Search

Occupational allergic diseases are likely to worsen or become intractable as a result of continuous exposure to high concentrations of causative allergens. These are socioeconomically important diseases that can lead to work interruptions for patients and potentially job loss. We published the first guideline for managing occupational allergic diseases in Japan. The original document was published in Japanese in 2013, and the following year (2014) it was published in English. This guideline consists of six chapters about occupational asthma, occupational allergic rhinitis, occupational skin diseases, hypersensitivity pneumonitis, occupational anaphylaxis shock, and the legal aspects of these diseases. Providing general doctors with the knowledge to make evidence-based diagnoses and to understand the occupational allergic disease treatment policies, was a breakthrough in allergic disease treatment.

In 2013, a guideline for occupational allergic diseases was published for the first time in Japan. Occupational allergic diseases are likely to worsen or become intractable as a result of continuous exposure to high concentrations of causative antigens, and are socioeconomically important diseases with which the patients might sometimes lose jobs due to work interruptions. Guidelines for occupational allergic diseases have been published in many countries. This guideline consists of six chapters about occupational asthma, occupational allergic rhinitis, occupational skin diseases, hypersensitivity pneumonitis and occupational anaphylaxis shock, and legal aspects of these diseases. The guideline is characterized with the following basic structure: Clinical Questions (CQs) are set with reference to Minds (Medical Information Network Distribution Service), statements by the committee are correspondingly listed, recommended grades and evidence levels are defined, and then descriptions and references are indicated.

Bowen disease with sebaceous differentiation has been rarely documented to date. Here, we present a case of Bowen disease with sebaceous differentiation. A 67-year-old man presented with a 6.0 × 3.5 cm erythematous plaque adjacent to a 7.0 × 3.0 cm erythematous plaque on his left abdomen. Dermoscopy revealed yellow structureless areas and dotted vessels on a pink homogenous background in addition to surface scales. Histopathological examination of the upper erythematous plaque showed parakeratosis and acanthosis with proliferation of atypical keratinocytes in the epidermis. Some of the atypical cells had large and hyperchromatic nuclei. Histopathological examination of the lower erythematous plaque showed tumor nests extending from the epidermis. Tumor nests with hyperchromatic and atypical cells had vacuolated cells. The diagnosis of Bowen disease with sebaceous differentiation was made. Immunohistochemistry revealed a positive reaction for cytokeratin 1 (CK1) in tumor cells of Bowen disease and a negative reaction for CK1 in tumor cells with the sebaceous differentiation, whereas immunohistochemistry revealed no apparent adipophilin-positive granules in tumor nests of Bowen disease compared with the prominent staining of adipophilin in tumor nests with sebaceous differentiation. We show Bowen disease with sebaceous differentiation taking advantage of immunohistochemistry of adipophilin and CK1. Those findings of Bowen disease with sebaceous differentiation may deepen our understandings and insights into the pathogenesis of sebaceous carcinoma and Bowen disease.

IMPORTANCE: Most patients with tuberous sclerosis complex (TSC), an autosomal-dominant disorder that is caused by the constitutive activation of mammalian target of rapamycin, experience disfigurement caused by skin lesions involving facial angiofibromas. Many have been left untreated because of a lack of therapeutic options that are less invasive than surgery or laser treatment. OBJECTIVE: To confirm the efficacy and safety of sirolimus gel, 0.2%, for treatment of patients with angiofibromas and/or skin lesions. DESIGN, SETTING, AND PATIENTS: Multicenter, randomized clinical trial at 9 centers in Japan from December 2015 to October 2016 including 62 children and adults with TSC. INTERVENTIONS: Patients who developed angiofibromas were randomly assigned, in a 1:1 ratio, to receive sirolimus gel, 0.2%, or placebo, each applied topically twice daily for 12 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was composite improvement in the size and color of angiofibromas in photographs at week 12 of treatment. It was assessed by an independent review committee comprising 3 blinded dermatologists who categorized patient results into the following 6 categories: “markedly improved,” “improved,” “slightly improved,” “unchanged,” “slightly aggravated,” and “aggravated.” RESULTS: Sixty-two patients (27 pediatric and 35 adult; 34 [55%] female; mean [SD] age, 22.5 [11.9] years) were enrolled and randomly assigned to receive sirolimus gel, 0.2% (30 patients), or placebo (32 patients). The response rates of angiofibromas at weeks 4, 8, and 12 of treatment were 0 each in the placebo group in contrast to 20% (95% CI, 8%-39%; P = .01), 43% (95% CI, 26%-63%; P < .001), and 60% (95% CI, 41%-77%; P < .001), respectively, in the sirolimus group. None of the 31 assessable patients in the placebo group were rated improved or better, and 26 of them (84%) were rated unchanged. In contrast, 5 (17%) and 13 (43%) patients in the sirolimus group were rated markedly improved and improved, respectively. Adverse events were mild to moderate and were observed in 27 (90%) and 22 (69%) patients in the sirolimus and placebo groups, respectively; however, none of the trial participants discontinued treatment. Acute pancreatitis developed as a serious adverse event in 1 patient in the sirolimus group, and the patient recovered soon after hospitalization without discontinuing treatment. CONCLUSIONS AND RELEVANCE: Sirolimus gel, 0.2%, demonstrated a significant clinical benefit for patients with TSC involving angiofibromas, thus providing a promising therapeutic modality. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02635789

