by the two dermatologists, using data from a skin health survey.

Die Kombination aus Nivolumab und Ipilimumab ist einer der vielversprechenden Therapieansätze zur Steigerung der antitumoralen Immunreaktion bei Patienten mit fortgeschrittenem Melanom. Ein Hauptaugenmerk der Dermatologen liegt auf der Optimierung des Ansprechens. Aktuelle Berichte deuten darauf hin, dass – vor dem Hintergrund, dass CD8+-T-Zellen nach Anwendung von Immuncheckpoint-Inhibitoren beim Melanom die RANKL-Expression steigern und so ein immunsuppressives Tumormikromilieu schaffen – Denosumab die antitumorale Wirkung dieser Immuncheckpoint-Inhibitoren, z.B. Nivolumab und Ipilimumab, zusätzlich steigern könnte. Wir stellen hier den Fall eines Patienten mit multipel metastasierendem Melanom vor, der mit einer Kombinationstherapie aus Nivolumab, Ipilimumab und Denosumab behandelt wurde.

Croton roxburghiiand Croton sublyratushave been used as skin treatments in traditional medicine. The objective of the present study was to investigate the antimelanogenic effect of ethanol extracts of Croton roxburghii(CRE) and Croton sublyratus(CSE) leaves on cellular melanin content and cellular tyrosinase activity as mediated by the action of microthalmia transcription factor (MITF) and melanogenic enzymes. Croton roxburghiiand Croton sublyratusleaves were extracted by petroleum ether, dichloromethane and absolute ethanol, sequentially. The ethanolic crude extracts were examined for antimelanogenic activity by their ability to decrease melanin content and cellular tyrosinase activity in alpha-melanocyte-stimulating hormone-stimulated B16F10 melanoma cells. In addition, the extracts were evaluated to determine a plausible mechanism of melanogenesis suppression through determining the activation of MITF transcription factor and melanogenic proteins (tyrosinase, tyrosinase-related protein 1 or TRP-1 and tyrosinase-related protein 2 or TRP-2) at the transcriptional and translation levels in α-MSH-induced B16F10 cells. Upon treatment with CRE and CSE, the cells showed significant decreases in melanin content and cellular tyrosinase activity. CRE and CSE also suppressed MITF, tyrosinase, TRP-1 and TRP-2 at the transcription and translation levels in α-MSH-stimulated melanin biosynthesis in B16F10 cells. Our finding shows that CRE and CSE inhibit melanin content and cellular tyrosinase activity through suppressing MITF and melanogenic enzymes. CRE and CSE may be useful to combine with skin whitening agents for cosmetic uses.

The immune system comprises innate and adaptive immunity. Both arms of the immune response function differently and are represented by different populations of cells. A variety of cells are involved in these two type of immune response. Innate immune response includes neutrophils and other types of granulocytes, macrophages, natural killer (NK) cells, innate lymphoid cells, and mast cells. Adaptive immune responses involve T cells and B cells. Then, macrophages and dendritic cells (DCs), which act as antigen-presenting cells (APCs), link the innate and adaptive immune responses because they can present antigens to T cells in the context of MHC class II molecules and stimulate their proliferation and effector functions after being stimulated via pathogen recognition receptors. Therefore, to detect the immunotoxicity of chemicals, in vitrotest methods must adequately assess their immunotoxic effects on both the innate and adaptive immune responses. On the other hand, considering the complexity of immune response, it would seem impossible for a limited number of in vitrotest methods to detect all of the immunotoxicants that could affect the immune system. Except for chemicals that either naturally target or are synthesized to target specific receptors or intracellular signaling molecules, however, it is conceivable that chemicals induce immune dysfunction by a limited number of cellular responses to deforming or damaging cellular macromolecules, such as membrane lipids, proteins, and/or DNA, so called cellular stress responses. In this section, we summarize the mechanism of chemicals to induce immunotoxicity and introduce several in vitromethods to detect immunotoxicants.

