BACKGROUND: Mycosis fungoides (MF) belongs to cutaneous T-cell lymphoma and is clinically divided into 3 stages: patch, plaque, and tumor stage. Thymus and activation-regulated chemokine (TARC/CCL17) is a member of the CC chemokines and is a chemoattractant for CC chemokine receptor 4 (CCR4)- and CC chemokine receptor 8 (CCR8)-expressing cells. OBJECTIVE: In this study, we examined the involvement of TARC among patients with each stage of MF. METHODS: We investigated the expression of TARC, CCR4, and CXC chemokine receptor 3 in patients with each stage of MF by immunohistochemistry. We measured serum TARC levels in 20 patients with MF in varying degrees and compared them with 10 patients with psoriasis vulgaris and 10 healthy controls. In addition, we compared serum TARC levels in patients with MF with other laboratory data. RESULTS: Immunohistochemical staining revealed that TARC was expressed in the lesional keratinocytes in the patch, plaque, and tumor stages. CCR4 was expressed on the epidermotropic cells in both patch and plaque stages and on the large cell-transformed cells in the tumor stage, whereas CXC chemokine receptor 3 was constantly expressed on the small cells in the lesional dermis. Serum TARC levels in patients with MF were significantly higher than those in patients with psoriasis vulgaris or healthy controls. Moreover, serum TARC levels in patients with the tumor stage of MF (n = 5) were remarkably higher than those with patch stage (n = 8) or plaque stage (n = 7). Serum TARC levels significantly correlated with serum lactate dehydrogenase levels (r = 0.62), serum immunoglobulin E levels (r = 0.60), serum soluble interleukin 2 receptor levels (r = 0.72), and serum macrophage-derived chemokine levels (r = 0.70). CONCLUSION: These data strongly indicate that serum TARC levels are useful for assessing the disease activity of patients with MF and that TARC and CCR4 may be involved in the pathogenesis of MF.

Adult↗

PubMed2003

Detection of herpes virus genomes in skin lesions from patients with Behçet's disease and other related inflammatory diseases.

Although the aetiology of Behçet's disease is still poorly understood, viral infection has long been postulated as one of the factors. To investigate the relationship between herpes viruses and Behçet's disease, we used polymerase chain reaction to detect herpes simplex virus 1 (HSV-1) and 2 (HSV-2), and human herpes virus 6 (HHV-6) and 7 (HHV-7) DNA in samples of lesional tissues from patients with Behçet's disease and other related inflammatory disorders. Four cases were positive for HSV-1; 1 of 11 Behçet's disease cases, 2 of 3 Sweet's disease cases and 1 of 3 erythema nodosum cases. Two cases were positive for both HSV-1 and HSV-2; one Behçet's disease and one erythema nodosum. All cases were negative for HHV-6 and HHV-7. These findings indicate that there might be some relationship between Behçet's disease and the presence of HSV-1 and/or HSV-2 DNA and that HHV-6 and HHV-7 do not seem to be involved in the pathogenesis of Behçet's disease. However, HSV-1 and HSV-2 DNAs were also detected in non-Behçet's disease lesions, suggesting that HSV-1/2 is not correlated to the direct pathogenesis of Behçet's disease.

Adult↗

PubMed2003

Demonstration of TARC and CCR4 mRNA expression and distribution using in situ RT-PCR in the lesional skin of atopic dermatitis.

Thymus- and activation-regulated chemokine (TARC/CCL17) and its receptor, CC chemokine receptor 4 (CCR4), have been proven to be involved in a number of allergic diseases, especially atopic dermatitis (AD). The purpose of this study was to examine the expression and distribution of TARC and CCR4 mRNAs in samples of AD (n=15, acute lesions 8, chronic lesions 7) and normal skin (n=6). The expression and distribution of TARC and CCR4 mRNAs were detected with the in situ reverse transcription (RT) -polymerase chain reaction (PCR) technique. TARC mRNA was expressed in epidermal keratinocytes, dermal endothelial cells and infiltrating cells. CCR4 mRNA was expressed in dermal endothelial cells and infiltrating cells. In acute AD lesional skin, there were more positive cells, and the staining intensity was stronger than in chronic lesions (p<0.05). The distribution of positive cells was as follows: In the epidermis, keratinocytes in the basal layer showed the strongest staining, and keratinocytes in the spinous layer showed moderate staining; the superficial area showed faint staining. In the dermis, infiltrating cells located in the superficial area of the dermis showed the strongest staining, positive staining intensity became weaker and the percentage of positive cells became less as the location became deeper. There were no positive cells in normal skin. These data further substantiate the role of TARC/CCR4 in the pathogenesis of AD.