In 2013, a guideline for occupational allergic diseases was published for the first time in Japan. Occupational allergic diseases are likely to worsen or become intractable as a result of continuous exposure to high concentrations of causative antigens, and are socioeconomically important diseases with which the patients might sometimes lose jobs due to work interruptions. Guidelines for occupational allergic diseases have been published in many countries. This guideline consists of six chapters about occupational asthma, occupational allergic rhinitis, occupational skin diseases, hypersensitivity pneumonitis and occupational anaphylaxis shock, and legal aspects of these diseases. The guideline is characterized with the following basic structure: Clinical Questions (CQs) are set with reference to Minds (Medical Information Network Distribution Service), statements by the committee are correspondingly listed, recommended grades and evidence levels are defined, and then descriptions and references are indicated.

IMPORTANCE Linear IgA/IgG bullous dermatosis (LAGBD) is a relatively rare autoimmune bullous disease characterized by both IgA and IgG antibodies to epidermal basement membrane zone. The heterogeneity and pathogenesis of the LAGBD autoantigens have not been fully elucidated. OBSERVATIONS We report 3 Japanese cases of LAGBD (ages 81, 88, and 64 years; 1 woman and 2 men). The patients showed bullous and erosive lesions on the trunk and extremities with minimal mucosal lesions. Histopathological analysis revealed a subepidermal blister with neutrophilic infiltration with eosinophils in 2 cases. Direct and indirect immunofluorescence studies disclosed IgG and IgA antibasement membrane zone antibodies. In immunoblot analyses of various antigen sources, all cases showed IgG and IgA antibodies to various subunits of laminin-332, in addition to IgG and IgA reactivity with type VII collagen, laminin-γ1, and BP230 and BP180 recombinant proteins. CONCLUSIONS AND RELEVANCE Our studies revealed that the 3 LAGBD cases showed prominent IgG and IgA reactivity with laminin-332, which was only rarely reported. In addition, all cases showed IgG and IgA reactivity with other multiple antigens, indicating the role of epitope-spreading mechanisms initiated from laminin-332. The significance of IgA antibodies to laminin-332 should be studied in larger cohorts of both LAGBD and linear IgA bullous dermatosis.

Prostaglandin (PG) D2 and PGE2 are arachidonic acid metabolites that are generated though an isomerization reaction catalyzed by PG synthases. PGs have been implicated in immunologic reactions in addition to a wide range of physiological functions. It has long been thought that basophils, in contrast to mast cells, do not synthesize PGs, although they do release leukotrienes and platelet-activating factor. Here, we show that basophils function as a source of PGD2 and PGE2. In vitro-cultured basophils from mouse bone marrow produced both PGD2 and PGE2 in response to IgE + antigen (Ag), but not to IgG + Ag. Release of PGs was almost completely abrogated in cultured basophils from FcRγ-chain−/−mice, indicating the involvement of FcεRI. Basophils freshly isolated from bone marrow cells (primary basophils) were also capable of secreting PGD2 and PGE2. Although the amount of PGD2 released from primary basophils was lower than that from mast cells, the capability of primary basophils to generate PGE2 was more potent than that of mast cells. Transcripts and proteins for both hematopoietic-type PGD synthase and PGE synthase were detected in basophils. In addition, human basophils, like mouse basophils, also produced PGD2 through IgE-mediated stimulation. Thus, basophils could be an important source of PGD2/PGE2 and may contribute to allergic inflammation and immune responses.

Prostaglandin D2 (PGD2) exerts its effects through two distinct receptors: the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and the D prostanoid (DP) receptor. Our previous study demonstrated that CRTH2 mediates contact hypersensitivity (CHS) in mice. However, the function of DP receptor remains to be fully established. In this study, we examine the pathophysiological roles of PGD2 using DP-deficient (DP−/−) and CRTH2/DP-deficient (CRTH2−/−/DP−/−) mice to elucidate receptor-mediated PGD2 action in CHS. We observed profound exacerbation of CHS in DP−/−mice. CRTH2−/−/DP−/−mice showed similar exacerbation, but to a lesser extent. These symptoms were accompanied by increased production of interferon-γ and IL-17. The increase in IL-17 producing γδ T cells was marked and presumably contributed to the enhanced CHS. DP deficiency promoted the in vivomigration of dendritic cells to regional lymph nodes. A DP agonist added to DCs in vitrowas able to inhibit production of IL-12 and IL-1β. Interestingly, production of IL-10 in dendritic cells was elevated via the DP pathway, but it was lowered by the CRTH2 pathway. Collectively, PGD2 signals through CRTH2 to mediate CHS inflammation, and conversely, DP signals to exert inhibitory effects on CHS. Thus, we report opposing functions for PGD2 that depend on receptor usage in allergic reactions.