Atopic dermatitis is increasing worldwide in correlation with air pollution. Various organic components of pollutants activate the transcription factor AhR (aryl hydrocarbon receptor). Through the use of AhR-CA mice, whose keratinocytes express constitutively active AhR and that develop atopic-dermatitis-like phenotypes, we identified Artn as a keratinocyte-specific AhR target gene whose product (the neurotrophic factor artemin) was responsible for epidermal hyper-innervation that led to hypersensitivity to pruritus. The activation of AhR via air pollutants induced expression of artemin, alloknesis, epidermal hyper-innervation and inflammation. AhR activation and ARTN expression were positively correlated in the epidermis of patients with atopic dermatitis. Thus, AhR in keratinocytes senses environmental stimuli and elicits an atopic-dermatitis pathology. We propose a mechanism of air-pollution-induced atopic dermatitis via activation of AhR.

Milia en plaque (MEP) is an uncommon disorder characterized by an erythematous plaque containing numerous milia. The pathogenesis of MEP is not clear. The authors report a man with an erythematous plaque on the right retroauricular area, containing numerous white-yellow cysts varying in size. Histological examination showed that multiple cystic structures at various levels of the dermis that were lined by stratified squamous epithelium and contained keratinous material—these findings were consistent with the diagnosis of multiple milia. In addition to epidermal cysts, however, the lesion consisted of a branched proliferation of pale-staining keratinocytes lined with basal keratinocytes budding from the overlying epidermis. Moreover, some cysts were formed within the branched epithelial proliferation, had thicker cyst walls than the ordinary milium, or had irregular or branched projections toward the surrounding dermis. From these findings, the authors conclude that MEP is a distinct follicular hamartoma with cystic trichoepitheliomatous features.

Damnacanthal is identified as an effective inhibitor of LIM-kinase. It inhibits chemotaxis of T-cells and migration and invasion of breast carcinoma cells in culture and hapten-induced migration of epidermal Langerhans cells in mouse ears. Damnacanthal is a useful tool for investigating the cellular and physiological functions of LIM-kinase.

In this review we discuss the role of dendritic cells (DC) in the pathogenesis of allergic contact hypersensitivity (ACH) and atopic disorders, such as asthma and atopic eczema. In ACH patients, DC recognize the invasion of simple chemicals such as haptens, and trigger antigen-specific T cell responses leading to the characteristic histological and clinical changes such as spongiosis and papulovesicular eruptions. During atopic disorders, it is well known that the Th2-deviated immune response plays a crucial role in their pathogenesis. DC provide T cells with antigen and costimulatory signals (signals 1 and 2, respectively), as well as with a polarizing signal (signal 3). When studying ACH, it is important to understand how simple chemicals induce the activation of DC and their migration to the draining lymph nodes where they supply signals 1 and 2 to naïve T cells. The mechanisms by which DC induce the Th2-deviated immune response, namely via the Th2-deviated signal 3, are central topics in the pathogenesis of atopic disorders.

Abstract: Fatty acids are shown to be important in various skin functions. Fatty acid binding protein (FABP) is postulated to serve as a lipid shuttle, solubilizing hydrophobic fatty acids and delivering them to the appropriate metabolic system. Among the FABP family proteins, epidermal-type FABP (E-FABP) is solely expressed in keratinocyte but its specific role in skin is not yet fully established. We found an elevated expression of E-FABP in regenerative keratinocytes of healing wounds. However, E-FABP null mice showed no marked differences compared to wild type mice in the process of wound closure, in vivo. On the other hand, in keratinocyte culture, E-FABP gene disruption decreased the cell motility, but did not affect the cell proliferation. E-FABP deletion may be compensated for in vivo by the microenvironment comprised of various cells such as fibroblasts and endothelial cells around the wound. Our analyses suggest that the E-FABP elevation may be necessary for the activation of cell motility within regenerative epidermis during wound healing.