Case-Control Studies↗

PubMed2003

A case of intravascular large B-cell lymphoma with multiple organ involvement.

Intravascular large B-cell lymphoma (IVL) is a rare systemic disease characterized by clonal proliferation of neoplastic lymphoid cells within the capillary lumina of small blood vessels. The most common sites of involvement are cerebrovascular or sinusoid areas, resulting in a wide variety of neurologic deficits. Herein we describe a case of IVL that presented with multiple internal and external organ involvements, including the skin, bilateral kidneys, and lung, and with an aggressive clinical course. The confirmative diagnosis was based on the microscopic findings of the skin lesion with a B-cell immunophenotype. The patient suffered from repeated severe dyspnea, hypoxemia, and high-grade fever with a simultaneous increase in serum lactate dehydrogenase and soluble IL-2 receptor levels. These manifestations responded dramatically to intravenous injection of corticosteroid (500 mg/day for 3 days). Despite various clinical presentations, no neurological abnormality was observed until the patient died 12 months after the initial combination chemotherapy.

Diagnosis, Differential↗

PubMed2003

Multicentric Castleman's disease associated with inherited epidermolysis bullosa.

Multicentric Castleman's disease (MCD) is a rare disorder characterized by fever, polyclonal hypergammaglobulinemia, and generalized lymphadenopathy. It has three histological characteristics: a recognizable architecture, germinal center abnormalities, and plasmacytosis. Inherited epidermolysis bullosa (EB) is also a rare disorder caused by a genetic defect. We report a 43-year-old patient with dystrophic EB, non-Hallopeau-Siemens recessive type or dominant type, displaying clinicopathologic features of MCD. In addition, his serum interleukin-6, which is thought to be responsible for the clinical symptoms in MCD, was elevated.

Adult↗

PubMed2003

A frameshift mutation of the ED1 gene in sibling cases with X-linked hypohidrotic ectodermal dysplasia.

X-linked hypohidrotic ectodermal dysplasia (XLHED; MIM 305100) is characterized by the absence or hypoplasia of hair, teeth, and sweat glands. The ED1 gene was identified as a responsive gene for XLHED. The patients were 2 Japanese brothers. Both had the same mutation in exon 1 of the ED1 gene, i.e. C deletion at nucleotide 49, which induced a frameshift starting from amino acid 17 and made a stop codon at amino acid 56, encoding the transmembrane site. The mutation caused the extracellular domain of ectodysplasin A to be completely absent. Their mother had a heterozygous allele; she congenitally lacked 1 tooth, and incisors appeared conical in form.

Child, Preschool↗

PubMed2003

Lack of association between the promoter polymorphisms at positions -308 and -238 of the tumor necrosis factor alpha gene and psoriasis vulgaris in Japanese patients.

BACKGROUND: Psoriasis features an increased level and activity of tumor necrosis factor alpha (TNF-alpha). The TNF-alpha gene has single nucleotide polymorphisms (SNPs) at positions -308 (-308G>A) and -238 (-238G>A) in the promoter region, and the -238G>A SNP has been reported to be associated with psoriasis vulgaris (PV) and psoriatic arthritis in Caucasians. OBJECTIVE: To examine whether these SNPs are associated with susceptibility to PV in Japanese patients, we investigated the genotype and allele frequencies at each SNP in Japanese PV patients and in controls. METHODS: We examined 163 PV patients and 96 healthy individuals. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: No significant association between the genotypes or alleles of these SNPs and susceptibility to PV was observed. CONCLUSION: These SNPs themselves are not associated with susceptibility to PV in the Japanese.

Gene Frequency↗

PubMed2002

Different properties of three isoforms (alpha, beta, and gamma) of transcription factor AP-2 in the expression of human keratinocyte genes.