Prostaglandin D2 (PGD2), an arachidonic acid metabolite, has been implicated in allergic responses. A major source of PGD2 in the skin is mast cells that express hematopoietic PGD synthase (H-PGDS). In this study, we show the expression of H-PGDS in human dendritic cells (DCs) and the regulatory mechanisms by which DCs produce PGD2. We detected H-PGDS in epidermal Langerhans cells, dermal DCs, plasmacytoid DCs, and myeloid DCs. Monocyte-derived DCs rapidly secreted PGD2 when stimulated with the calcium ionophore A23187. More importantly, pretreatment of monocyte-derived DCs with PMA (phorbol 12-myrisate 13-acetate) synergistically enhanced the rapid PGD2 secretion induced by A23187, whereas PMA alone did not induce PGD2 secretion. Lipopolysaccharide (LPS) reduced H-PGDS expression, but interferon-γ followed by LPS induced significant PGD2 production in a delayed time course at 6 hours. This effect was associated with inhibition of LPS-induced H-PGDS reduction. Interestingly, an irritant compound, SDS, also induced a rapid PGD2 release. PGD2 synergistically enhanced CCL22/macrophage-derived chemokine synthesis in interferon-γ-treated human keratinocytes. In addition, bone marrow-derived DCs from wild-type mice stimulated lymph node cells to produce higher amounts of interleukin-17 than did DCs from mice lacking the H-PGDS gene. Thus, DCs could be an important source of skin PGD2 and may mediate or regulate skin inflammation by releasing PGD2 in response to various stimuli, contributing to the innate and/or acquired immune responses.

mMCP‐11 is the first mast cell tryptase whose expression is documented in mouse basophils. Tryptases and chymases are the major proteins stored and secreted by mast cells, and they have various biological functions. However, the nature of proteases produced by basophils has been poorly characterized, particularly in mice. mMCP‐11 is the most recently discovered mast cell tryptase in mice and was originally identified as Prss34, which is transcribed in some mast cell‐like cell lines and at the early stage in the culture of BMMC with IL‐3. Curiously, Prss34is preferentially expressed in the BM and spleen among normal tissues in contrast to other mast cell tryptases. Therefore, it remains elusive what types of cells express mMCP‐11 in vivo. Here, we show that mMCP‐11 is highly expressed by primary basophils and to a much lesser extent, by some mast cells. Prss34transcripts were detected abundantly in primary and cultured basophils and very weakly in peritoneal mast cells or cultured BMMC. Conversely, transcripts for mMCP‐6 and mMCP‐7 tryptases were preferentially expressed by cultured and peritoneal mast cells but not basophils. We established a mMCP‐11‐specific mAb and showed that mMCP‐11 proteins are indeed expressed by primary basophils and those infiltrating the affected tissues during allergic inflammation and parasitic infections. Some primary mast cells also expressed mMCP‐11 proteins, albeit at a much lower level. Thus, basophils rather than mast cells are the major source of mMCP‐11. This is the first study to demonstrate that mouse basophils produce a trypsin‐like protease.

In patients with wheat-dependent exercise-induced anaphylaxis (WDEIA), anaphylactic shock occurs frequently, therefore avoidance of wheat products is recommended. We aimed to evaluate efficacy and safety of long-term omalizumab treatment for adult patients with WDEIA.

P-Selectin expressed on endothelial cells contributes to acute and chronic inflammation by promoting leukocyte tethering/rolling. Despite increasing evidence of P-selectin expression on human umbilical vein endothelial cells in vitro, the regulatory mechanisms of P-selectin expression on dermal endothelial cells in skin diseases are not fully understood. Here, we demonstrate increased expression of P-selectin in dermal vessels of regional skin in urticaria and atopic dermatitis. The present in vitroanalyses with human dermal microvascular endothelial cells (HDMECs) revealed that histamine rapidly induced P-selectin expression. Interleukin (IL)-4 and IL-13 induced prolonged expression of surface P-selectin by HDMECs. A combination of tumor necrosis factor-α and IL-4 inhibited P-selectin expression. Pretreatment of HDMECs with tumor necrosis factor-α followed by incubation with IL-4 markedly increased P-selectin expression. Notably, incubation with substance P alone induced prolonged P-selectin expression. Activation of STAT6 appears to be a key factor in P-selectin expression induced by substance P and IL-4 because treatment with STAT6 decoy oligodeoxynucleotides significantly inhibited P-selectin expression. The present results indicate that novel, complex mechanisms are involved in endothelial P-selectin expression in the skin. STAT6 in dermal endothelial cells appears to be a potent target for controlling cellular infiltrate in allergic and/or neuroinflammatory skin diseases.