ABSTRACTA synthetic Nod2 agonist, muramyldipeptide (MDP), and two Nod1 agonists, FK565 and FK156, mimic the bacterial peptidoglycan moiety and are powerful adjuvants that induce cell-mediated immunity, especially delayed-type hypersensitivity. In this study, we used human dendritic cell (DC) cultures to examine possible T helper type 1 (Th1) responses induced by MDP and FK565/156 in combination with various synthetic Toll-like receptor (TLR) agonists, including synthetic lipid A (TLR4 agonist), the synthetic triacyl lipopeptide Pam3CSSNA (TLR2 agonist), poly(I:C) (TLR3 agonist), and CpG DNA (TLR9 agonist). Immature DCs derived from human monocytes expressed mRNAs for Nod1, Nod2, TLR2, TLR3, TLR4, and TLR9. The stimulation of DCs with MDP and FK565 in combination with lipid A, poly(I:C), and CpG DNA, but not with Pam3CSSNA, synergistically induced interleukin-12 (IL-12) p70 and gamma interferon (IFN-γ), but not IL-18, in culture supernatants and induced IL-15 on the cell surface. In correlation with the cytokine induction, an upregulation of the mRNA expression of these cytokine genes was observed. Notably, IL-12 p35 mRNA expression increased >1,000-fold upon stimulation with lipid A plus either MDP or FK565 compared with stimulation with each stimulant alone. In contrast, for the expression of CD83 and costimulatory molecules such as CD40, CD80, and CD86, no synergistic effects were observed upon stimulation with Nod plus TLR agonists. The culture supernatants of DCs stimulated with lipid A plus either MDP or FK565 activated human T cells to produce high levels of IFN-γ, and the activity was attributable to DC-derived IL-12. These findings suggest that Nod1 and Nod2 agonists in combination with TLR3, TLR4, and TLR9 agonists synergistically induce IL-12 and IFN-γ production in DCs to induce Th1-lineage immune responses.

A synthetic Nod2 agonist, muramyldipeptide (MDP), and two Nod1 agonists, FK565 and FK156, mimic the bacterial peptidoglycan moiety and are powerful adjuvants that induce cell-mediated immunity, especially delayed-type hypersensitivity. In this study, we used human dendritic cell (DC) cultures to examine possible T helper type 1 (Th1) responses induced by MDP and FK565/156 in combination with various synthetic Toll-like receptor (TLR) agonists, including synthetic lipid A (TLR4 agonist), the synthetic triacyl lipopeptide Pam3CSSNA (TLR2 agonist), poly(I:C) (TLR3 agonist), and CpG DNA (TLR9 agonist). Immature DCs derived from human monocytes expressed mRNAs for Nod1, Nod2, TLR2, TLR3, TLR4, and TLR9. The stimulation of DCs with MDP and FK565 in combination with lipid A, poly(I:C), and CpG DNA, but not with Pam3CSSNA, synergistically induced interleukin-12 (IL-12) p70 and gamma interferon (IFN-γ), but not IL-18, in culture supernatants and induced IL-15 on the cell surface. In correlation with the cytokine induction, an upregulation of the mRNA expression of these cytokine genes was observed. Notably, IL-12 p35 mRNA expression increased >1,000-fold upon stimulation with lipid A plus either MDP or FK565 compared with stimulation with each stimulant alone. In contrast, for the expression of CD83 and costimulatory molecules such as CD40, CD80, and CD86, no synergistic effects were observed upon stimulation with Nod plus TLR agonists. The culture supernatants of DCs stimulated with lipid A plus either MDP or FK565 activated human T cells to produce high levels of IFN-γ, and the activity was attributable to DC-derived IL-12. These findings suggest that Nod1 and Nod2 agonists in combination with TLR3, TLR4, and TLR9 agonists synergistically induce IL-12 and IFN-γ production in DCs to induce Th1-lineage immune responses.

Psoriasis is characterized by sustained T cell activation by antigen-presenting cells (APCs) in the lesions, and by a deviation of T cell differentiation to type 1 helper T and type 1 cytotoxic T cells, although no specific antigens have yet been determined. These characteristics are at least promoted by decreased IL-10 expression and the increased IL-12 expression observed in both the skin and stimulated peripheral blood mononuclear cells of psoriatic patients. Some of the cytokines produced by activated T cells are suspected to stimulate the proliferation of psoriatic keratinocytes. Among them, interferon-γ is the most likely candidate, although interferon-γ does not promote the growth of normal keratinocytes. In addition to the abnormal proliferation, psoriatic keratinocytes show abnormal differentiation and resistance to apoptosis. So far, however, it is still unknown whether these phenotypic and functional characteristics of psoriatic keratinocytes are only the consequences of the stimulation by activated T cells or are at least based on an inherent susceptibility. Recently, it has become clear that chemokines derived from activated keratinocytes or endothelial cells play a crucial role in recruiting T cells in the skin and inducing the neutrophilic infiltration that leads to the formation of subcorneal pustules (Munros microabscess). Finally, recent developments in the detection and analysis of gene expression have revealed the molecules responsible for these steps. Some of them have become target molecules for the treatment of psoriasis. And indeed, it has become possible now to treat patients with new, innovative drugs.

