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Basal cell carcinoma is the most common cutaneous malignant tumor and usually arises from the facial skin and is diagnosed as the solid tumor. However, rarely it arises from genital skin and/or proceeds with ulcerative manner. We report a case of male basal cell carcinoma arising from penile base, which showed urinary disturbance. Tumor resection including total penectomy and skin resection was performed then scrotal myofasciocutaneous flap was used to cover the defect. Scrotal myofasciocutaneous flap was useful for covering the defect in the genital lesion. Moreover, this simple closure was helpful for early postoperative ambulation especially for aged male patients.

Cutaneous candidiasis is a common skin infection caused by the Candida species, especially in intertriginous areas, and neutrophils usually infiltrate histopathologically. We describe a case of secondary cutaneous candidiasis which spread extensively to the trunk and extremities and showed marked dermal eosinophilia. This case and a similar reported case suggest that Candida can sometimes cause cutaneous inflammation predominantly composed of eosinophils.

A 46-year-old man had a cystic mass on the right side of his scalp. Histological examination revealed a cystic dermal nodule composed of relatively circumscribed lobules of proliferating squamous epithelium, with atypical mitoses and dyskeratotic cells of invasive structure, which was diagnosed as proliferating tricholemmal cystic carcinoma (PTCC). Most of the cyst was composed of thick layers of highly proliferating, atypical, dedifferentiated epithelium (dedifferentiated part), which was attached to a highly proliferative but mildly differentiated part. A completely differentiated, tricholemmal cyst (TC)-like part was also attached to the main cyst, which supports the idea of PTCC beginning in a pre-existing TC. The dedifferentiated and mildly differentiated parts exhibited a high frequency of proliferating cell nuclear antigen (PCNA)-positive cells both in the basal and the suprabasal layers, while PCNA staining was almost negative in the TC-like part. Expression of cytokeratin (CK)10 and CK16 suggested disturbed epidermal differentiation in dedifferentiated part, while TC-like part showed well-differentiated trichilemmal epithelium and the mildly differentiated part was in the middle of these two.

To identify tumor-suppressor genes inactivated by aberrant methylation of promoter CpG islands (CGIs) in human malignant melanomas, genes upregulated by treatment of cells with a demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), were searched for using oligonucleotide microarrays in melanoma cell lines, HMV-I, MeWo and WM-115. Seventy-nine known genes with CGIs were identified as being upregulated (>or=16-fold), and 18 of them had methylation of their putative promoter CGIs in 1 or more of 8 melanoma cell lines. Among the 18 genes, TFPI-2, which is involved in repression of the invasive potential of malignant melanomas, was further analyzed. Its expression was repressed in a melanoma cell line with its complete methylation, and was restored by 5-aza-dC treatment. It was unmethylated in cultured neonatal normal epidermal melanocyte, and was induced by ultraviolet B. In surgical melanoma specimens, TFPI-2 methylation was detected in 5 of 17 metastatic site specimens (29%), while it was not detected in 20 primary site specimens (0%) (p=0.009). By immunohistochemistry, the 5 specimens with promoter methylation lacked immunoreactivity for TFPI-2. The results showed that TFPI-2 is silenced in human malignant melanomas by methylation of its promoter CGI and suggested that its silencing is involved in melanoma metastasis.

Background Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are angiogenic cytokines, that have been reported to elevate serum levels in patients with collagen diseases such as systemic sclerosis and dermatomyositis as well as in those with inflammatory bowel diseases. Objective In this study, the serum levels of bFGF and VEGF were measured by using enzyme-linked immunosorbent assay in 20 patients with polyarteritis nodosa (PAN; 5 with systemic PAN and 15 with cutaneous PAN) and in 20 control subjects. We also investigated the expression of bFGF and VEGF in cutaneous lesions of patients by using immunohistochemical methods. Results Basic FGF was undetectable in the serum of control subjects, but detectable levels were found in 4 of 5 patients with classical PAN and 3 of 15 patients with cutaneous PAN. The serum bFGF level in these patients with systemic PAN was significantly elevated in comparison with that in healthy control subjects. The VEGF level was 178 ± 41 pg/mL in the serum of healthy individuals. The mean VEGF level in patients with systemic or cutaneous PAN was significantly higher than that in healthy controls. Serum bFGF and VEGF levels in patients with systemic PAN were significantly elevated in comparison with those having cutaneous PAN. Immunohistochemical studies showed elevated bFGF expression on damaged endothelial cells in necrotizing vasculitis lesions. Elevated expression of bFGF was also observed on fibroblasts around the vasculitis. Some of the infiltrating cells around vasculitis lesions expressed VEGF. Limitations The study was small. Conclusions Serum bFGF and VEGF levels may be useful markers of the disease activities of PAN.