Selectins mediate the initial adhesion of leukocytes to endothelial cells in many contexts of inflammation-dependent leukocyte recruitment. The glycans that contribute to P- and E-selectin counterreceptor activity arise through glycosylation reactions in which the terminal steps are catalyzed by α(1,3) fucosyltransferases (FTs). We examined how selectin ligand activities are controlled in eosinophils by characterizing FT expression profiles and regulatory mechanisms in eosinophils isolated from human blood. We found that FT-IV and FT-VII mRNAs were up-regulated by transforming growth factor-β1, but the FT-IV transcript consistently predominated in eosinophils. To further define the physiological role of FT-IV and FT-VII in expression of eosinophil selectin ligand, we characterized models of dermal eosinophilia in FT-IV- and/or FT-VII-deficient mice in vivo. FT-IV deficiency yielded a significant decrease in eosinophil recruitment to the skin. Likewise, deficiency of FT-VII also yielded a decrease in eosinophil recruitment. Eosinophil recruitment that remained in the absence of FT-VII was further inhibited by blocking P- or E-selectin and was essentially absent in mice deficient in both enzymes. These observations indicate that FT-IV and FT-VII are both important contributors to selectin-dependent eosinophil recruitment to the skin and may represent therapeutic targets for treating diseases in which eosinophil recruitment contributes to pathophysiology.

Cutaneous fibrous histiocytomas are usually regarded as superficial lesions and commonly known as dermatofibromas; however, unusual cases histologically showing fibrohistiocytic proliferation extending into the deeper dermis or subcutaneous tissues are occasionally experienced. Some authors propose this type as benign fibrous histiocytoma of the skin, distinct from dermatofibroma. We describe herein a case of systemic lupus erythematosus (SLE) who developed multiple nodules on the face, trunk and extremities. The nodule on the forehead did not present a typical clinical appearance of dermatofibroma, and histopathological examination showed fibrohistiocytic proliferation with a storiform pattern extending into the deep dermis and subcutaneous tissues. By contrast, histology of the nodule on the abdomen showed fibrohistiocytic proliferation confined to the dermis and compatible with dermatofibroma. Although multiple dermatofibromas are occasionally seen in patients with SLE, benign fibrous histiocytoma of the skin showing deeper invasion than dermatofibroma is rarely associated with SLE.

Psoriasis arthropathy (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis with psoriasis. Although the precise mechanisms of PsA still remain obscure, several genetic and environmental factors have been suggested to play important roles. HLA‐B51 has been strongly associated with Behçet's disease; however, its association with PsA has not been documented. We describe herein five Japanese patients (4 males and 1 female) with PsA and positive for HLA‐B51. The clinical forms defined by Moll and Wright revealed that the polyarticular pattern was noted in two cases, and oligoarticular, distal, and spondyloarthropathy patterns were noted in one case each. Positive rheumatoid factor was detected in one patient, and antinuclear antibody in two patients. The other HLA subclasses were A2 and A31 in 3 cases, respectively. HLA‐B51 was detected in 5 out of 17 patients with PsA examined in our department; in contrast, HLA‐B51 was not detected in 17 patients with psoriasis vulgaris. Our observations suggest that HLA‐B51 may play a role in the pathogenesis of PsA in the Japanese population.

Psoriasis arthropathy (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis with psoriasis. In this study, clinical, laboratory and radiographic signs of 21 patients (12 males and 9 females), mean age of 42.2 years old, with PsA were assessed. The clinical forms defined by Moll and Wright revealed that oligoarticular pattern was most commonly observed in ten patients (47.6%), followed by polyarticular (5 patients), distal (3 patients), spondyloarthropathy (2 patients), and mutilans (1 patient). Positive rheumatoid factor was detected in three patients and antinuclear antibodies in eight patients, suggesting the involvement of immunological disregulation in this disorder. Twelve patients were onychopathic, of whom 11 showed distal interphalangeal (DIP) joint arthritis. Based on radiologic observation, spur formation of the calcaneus (1 patient) and destructive changes of the articulatio coxa (1 patient) were seen, in addition to the findings such as joint space narrowing, erosive changes, resorptive changes and ‘pencil‐in‐cup’ appearances. Non‐steroidal anti‐inflammatory drugs (NSAIDs) were used in all cases for the control of joint pain, solely or in combination with immunomodulatory drugs such as bucillamine, sulfasalazine, methotrexate, cyclosporin, etretinate, and mizoribine. However, some of those drugs were often ineffective for the joint pain, while effective for cutaneous psoriasis. Immunohistological studies of the biopsied synovial tissues from two patients showed increased expressions of CD45RO and HLA‐DR, suggesting that the vast majority of inflammatory cells are mature and activated T‐cells. Parallel immunostaining using the involved psoriatic skin from one of the patients also showed enhanced expression of CD45RO, but less expression of HLA‐DR as compared with its expression in the synovium. On the other hand, cutaneous leukocyte antigen (CLA) was abundantly detected in the inflammatory cells in the lesional skin, although less expressed in the synovium. These results are consistent with earlier observations suggesting a different subpopulation of inflammatory cells in the skin than the joint.

We herein report six cases of localized involutional lipoatrophy, who presented with a depressive plaque on the lateralis of the upper arm. All patients were female, and three had previous injections for allergic rhinitis at the affected sites before the development of lipoatrophy. One patient received intramuscular injection at the affected site when she had a cold. Histological examination showed fat lobules composed of small lipocytes in the hyaline connective tissue. Immunohistochemical examination revealed a number of CD68‐positive macrophages in the fat lobules. We consider that localized involutional lipoatrophy is more common than has been reported, and is occasionally induced by local injections.