We describe an 88-year-old Japanese patient with pilotropic T cell lymphoma involving the peripheral blood as well as lymph nodes. This patient presented with multiple red follicular papules, confluent, infiltrated erythematous plaques and nodules. Moreover, he was conspicuous for the presence of total alopecia of the scalp and eyebrows. Histopathologically, the lesional skin showed dense follicular and perifollicular infiltrates of atypical lymphocytes. The flow cytometry disclosed the presence of weakly CD4+ CCR4+ cell populations that would not be detected in the peripheral blood from healthy controls. The patient responded well to topical PUVA and systemic etretinate (retinoid-PUVA) and intravenous IFN-γ. Parallel with the decrease in atypical cells in the peripheral blood, the percentage of weakly CD4+ CCR4+ T cells declined. However, about 1 week after we discontinued this treatment because of the side effects, the lymph node swelling became prominent, and, 4 weeks later, the patient died before restarting any specific chemotherapy.

Factor XIIIa-positive dendrocytes are abundant within the dermis and have been implicated in the pathogenesis of various disorders, including AIDS-related Kaposi's sarcoma. Purified cultures of factor XIIIa-positive normal dermal dendrocytes have not as yet been achieved. 12E2 is a cloned cell line derived from superficial murine dermis where factor XIIIa-positive dendrocytes are abundant. Subconfluent cultures of 12E2 demonstrate polydendritic cell contours with thin, elongated membranous projections. These cells express Factor XIIIa and VCAM-1 by immunohistochemistry and by Western blot analysis of 12E2 cell lysates. 12E2 cells also constitutively express the Langerhans-cell-related epitope DEC-205, detected by NLDC-145 antibody and the CD80 co-stimulatory molecule, as well as Ia antigen on exposure to interferon-γ. Cells so treated exhibit significant ability to present alloantigens in vitro. 12E2 cells are shown to express mRNA for numerous cytokines, including interleukin (IL)-1α, IL-1β, IL-5, IL-6, IL-7, tumor necrosis factor-α and granulocyte macrophage-colony stimulating factor, by reverse-transcriptase polymerase chain reaction followed by Southern blot hybridization. Microinjection of 12E2 cells, but not 3T3control fibroblasts, into footpads of syngeneic and SCID mice results in lesions that mimic the histology and immunohistochemistry of human Kaposi's sarcoma. In aggregate, these data indicate that 12E2 cells 1) share lineage characteristics with factor XIIIa-positive dermal dendrocytes, 2) produce mRNA for numerous cytokines and are cytokine responsive to interferon-γ, and 3) behave in vivoin a manner that resembles Kaposi's sarcoma, a condition known to involve proliferation of human dermal dendrocytes.

Background:Acetylcholine has been suspected to be a pathogenetic factor for cholinergic urticaria (CU), without definite evidence. In contrast, there are scattered reports of CU associated with acquired generalized hypohidrosis. We have recently examined 2 patients with CU in both of whom we noticed the presence of extensive hypohidrosis that occurred only in winter. Objective:In these 2 patients, acquired hypohidrosis due to superficial obstruction of the acrosyringium was suspected as the cause. Both case 1, a 22-year-old Japanese man, and case 2, a 21-year-old Japanese man, began to have anhidrosis and numerous red macules on their body whenever they felt hot in winter. These symptoms ceased to appear in summer. Methods:We studied histologically their lesional skin in addition to provocation tests for CU. Results:The diagnosis of CU was confirmed by the provocation of typical wheals after physical exercise in both cases. Histological study revealed findings suggestive of the presence of occlusion of the superficial acrosyringium. Conclusion:We think that such a hypohidrosis due to occlusion of superficial sweat ducts may also play a role in many other patients with CU of unknown etiology that becomes exacerbated in winter when sweating is not a frequent event.