The transcription factor AP-2/promoter system is essential for gene expression associated with ectodermal development, particularly in the neural crest and skin. Three AP-2 isoforms, alpha, beta, and gamma, exhibit a highly homologous structure, but their functions are considered to be different. Here, we report on the role of each AP-2 isoform in complex keratinocyte biology including proliferation, differentiation, and carcinogenesis. The expression of AP-2 was investigated immunohistochemically in serial skin sections from normal and psoriatic skin, and squamous cell carcinoma (SCC). AP-2alpha was present only in the nuclei of normal basal keratinocytes, but was significantly increased in lesional proliferating keratinocytes of both diseases. AP-2beta was completely absent from all skin samples except dermal sweat glands, whereas AP-2gamma was present homogeneously throughout the epidermis in normal and psoriatic skin as well as in the SCC lesion. Their restricted expression patterns correlated with in vitro DNA binding assays using selective keratinocyte gene promoters and three recombinant AP-2 isoforms generated bacterially as glutathione S-transferase fusion protein. Epidermal growth factor receptor and basal keratin K14 promoters bound to AP-2alpha and AP-2gamma with similar affinities, whereas suprabasal keratin K1, type I transglutaminase, and involucrin promoters predominantly bound to AP-2gamma rather than AP-2alpha. In contrast, AP-2beta did not bind to any of the five promoters despite specific binding to the AP-2 consensus probe. These results suggest that AP-2alpha is closely associated with keratinocyte proliferation and/or carcinogenesis rather than differentiation, while AP-2gamma is ubiquitous in all stages of keratinocyte biology. Taken together, three AP-2 isoforms perform unique roles in the spatial and temporal expression of human keratinocyte-related genes, thereby maintaining epidermal homeostasis. Disruption of the epidermal AP-2 balance may contribute to hyperproliferative conditions, such as psoriasis and SCC.

Adult↗

PubMed2002

Skin inflammation during contact hypersensitivity is mediated by early recruitment of CD8+ T cytotoxic 1 cells inducing keratinocyte apoptosis.

Contact hypersensitivity (CHS) is a T cell-mediated, Ag-specific skin inflammation induced by skin exposure to haptens in sensitized individuals. Th1/T cytotoxic 1 cells are effector cells of CHS, whereas Th2/T regulatory CD4(+) T cells have down-regulating properties. We have previously shown that CHS to 2,4-dinitrofluorobenzene is mediated by specific CD8(+) effector cells, whose cytolytic activity is mandatory for induction of skin inflammation. In this study, using immunohistochemistry and RT-PCR analysis, we show that CD8(+) T cells are rapidly recruited into the skin at the site of hapten challenge before the onset of clinical and histological signs of skin inflammation. This early CD8(+) T cell recruitment is concomitant with: 1) transient IFN-gamma mRNA expression suggesting local activation of effector cells; and 2) induction of keratinocyte (KC) apoptosis which gradually increased to a maximum at the peak of the CHS response. Alternatively, skin infiltration of CD4(+) T cells occurred later and coincided with the peak of the CHS reaction and the beginning of the resolution of skin inflammation. Mice deficient in CD8(+) T cells did not develop CHS, whereas mice deficient in CD4(+) T cells developed an enhanced inflammatory response with increased numbers of CD8(+) T cells recruited in the skin associated with massive KC apoptosis. These data show that CHS is due to the early and selective recruitment in the skin of CD8(+) T cytotoxic 1 effector cells responsible for KC apoptosis.

Animals↗

PubMed2002

Lack of association of TNF-238A and -308A in Japanese patients with psoriasis vulgaris, psoriatic arthritis and generalized pustular psoriasis.

Tumor necrosis factor (TNF)-alpha is one of the proinflammatory cytokines and immunomodulators, and has an important pathogenetic role in psoriasis. The TNF-alpha gene (TNFA) is in the human leukocyte antigen (HLA) class III locus on chromosome 6, which might be related to the pathogenesis of psoriasis. It has been suggested that some polymorphisms of the TNFA gene promoter, especially G to A conversions at nt-238 and -308 (TNF-238A and -308A), may be associated with psoriasis in Caucasians. We investigated single nucleotide polymorphisms (SNPs) of the TNFA gene promoter in Japanese psoriasis patients, including 18 with psoriasis vulgaris (PsV), 11 with psoriatic arthritis (PsA), two with generalized pustular psoriasis (GPP), and six with GPP with arthritis. The DNA fragment of the TNFA gene from nt-400 to -69 was amplified by polymerase chain reaction (PCR) and the products were sequenced. Although TNF-238A and other polymorphisms were not found in PsV and psoriatic arthritis patients, one male patient with GPP and PsA had TNF-308A. This suggests that TNFA gene promoter polymorphism in the region examined is less associated with the pathogenesis of psoriasis in Japanese patients, however there might be the possibility that TNFA gene promoter polymorphism is associated with GPP. Further investigation will be required to prove this.