We report a case of Kikuchi's disease (histiocytic necrotizing lymphadenitis) in a 22‐year‐old Japanese man who presented with cervical and axillary lymphadenopathy and who developed edema of lips with desquamation and erosions and transient indurated erythematous papules on the face, neck and upper extremities. A lymph node biopsy specimen showed the typical necrotizing lymphadenitis of Kikuchi's disease. A skin biopsy specimen showed a dense, lymphohistiocytic, superficial, deep perivascular, and interstitial infiltrate, papillary dermal edema, and abundant nuclear debris with a conspicuous absence of neutrophils, paralleling the nodal histology of Kikuchi's disease. CD68 immunohistochemistry showed many plasmacytoid monocytes. Oral corticosteroid (prednisolone 40 mg) therapy improved the skin lesions and other clinical symptoms. Lip involvement by Kikuchi's disease has not been reported, and should be included as one of the possible cutaneous manifestations of Kikuchi's disease.

Leukocyte extravasation is initiated by interaction with endothelial selectins through selectin ligands. To understand the relative roles of E- and P-selectin in eosinophil recruitment in inflamed skin, we examined the expression of sialyl-Lewis x (sLex) structures and selectin ligands on eosinophils from patients with atopic dermatitis using whole blood flow cytometry. None of the eosinophils from the blood of patients expressed HECA452 (a lymphocyte receptor for skin homing) or CSLEX1 epitopes, and they had little avidity for soluble E-selectin. Whereas levels of the FH6 epitope (sialyl-dimeric Lex) varied on blood eosinophils, none of the infiltrative eosinophils in the skin lesions of patients expressed any type of sLex structures on the surface. In contrast, blood eosinophils bound to soluble P-selectin. The amount of P-selectin that bound to eosinophils was significantly greater in patients with atopic dermatitis than in healthy donors. PSGL-1 expression between these two groups did not differ. Furthermore, eosinophils expressed a large amount of α (1, 3) fucosyltransferase (FucT)-IV mRNA, but remarkably little or no FucT-VII mRNA compared with neutrophils. Thesedata indicate that eosinophil interaction with endothelial P-selectin is far more important than interaction with E-selectin for recruitment into the inflamed skin of patients with atopic dermatitis. None of HECA452, 2H5, CSLEX1 or FH6 antigens functioned as a specific receptor to promote preferential skin infiltration via adhesion to endothelial E-selectin. FucT-IV in eosinophils may be morerelavent to the generation of functional P-selectin ligand than FucT-VII.

In the last decade, several new aspects of glucocorticoid (GC)-actions on immune cells have been recognized. This recognition has been largely obtained through clinical observations of stress-induced exacerbations of certain dermatologic diseases. To clarify whether GC modulates cutaneous inflammatory reactions besides its known anti-inflammatory effect, first we examined the effect of long-term application of topical GC on several kinds of inflammatory responses induced in the murine model and demonstrated that these regimens significantly augmented the classical contact sensitivity reaction, the croton oil-induced irritant reaction, and the IgE-mediated biphasic cutaneous reaction. In addition, large dose topical steroid and its withdrawal enhanced scratching behavior in hapten-challenged mice. This augmented scratching behavior correlated with the induction of preprotachykinin mRNA expression in the challenged skin. In an in vitro experiment, a low-dose, stress-induced level of glucocorticoid significantly upregulated hapten-induced proinflammatory cytokine (IL1α) production by murine keratinocyte cell line Pam 212 and induced substance P peptide production from cultured human keratinocytes. Our results suggest that unsuitable use of GC in addition to stress-induced GC may modulate immune function in the skin through aberrant production of tachykinin, such as substance P or other epidermal cell derived cytokines.Journal of Investigative Dermatology Symposium Proceedings (2001) 6, 81–86; doi:10.1046/j.0022-202x.2001.00015.x

Blood and tissue eosinophilia is obtained when mice pretreated with cyclophosphamide (CY) and sensitized with picryl chloride are challenged on each ear lobe on day 13. To gain important insights into the cellular mechanisms involved in CY-induced eosinophilia in the contact-sensitivity reaction, we examined the cytokine profile expressed in regional lymph node cells and spleen cells. CY pretreatment 2 days before sensitization enhanced expression of IL-4 mRNA in the regional lymph node cells more strongly than expressions of both IL-2 and IFN-γ mRNA on day 13. Five days after sensitization, spleen cells expressed IL-5 mRNA and produced IL-5 in vitro. Depletion of CD4⁺ cells from spleen cells completely abrogated the secretory capacity of IL-5. In vivo blocking of IL-5 on day 3 entirely inhibited spleen, bone marrow, and subsequent blood eosinophilia. When immune lymph node cells prepared on day 13 were stimulated with hapten-modified cells in vitro, the level of IL-4 secreted in the culture supernatant was enhanced by CY pretreatment, but that of IL-2 was not. One important result was that IL-5 was not produced in response to in vitro stimulation, despite the fact that marked eosinophil infiltration in the dermis was observed in vivo. Thus, eosinophilopoiesis was stimulated by IL-5-producing CD4⁺ immune T cells that were present in the eosinophil production site, particularly in the spleen before elicitation. In contrast, eosinophil recruitment into the dermis in the efferent phase can be induced without production of IL-5 from lymphocytes. Copyright 2000 Academic Press.