AbstractBackground:Athough alopecia areata (AA) usually starts with focal lesions of hair loss and then presents several different clinical forms, AA may begin as diffuse hair loss. We examined 9 female patients who presented with acute, diffuse and total hair loss of the scalp and took a similar clinical course with a favorable prognosis. Objective:To categorize such cases as a new subgroup of diffuse alopecia. Methods:We studied 9 patients who showed acute, diffuse and total hair loss of the scalp within 1 month after their first visit to our hospital by comparing their clinical course, laboratory tests and histopathological findings with those of common, patchy AA, alopecia totalis or alopecia universalis. Results:None of the patients had a background of systemic diseases or telogen effluvium. All the patients were female, and 8 of the 9 cases recovered cosmetically acceptable hair growth within 6 months regardless of steroid administration. The histology of he lesions was indistinguishable from that of AA except for a remarkable eosinophilic infiltrate. Conclusions:These cases can be categorized as a new subtype of inflammatory noncicatricial alopecia that is characterized by a marked female predominance, tissue eosinophilia and uniquely short clinical course. We suggest to name it ‘acute diffuse and total alopecia of the female scalp (ADTAFS)’.Copyright © 2002 S. Karger AG, Basel

Recently, it has been demonstrated that immunity to infectious agents is composed of innate immunity and acquired immunity, and that dendritic cells (DC) and macrophages, both of which are the participants in the innate immunity, play a crucial role in acquired immune responses, via their expression of several costimulatory molecules and production of cytokines. It is clear that the immune system responds not only to infectious organisms but also to simple chemicals. Allergic contact hypersensitivity reaction is a good example of the immune response to simple chemicals. In contrast to the immunity to microorganisms, however, the role of the innate immune system in responses to simple chemicals still remains unclear. This paper demonstrates that the activation and apoptosis of DC are directly induced by certain simple chemicals, and we suggest that DC, as cells involved in the innate immune system, play a crucial role in the immunity to simple chemicals.Journal of Investigative Dermatology Symposium Proceedings (1999) 4, 158–163; doi:10.1038/sj.jidsp.5640201

Abstract: Although reduced cutaneous reactivities to Candida albicans have been reported in patients with atopic dermatitis (AD), there is still controversy as to whether the in vivo lymphocyte proliferation response is normal or reduced. We have also reported that patients with AD manifest a decreased cutaneous response only to C. albicans antigen in scarification patch tests. The purpose of this study was to examine whether patients with AD show normal lymphocyte transformation responses to C. albicans antigen. Peripheral blood leucocytes (PBL) from 21 patients with AD and 14 healthy control (HC) subjects were cocultured with optimal concentrations of C. albicans antigen and of superantigens (staphylococcal enterotoxin A and B). PBL from the patients with AD showed a significantly lower response to C. albicans antigen, but there was no statistically significant difference in PBL responses to superantigens between the patients with AD and the HC subjects. This decreased proliferative response of PBL was particularly noticeable in those whose RAST scores for C. albicans antigen were high. These results suggest the development of a specific anergy to C. albicans antigen in patients with AD.

• Biopsy specimens of the skin lesions of pityriasis rosea obtained from 15 patients were studied. Characteristic histologic changes were composed of focal intercellular edema, epidermotropism of mononuclear cells often associated with the formation of focal intraepidermal collections of mononuclear cells, and of a perivascular lymphohistiocytic cell infiltration in the superficial dermis. Immunologic analysis using monoclonal antibodies showed that large numbers of lymphoid cells in the perivascular infiltrate reacted with anti—pan-T-cell, anti— helper-inducer subset, and anti-HLA-DR monoclonal antibodies, while the epidermotropic mononuclear cells consisted of helper-inducer cells or supressor-cytotoxic cells without any predominance pattern. In addition to epidermal Langerhans' cells, some of the dermal infiltrating cells were reactive with monoclonal antibody OKT6. Moreover, there was localized expression of HLA-DR antigen on the keratinocytes. We think that cellular immune reactions are taking place in the lesional epidermis of pityriasis rosea.(Arch Dermatol 1985;121:761-765)

As far as we know there has been no specified report of cutaneous metastasis from invasive lobular carcinoma of the breast. This type of carcinoma constitutes a minor histological group in all breast cancers, especially in Japan. We describe two such cases whose histologic features were conspicuous; numerous dissociated round cells that were arranged in linear arrays. It resembled the histology of cancer en cuirasseto some extent, but the density and variety of tumor cell nests were much richer. The arrangement of the tumor cells as well as their cytology was identical to that of the primary lesions.