Adult↗

PubMed2002

TGF-beta1-mediated regulation of thymus and activation-regulated chemokine (TARC/CCL17) synthesis and secretion by HaCaT cells co-stimulated with TNF-alpha and IFN-gamma.

Thymus and activation-regulated chemokine (TARC/CCL17) contributes not only to the recruitment of leukocytes, but is also involved in immune disorders, such as atopic dermatitis (AD) and bronchial asthma. We have previously reported that the levels of TARC were high in patients with AD and that lesional epidermis were strongly immunoreactive for TARC. In this paper, the effects of transforming growth factor (TGF)-beta(1) on the expression of TARC/CCL17 were examined in HaCaT cells, a human keratinocytes (KCs) cell line, co-stimulated with TNF-alpha and IFN-gamma. We found that TGF-beta(1) down-regulated the TARC synthesis and secretion of HaCaT cells co-stimulated with TNF-alpha and IFN-gamma in a dose-dependent manner. TGF-beta(1) at a concentration of 10ng/ml maximally inhibited this secretion. Northern blot analysis showed a similar inhibitory effect of TGF-beta(1) on TARC mRNA expression by HaCaT cells. The TGF-beta(1)-induced down-regulation of TARC/CCL17 in HaCaT cells suggests that TGF-beta(1) might regulate the TARC-related inflammatory processes, which may be important for understanding the pathogenesis of allergic diseases.

Cell Line↗

PubMedDate not supplied

Neutrophilic eccrine hidradenitis in actinic reticuloid syndrome.

Neutrophilic eccrine hidradenitis (NEH) is a rare, transient complication, which usually occurs in patients with leukemia receiving various chemotherapeutic regimens. However, similar eruptions have been observed in other conditions, including HIV-positive patients, and are often preceded by the onset of malignancies. We report the first case of NEH arising in a patient with actinic reticuloid syndrome who had been treated with methotrexate.

Diagnosis, Differential↗

PubMedDate not supplied

Hypersensitivity to mosquito bites with natural-killer cell lymphocytosis: the possible implication of Epstein-Barr virus reactivation.

Hypersensitivity to mosquito bites (HMB) has been recognized as one of the wide variety of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders, some of which overlap with chronic active EBV infection and hydroa vacciniforme. It frequently predisposes to hemophagocytic syndrome or lymphoid malignancy with a clonal EBV replication. Here we report an 8-year-old Japanese boy who presented with a 3-year history of HMB. Every summer, he had repeated severe local skin reactions with high-grade fever, lymphadenopathy, and mild liver dysfunction after mosquito bites. Histologically, lymphoid cells overexpressing EBV-encoded small nuclear RNAs (EBER), a marker of latent EBV infection, and eosinophils infiltrated diffusely into the lesional skin. His blood tests showed a marked increase in the CD11b+ 16+ 56+ natural-killer cell population (~ 50% of the peripheral lymphocytes), but neither a clonal proliferation of EBV nor abnormal antibody titers to EBV. Quantitative PCR using a cloned EBV-determined nuclear antigen (EBNA)-1 vector revealed that a high copy number of the EBV genome is integrated into his peripheral blood cells even during the mosquito-free winter. Based on this evidence, he was diagnosed as being in a smoldering stage of HMB, in which EBV-associated NK cell lymphoproliferation might participate in its pathogenesis.

Animals↗

PubMedDate not supplied

Ultraviolet A irradiation inhibits thymus and activation-regulated chemokine (TARC/CCL17) production by a human keratinocyte HaCaT cell line.

Ultraviolet A (UVA) irradiation modulates the immunological functions of skin. We examined the effect of UVA irradiation on the basal and the IFN-gamma-and TNF-alpha-stimulation-induced production of thymus-and activation-regulated chemokine (TARC/CCL17) using HaCaT cells. UVA irradiation inhibited the basal levels of both TARC mRNA expression and TARC protein production. UVA irradiation also significantly inhibited TARC mRNA expression and TARC protein secretion that were induced by co-stimulation with IFN-y and TNF-alpha. A time course study showed that: the significant suppression of TARC mRNA expression was detected 8 hours after irradiation and continued for 36 hours; the strongest inhibition of TARC protein secretion occurred in the first 8 hours after UVA irradiation and continued for 36 hours. Our data provide the first evidence that UVA inhibits TARC mRNA expression and TARC protein production by keratinocytes in a dose-dependent manner. These results may suggest an explanation for the UV-induced therapeutic effect.

Cell Line↗