The expression of Heat Shock Protein (HPS) 72/73, HSP65 and HSP27 in skin lesions of atopic dermatitis (n=21) was studied and compared with that in contact dermatitis (n=18) and normal skin (n=9). Keratinocytes in the whole epidermis expressed both HSP65 and HSP72/73 with a membranous, cytoplasmic or nuclear/perinuclear staining pattern much more intensely in atopic dermatitis than in contact dermatitis and normal subjects. In approximately half of the subjects with atopic dermatitis, infiltrating cells in the dermis expressed HSP65 and HSP72/73; this was not observed in contact dermatitis. HSP27 was expressed in the upper epidermis with a cytoplasmic or nuclear/perinuclear staining pattern in all groups. HSP27 was not expressed by infiltrating cells. A clinical evaluation of atopic dermatitis showed that more severe types of atopic dermatitis expressed more intense expression of HSP65 and HSP72/73, but not HSP27, in their skin lesions. These findings suggested that HSP65 and HSP72/73 may play roles in the pathogenesis of atopic dermatitis.

Contact hypersensitivity (CHS) is thought to be mainly associated with the activation of T helper type 1 (Th1) cells. However, there is also evidence that Th2 cells or Th2 cytokines play a role in the development of CHS. To analyze the functional contribution of Th2 cytokines interleukin (IL)-4 and IL-13, signal transducer and activator of transcription 6 (STAT6)-deficient (STAT6−/−) and wild-type (wt) control C57BL/6 mice were contact sensitized with 5% 2,4,6-trinitrochlorobenzene (TNCB), 0.5% 2,4-dinitrofluorobenzene, or 5% 4-ethoxyl methylene-2-phenyl-2-oxazolin-5-one, and any skin reactions were examined. Ear swelling was significantly reduced with a delayed peak response in STAT6−/− mice compared with wt mice. A histological analysis revealed that the infiltration of both eosinophils and neutrophils in the skin challenged after 24 h in STAT6−/− mice decreased substantially compared with that in wt mice. The expression of Th2 cytokines (IL-4, IL-5) in TNCB-challenged skin tissues and the supernatants from T cells stimulated by 2,4,6-trinitrobenzene sulfonate–modified spleen cells, as well as the immunoglobulin (Ig)E and IgG1 response after challenge, were also profoundly reduced in STAT6−/− mice, whereas the expression of interferon γ was the same in STAT6−/− and wt mice after challenge. Furthermore, adoptive transfer experiments revealed that STAT6−/− mice induced CHS after injection of lymph node cells obtained from sensitized wt mice. Our data suggest that the STAT6 signal plays a critical role in the induction phase of CHS.

Early differential diagnosis between malignant and benign tumors and their underlying intrinsic differences are the most critical issues for life-threatening cancers. To study whether human acral melanomas, deadly cancers that occur on non-hair-bearing skin, have distinct origins that underlie their invasive capability, we develop fate-tracing technologies of melanocyte stem cells in sweat glands (glandular McSCs) and in melanoma models in mice and compare the cellular dynamics with human melanoma. Herein, we report that glandular McSCs self-renew to expand their migratory progeny in response to genotoxic stress and trauma to generate invasive melanomas in mice that mimic human acral melanomas. The analysis of melanocytic lesions in human volar skin reveals that genetically unstable McSCs expand in sweat glands and in the surrounding epidermis in melanomas but not in nevi. The detection of such cell spreading dynamics provides an innovative method for an early differential diagnosis of acral melanomas from nevi.

Many patients with severe atopic dermatitis (AD) in Japan are afflicted with persistent erythema of the face (atopic red face) that is not only resistant to topical corticosteroid, but often becomes worse with its use. During a three‐year period (1991–1993), we treated 79 inpatients with severe AD by a combination of careful daily skin care, use of emollients, and exclusion of exacerbating factors. Occular complications before and after treatment were examined in these cases. After withdrawal of topical corticosteroid, almost all of the patients showed a temporary worsening of their skin condition. Immediately thereafter, their occular symptoms did not change. Cataract was found in 20 cases (25.3%), and retinal detachment in 9 (11.4%). After 2 months, 11 cases of cataract and 5 cases of retinal detachment in the peripheral retina were observed. However, these incidences were similar to the numbers reported in Japan during conventional treatment with topical corticosteroid.