BACKGROUND AND DESIGN: Atopic dermatitis (AD) is a chronic eczematous skin disease that develops in a patient with atopic diathesis, which is characterized by an increased liability to produce IgE antibodies for environmental allergens mostly derived from other living organisms. Experimentally, eczematous skin lesions cannot be induced by immediate IgE-mediated reactions alone. They are produced by cell-mediated allergic contact reactions, and recently contact sensitivity to various environmental allergens has been demonstrated in patients with AD. However, the pathologic role of IgE-mediated skin hypersensitivity or that of delayed-type hypersensitivity to various environmental allergens in AD is not fully evaluated. They have been studied separately and against only specific allergens. Thus, we performed a combined testing procedure consisting of radioallergosorbent test, prick, and scarification patch tests for eight environmental allergens in 97 Japanese adult patients with AD; 48 of them had a history of atopic respiratory diseases (ARD), whereas the remaining 49 had no history of ARD (pure AD). RESULTS: Patients with AD, particularly those with ARD (AD+ARD), showed a higher incidence of positive radioallergosorbent test and prick test results as well as patch test results against multiple environmental allergens than healthy age—matched control subjects. Among them, we found a significantly high positive correlation between radioallergosorbent test scores and patch test reactions to two allergens, Japanese cedar, and Dermatophagoides farinae allergens in patients with AD. However, the patients with AD displayed a significantly lower incidence of positive patch test reactions to Candida albicans allergen than the healthy control subjects. Patients with AD with negative C albicans patch tests tended to have higher levels of total serum IgE including anti—C albicans IgE antibody. We found negative correlations between total serum IgE levels including specific antibodies and patch test reactions to C albicans allergen. CONCLUSIONS: Except for the dissociated reactivities to C albicans allergen consisting of decreased contact sensitivity and heightened IgE response, generally both IgE-mediated skin hypersensitivity and delayed-type hypersensitivity to various environmental allergens are pronounced in patients with AD. The combined use of these in vivo and in vitro tests is useful to estimate the immunological state of patients with AD.(Arch Dermatol. 1994;130:1393-1401)

BACKGROUND AND DESIGN: The pathogenesis of scleroderma is still unknown. Recently, it has become possible to identify different subpopulations of dermal spindle-shaped cells using anti-CD34 and anti-factor XIIIa antibodies. To elucidate whether entire populations of dermal fibroblasts or only a subpopulation of cells are involved in the fibrosis of scleroderma, we compared the staining pattern of these antibodies and antiprocollagen antibody in paraffin-embedded skin sections from the lesions of 27 patients with scleroderma and 15 patients with other collagen diseases and from normal skin of 17 subjects. Cryostat sections from both involved and uninvolved skin of four patients with scleroderma were also stained with antiCD34, anti-factor XIIIa, and anti—proline-4-hydroxylase antibodies. RESULTS: CD34+ cells were few or absent in the lesions of scleroderma, while a number of CD34+ cells were found in the lesions of other collagen diseases and in normal skin. In contrast, large numbers of factor XIIIa— and procollagen-positive cells were noted in the lesions of scleroderma. Even in the study in which cryostat sections were used, CD34+ cells were totally absent from the lesions of scleroderma, while there were numerous proline-4-hydroxylase—positive cells. Furthermore, although detectable in the clinically uninvolved skin of these patients, CD34+ cells were less frequent and more slender than those in normal skin. CONCLUSION: Immunohistologic staining with anti-CD34 and other antibodies to dermal spindle-shaped cells demonstrated a selective disappearance of CD34+ spindle-shaped cells from the lesions of scleroderma. It suggests that CD34+ cells might be important target cells in the autoreactive phenomenon in scleroderma.(Arch Dermatol. 1994;130:593-597)