To date, there are no successful treatments for reticular erythematous mucinosis (REM) other than antimalarial drugs such as chloroquine; these have many adverse side effects and are prohibited for use in Japan. We report a case of REM improved by a large dose of ultraviolet B (UVB) radiation and a steroid impregnated tape. The large dose of UVB radiation improved the erythema after 5 weeks. Application of steroid impregnated tape to a lesion where a large dose of UVB had been given produced an additive clinical effect. UVB radiation and steroid impregnated tape are considered to be effective treatments for REM.

Heat shock proteins are chaperones to construct protein molecules and are widely distributed in prokaryotic and eukaryotic cells. They are also induced by environmental stress to protect cells. Human heat shock proteins cross-react with bacterial heat shock proteins to modulate immune responses to induce autoimmunity. They are involved in the differentiation and growth of neoplastic cells as well as normal cells. They are also involved in various inflammatory skin diseases and in fibrotic process. Heat shock proteins play important roles in the pathogenesis of many skin diseases.

The elevation of tumor markers in benign diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, or diabetes mellitus has been reported recently. We had the opportunity to observe a female patient with progressive systemic sclerosis (PSS) and pleuritis who demonstrated a high level of CA125 in her pleural effusion and blood serum. The purpose of this report is to describe this case. We also investigated whether tumor markers are elevated in collagen disease. We measured the serum levels of CA125 and CA19‐9 in our case of PSS with pleuritis, 27 female patients with collagen diseases including SLE, PSS, dermatomyositis and Sjögren syndrome, and 11 normal females as controls.

A 73‐year‐old male developed disseminated erythema over his entire body after exposure to indeloxazine hydrochloride, a cerebral activator. Patch testing with indeloxazine hydrochloride showed a positive reaction, and plaques, vesicles and pustules developed on the face after the patch test. These had the pathologic feature of eosinophilic pustular folliculitis (EPF, Ofuji's disease). A challenge test also provoked eruptions on the face, trunk, arms and legs, which were compatible with EPF. Moreover, both the patch and challenge tests with indeloxazine hydrochloride induced eosinophilia. This is the first report of drug allergy‐induced EPF, where drug sensitivity induced an abnormal eosinophilic response mimicking EPF.

A 62‐year‐old woman with systemic sarcoidosis developed erythematous plaques on her lower legs. Clinically, two kinds of skin lesions were distinguished; one type formed brownish‐red plaques with induration suggesting plaque‐type skin sarcoid, and the other formed purplish erythematous plaques with atrophic centers resembling necrobiosis lipoidica. In spite of this clinical appearance, a biopsy specimen from one of the latter lesions revealed typical skin sarcoid histology composed of discrete non‐caseating granulomas, while that from one of the other lesions showed necrobiotic changes of collagen bundles surrounded by epitheloid histiocytes and foreign‐body giant cells. Because cutaneous involvement of sarcoidosis may mimic necrobiosis lipoidica clinically and/or histologically, we diagnosed her skin lesions as necrobiosis‐like skin sarcoid.

Epidermal cells produce various kinds of cytokines and express cell adhesion molecules. To analyze early events which induced in human epidermis by stimulation with various chemicals, we analyzed mRNA of cytokines expressed in epidermis in a human skin organ culture system. After painting haptens, primary irritants or vehicle control on human skin specimens sliced to 1 mm thickness and cut into approximately 5×5 mm blocks, the pieces were cultured in serum‐free medium. After separating epidermis from dermis, total RNA was extracted and mRNA of cytokines was assessed by the reverse transcriptase‐polymerase chain reaction. Only haptens induced IL‐1β mRNA at 1–3 hours. TNF‐α mRNA was induced 9 hours after application of haptens and 1 hour after application of primary irritants. IL‐1α mRNA was not induced by either haptens or primary irritants. Thus, cytokine mRNA expression induced by haptens in epidermis differs from that induced by primary irritants.

Two Japanese women developed well‐dermarcated ichthyosiform plaques on the lateral aspect of their lower legs. Deposition of mucin was demonstrated throughout the papillary dermis, unlike the site of mucin deposition seen in pretibial myxedema. Their thyroid function was normal. The condition of both women was complicated by Sjögren's syndrome. One of them who presented with positive anti‐microsomal and anti‐thyroglobulin antibodies had goiter, suggesting that her malady was also complicated by Hashimoto's thyroiditis.

Biopsied specimens from skin lesions of SLE were studied for expression of 70 KD heat shock protein (HSP70). The pattern of HSP70 expression in SLE was diffuse in whole epidermis, hair follicles, and sweat gland cells and rather more intense than that in other control groups or normal skin. No significant differences in HSP70 expression were observed between sun‐exposed and protected areas of SLE skin lesions. Unlike SLE, reduced or no expression of HSP70 was observed in skin lesions of DLE. In tissue culture, UVB radiation in vitroinduced relatively intense expression of HSP70 in the nuclear area of keratinocytes. A few γδT cell receptor positive cells which might respond to HSP70 expressing cells were detected in the basal layer of skin lesions of diseases.