• A 34-year-old man with epidermodysplasia verruciformis showed increased natural killer (NK) cell activity in his peripheral blood cells, which was found to be due to abnormal expansion of large granular lymphocytes (LGL). Surface marker analysis of LGL in a two-color immunofluorescence test demonstrated that all LGL subsets, Leu7+11-, Leu-7+11+, and Leu-7-11+, were increased. In contrast, his peripheral blood mononuclear cells showed a remarkable decrease in response to T cell mitogens, which could not be restored by depletion of the LGL subpopulation from the mononuclear cells. Immunohistologic studies for dermal distribution of LGL showed numerous Leu-7+ cells but no Leu-11+ cells at the sites of delayed hypersensitivity reaction or interferon β- or interferon γ-injected sites. These findings suggest that the elevated NK cell activity in this patient with epidermodysplasia verruciformis was caused by overall expansion of normal LGL subpopulations, but that the decreased T-cell mitogenic response represented a primary T-cell defect rather than a direct suppression by increased NK cells. It is noteworthy that despite this extraordinary increase of all LGL subpopulations in the blood, Leu-11+ NK cells never appeared in the skin.(Arch Dermatol 1989;125:660-665)

• We studied eight cases of Schamberg's disease immunohistologically by using monoclonal antibodies. The dermal infiltrate was composed of Leu-1-reactive T cells, 0KT6-reactive Langerhans' cells, and Leu-M5-reactive (Leu-M5+) macrophages. Among them, the major population consisted of T cells with the predominance of Leu-3a-reactive (Leu-3a+) T cells over Leu-2a-reactive (Leu-2a+) T cells. On the other hand, the epidermotropic mononuclear cells consisted of Leu-2a+ and Leu-3a+ T cells without any predominant pattern, and Leu-M5+ macrophages. Furthermore, note that a pemphiguslike intercellular staining pattern was observed in the epidermis in most of the cases, when the sections were stained either with anti-HLA-DR antibody or with OKT6, suggesting the HLA-DR antigen expression on the keratinocyte surface and possibly an enlargement of Langerhans' cells. Based on these immunohistologic findings, we think that Langerhans' cells play an important role in the pathomechanism of Schamberg's disease, and that cellular immune reactions are taking place in the lesional skin.(Arch Dermatol 1988;124:1058-1062)

• We used patch testing to compare the ability to elicit contact sensitivity to dinitrochlorobenzene (DNCB) of uninvolved with vitiliginous skin of 31 patients with vitiligo. The induction of DNCB contact sensitivity was possible in the vitiliginous skin in the same way as in normal skin. The DNCB contact sensitivity reactions, however, were generally diminished in vitiliginous skin, although the number of cases showing similar DNCB contact reactivity between normal and vitiliginous skin increased when the sensitization procedure was performed in vitiliginous skin instead of normal skin. On the other hand, delayed skin reactions to intradermally injected Candida albicans antigen were not suppressed in vitiliginous skin. The number of Langerhans' cells was not decreased in vitiliginous skin as compared with that of normal skin. The epidermal cells derived from vitiligonous skin, however, tended to show a lower stimulatory effect in the allogeneic mixed skin cell lymphocyte culture reaction than those from normal skin. These results suggest a possibility of functional impairment of Langerhans' cells in vitiliginous skin.(Arch Dermatol 1987;123:51-54)

In 1988, Ramsay et al proposed an entity of acral pseudolymphomatous angiokeratoma of children (with an abbreviation of APACHE) for the unilateral multiple angiomatous papules affecting the acral region of the extremities of children. We report here similar lesions that developed in the acral portions of 1 female adolescent and 2 women. Histopathologically, they showed pseudolymphomatous features rather than those of angiokeratoma. Thus, the term should be acral angiokeratoma-like pseudolymphoma would be more appropriate than APACHE originally proposed. (J Am Acad Dermatol 2001;45:S209-11.)

A 64‐year‐old Japanese woman developed therapy‐resistant erythematous swelling of her upper lip. Our tentative clinical diagnosis of cheilitis granulomatosa was ruled out later by the laboratory findings including increased levels of anti‐nuclear‐antibody (ANA), anti‐SS‐A/Ro antibody, and positive Schirmer test as well as by a histopathological picture showing a dense perivascular infiltration of plasma cells and mononuclear cells in the dermis instead of granulomatous changes. To the best of our knowledge, this is the first patient in whom annular erythema associated with Sjögren's syndrome involved only the upper lip and produced clinical features simulating cheilitis granulomatosa.