Three cases of keratosis follicularis squamosa (Dohi) and one case of papillomatose confluente et reticulee were successfully treated with oral minocycline (50‐100 mg/day). The clinical effect first appeared at 2 weeks after the initiation of therapy and no recurrence was observed for more than 3 months without minocycline. Gram positive cocci were demonstrated inside the hair follicle and horny layers in all 4 case. Minocycline might modulate abberant keratinization through its bactericidal effects in these keratinizing disorders.

Using a murine model, topical application of glucocorticoid ([GC], 50 μg diflucortolone valerate in ethanol) on a sensitized site (flank skin) for 7 times before and 2 times after sensitization on alternate days, augmented expression of contact sensitivity reactions on the challenged site (ear skin). This augmentation was due to the systemic effect of percutaneously absorbed GC, because topical GC also augmented the skin reaction in mice that had been sensitized on a separate site from that of the GC application. In contrast, topical application of GC inhibited the contact sensitivity skin reaction when applied on the challenged sites. Intraperitoneal injection of the same dose of GC also failed to augment the skin reactions. Glucocorticoid augmented the contact sensitivity skin reactions and these persisted for 96 h after the control skin reactions subsided. Early phase (1–6 h) skin reactions were also induced or augmented when dinitrofluorobenzene or trinitrochlorobenzene but not oxazolone were used as the sensitizer; GC also augmented the non-specific reactions to croton oil or to suboptimal concentration of hapten in normal mice. The numbers of Langerhans cells (LC) were reduced in both the GC-application and challenged sites. Haptenated LC from GC-treated skin showed a rather weak sensitizing ability, which was not statistically significant. Transfer of lymph node cells and/or spleen cells or serum from GC-pre-treated mice failed to induce a contact sensitivity reaction in normal recipient mice. These results suggest that topical GC might augment cutaneous inflammation through a possible modulation of local cytokine production, regardless of the number of LC or the presence of sensitized lymphocytes.

Pompholyx (Dyshidrosis) is a disease of unknown etiology presenting as symmetrical, vesicular hand and foot dermatitis. To clarify the pathogenetic role of sweat and metal allergy, twenty five patients with pompholyx were examined with respect to their perspiration volume using equipment that continuously recorded the local perspiration volume. Patients were also examined for metal allergy by patch testing and oral challenge tests. The perspiration volumes were measured using recently developed equipment for continuous recording of local perspiration volume (Kenz‐Perspiro oss‐100®). The perspiration volume of pompholyx patients was found to be 2.5 times higher than that of age‐matched normal controls. Twenty percent of the patients showed sensitivity to chromate, 16% to cobalt, and 28% to nickel on patch testing. Six patients with positive results were challenged orally in a controlled trial with 2.5 mg nickel, 1 mg cobalt, or 2.5 mg chromium. Four of them (67%) showed vesicular reactions on their hands with challenge testing. These results indicated a sensitivity to metal compounds which, in combination with local hyperhidrosis, may contribute to the development of vesicular lesions in pompholyx.

Stasis dermatitis (SD) is a common disease in the elderly population, with pruritus being one of the troublesome symptoms. However, there are few therapeutic modalities available for SD-associated itch because little is known about its pathophysiological mechanism. Therefore, we sought to investigate the mediators of itch in SD using an immunofluorescence study on patient lesions focusing on IL-31. Ex vivo stimulation studies using murine peritoneal macrophages were also used to elucidate the pathological mechanisms of the generation of IL-31. In SD lesions, dermal infiltrating IL-31(+) cells were increased in number compared with the healthy controls, and the majority of IL-31(+) cells were CD68(+) macrophages. The presence of itch in SD was significantly associated with the amount of CD68(+)/IL-31(+) macrophages and CD68(+)/CD163(+) M2 macrophages. The number of CD68(+)/IL-31(+) macrophages was correlated with the number of dermal C-C chemokine receptor type 4(+) T helper type 2 cells, IL-17(+) cells, basophils, substance P(+) cells, and dermal deposition of periostin and hemosiderin. Furthermore, murine peritoneal macrophages expressed an M2 marker arginase-1 and generated IL-31 when stimulated with a combination of substance P, periostin, and red blood cell lysate (representing hemosiderin). IL-31 from macrophages may play a role in itch in SD.

Three cases of palpebral edema associated with Graves' disease are described. These patients had unilateral edema and minimal erythema of the upper eyelid. Notable was that, histologically, dermal edema and dilation of lymphatic vessels were observed, but deposition of mucopolysaccharides was not. In 2 cases, edema of the eyelid was resistant to treatment with an antithyroid drug. Unilateral edema of the upper eyelid is an important cutaneous manifestation that indicates the presence of hyperthyroidism. (J Am Acad Dermatol 2003;48:617-9.)

Five patients with chronic pigmented purpura associated with odontogenic infection are described. Four patients had Schamberg's disease, and one had itching purpura. These patients were resistant to topical corticosteroid treatment, but appearance of purpuric spots ceased after treatment for periodontitis, pulpitis, or both. No circulating immune complexes were detected, and neither immunoglobulin nor complement was deposited in the papillary vessels of the skin. Odontogenic infection might be one of the precipitating factors for chronic pigmented purpura. (J Am Acad Dermatol 2002;46:942-4.)