• An erythematous patch was noted on the abdominal wall of an 8-year-old boy. The lesion showed a prolonged initial clinical course, followed by rapid later growth, finally reaching 3.7 × 7.0 cm in size over four years. Despite the harmless clinical appearance, the lesion was histologically characterized by tortuous vascular channels with some cellular atypia. Immunoperoxidase staining disclosed no factor VIII-related antigen or reaction to Ulex europaeus I lectin on tumor cells. There has been no recurrence three years after local excision. Although many features in our case resemble those reported in the literature under the term low-grade angiosarcoma, our preferred designation for such cases is acquired progressive lymphangioma, rather than angiosarcoma, because of their benign behavior.(Arch Dermatol 1988;124:699-701)

TO THE EDITOR.— Involving the Central Nervous System Mycosis fungoides (MF) lymphoma affects the skin primarily, but ultimately can involve almost every organ and tissue of the body.1 Immunohistochemical studies with monoclonal antibodies specific for T-cell subsets disclose helper T-cell predominance in most cases,2,3 but, in some cases, the malignant clone of the cells belongs to a suppressor-cytotoxic subclass.2-4 We herein describe a case of MF that had a fulminant clinical course followed by widespread central nervous system involvement. Unique features in this case are the single proliferation of monoclonal OKT8-reactive T cells and peculiar palmar lesions resembling pustules. REPORT OF A CASE.— A 48-year-old man was hospitalized on Oct 25, 1982, because of numerous infiltrative erythematous plaques, pigmented patches, and ulcerated or crusted tumors all over his body (Fig 1). Pruritic, scaly erythema first appeared on the extremities and buttocks in 1977. On admission, lymph node enlargement was palpable in the axillae and groin. Laboratory studies revealed elevated levels of aspartate aminotransferase

Previous studies suggest that altered peripheral blood circulation might be associated with erythema or inflammation in atopic dermatitis (AD) patients. However, the overall structure of blood vessels and capillaries in AD skin is poorly understood because most studies have involved light-microscopic observation of thin skin sections. In the present study, we compared the 3-dimensional structures of peripheral blood vessels of healthy subjects and AD patients in detail by means of 2-photon microscopy. In skin from healthy subjects, superficial vascular plexus and capillaries originating from flexous blood vessels were observed. However, skin from AD patients contained thickened, flexuous blood vessels, which might be associated with increased blood flow, in both erythematous and nonlesional areas. However, patients with lichenification did not display these morphological changes. Bifurcation of vessels was not observed in either erythematous or lichenification lesions. These results might be helpful for developing new clinical strategies to treat erythema in AD patients.

Myeloid derived suppressor cells (MDSCa) are a heterogeneous population of cells that promote an immunosuppressive environment in tumor-bearing hosts. Recently, B7-H1 signaling has been reported to be critical for the maintainancer of regulatory T cells (Tregs), another immunosuppressive cell population. Here, we discuss the immunosuppressive function of B7-H1 on MDSCs, and the functional crosstalk between Tregs and MDSCs.

An imbalance of immunosuppressive cells and cytotoxic cells plays an important role in the tumor-bearing host. Together with regulatory T cells (Tregs), tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment. Since interferon beta (IFN-β) has been clinically used for the treatment of malignant melanoma, we investigated the immunomodulatory effect of IFN-β during melanoma growth to elucidate the effects of IFN-β on the tumor microenvironment by using the B16F10 melanoma model. Peritumorally administered IFN-β significantly decreased the mRNA expression and production of Th2-related chemokines, which suppressed the recruitment of Tregs in B16F10 melanoma. Since the administration of IFN-β augments the expression of PD-1 on TILs, the co-administration of anti-PD-1 Ab augmented the therapeutic effect of IFN-β for the treatment of B16F10 melanoma. Moreover, in parallel with the mouse model, in the human system, IFN-β decreased the production of Th2-related chemokines and augmented the production of Th1-related chemokines from monocyte-derived M2 macrophages. Since these immunomodulatory effects of IFN-β on macrophages were also observed in the lesional skin of human in-transit melanoma, our present data suggest one of the possible immunomodulatory effects of IFN-β and support the possibility of IFN-β in combination with anti-PD-1 Ab for the treatment of melanoma.