A 11-year-old female admitted to our hospital because of erythema of the face and the trunk, and a wide and dense cluster of verruca vulgaris on the right sole. She had no family history of immunodeficiency, no perinatal abnormality, no growth abnormality, or no history of severe infections. From the age of 4 years, she noticed erythema around her nose. At the age of 9 years, small erythema and papules appeared on her chest. In January, 2003, erythema around her nose and papules of the trunk spread rapidly, and she also felt fatigue and effort dyspnea. Laboratory examinations revealed near absence of serum IgG, and IgE, high serum IgM (525 mg/dl), and normal IgA and IgD. Thl/Th2 ratio was 36.9. We diagnosed her as having hyper-IgM syndrome. Histological examinations of a skin biopsy showed the infiltration composed of mainly histiocytes,and mildly atypical CD8 + T cells around the blood vessels in the dermis. We concluded her skin manifestations as reactive lymphohistiocytic infiltration at the base of immunodeficiency and durable stimulation of various antigens. Her skin manifestations improved transiently by the intravenous immunogrobulin and corticosteroids therapy.

Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) have been suggested to play important roles in wound healing. We investigated the effect of TGF-beta1 on the mitogenic and chemotactic activities of PDGF A-chain homodimer (PDGF-AA) and B-chain homodimer (PDGF-BB) in primary cultures of human skin fibroblasts. TGF-beta1 inhibited the growth-promoting activity of both PDGFs. Proliferative responses to basic fibroblast growth factor and epidermal growth factor were also restricted by TGF-beta1. A Boyden chamber chemotaxis assay revealed that the chemotactic migration to PDGF-AA was inhibited by TGF-beta1 pretreatment, but in contrast, the response to PDGF-BB was not affected by the same treatment. Western blot analysis showed that TGF-beta1 downregulated PDGF alpha-receptors, but not beta-receptors, indicating that the isoform-specific inhibition of chemotaxis is related to differential effects of TGF-beta1 on PDGF receptor expression. The present findings suggest that TGF-beta1 may act antagonistically towards PDGFs in humans under certain conditions, and this antagonistic nature of TGF-beta1 must be considered when it is applied to human wounds as a therapeutic agent.

We investigated the role of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in the growth regulation. Primary (PM-WK and KHm-4), recurrent primary (RPM-EP and RPM-MC), lymph node metastatic (MM-AN, MM-BP and MM-RU), and a visceral metastatic (MM-LH) melanoma cell lines were used. Reverse transcriptase-coupled polymerase chain reaction and Western blotting revealed that all expressed and produced TIMP-1 and TIMP-2 except for PM-WK, which neither expressed nor produced TIMP-1. TIMP-1 and TIMP-2 secretion levels were measured by enzyme-linked immunosorbent assay in supernatants of cells. We found that the TIMP-1 production level was correlated with the cell migration rate. Moreover, TIMP-1 enhanced the cell migration of PM-WK. The growth of the primary melanoma cell lines was stimulated by TIMP-1 and inhibited by TIMP-2. In contrast, the growth of the visceral metastatic melanoma cell line was stimulated by TIMP-2.

Inflammatory bowel disease (IBD), the precise etiology of which remains unknown, is comprised of two forms of chronic intestinal inflammation; ulcerative colitis (UC) and Crohn's disease (CD). Recent evidence increasingly suggests that IBD is the result of dysfunctional immunoregulation manifested by inappropriate production of mucosal cytokines. An abnormal microcirculatory system has also been implicated in its pathogenesis. To elucidate the mechanism of ischemic change in IBD, we assesse serum concentration levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF), and plasma level of endothelin-1 (ET-1). We also investigated the expression of VEGF, b-FGF, and transforming growth factor-beta1,2,3 (TGF-beta1,2,3) in tissue by immunostaining.Blood samples were obtained from 11 patients with UC, 11 patients with CD, and 10 patients as controls. Paraffin-embedded samples were used for an immunohistochemical study.The concentration levels (in picograms per milliliter) were as follows: for ET-1, UC: 127+/-47.0, CD: 167.3+/-35.1, and controls (asthma: 38.5+/-23.8, p0.01; diverticulitis: 40.5+/-25.6, p0.01), for b-FGF, UC: 9.2+/-1.9, CD: 9.1+/-1.5, and controls (asthma: 5.0+/-0, p0.01; diverticulitis: 5.0+/-0, p0.01), for VEGF, UC: 659.8+/-181.0, CD: 740.0+/-182.3, and controls (asthma: 193.7+/-58.7, p0.01; diverticulitis: 199.6+/-59.7, p0.01). The levels of VEGF and b-FGF were significantly higher in active IBD than those in the controls. There was a significant positive correlation among the serum levels of VEGF and b-FGF and the plasma level of ET-1; that is, elevated VEGF, b-FGF, and ET-1 levels correlated well with each other. Immunohistochemical studies showed increased venula in the submucosa and lamina propria. Overexpression of VEGF and b-FGF in endothelial cells was revealed and TGF-beta2 and TGF-beta3 were found in inflammatory cells of active IBD, but no change was observed around the vessels in the controls.It is suggested that the reciprocal reaction of these cytokines may contribute to angiogenesis in IBD b inducing intestinal ischemia through vasoconstriction.

Serum containing anti-U1RNP antibodies reacts with the nuclear matrix, the relatively insoluble component of the cell nucleus, in addition to U1RNP. In this study, we determine the serum titer and clinical correlations of antinuclear matrix antibodies in samples from patients with anti-U1RNP antibodies. The patients with anti-U1RNP antibodies were classified as having mixed connective tissue disease (MCTD, 15 patients), systemic sclerosis (SSc, 12 patients), systemic lupus erythematosus (SLE, 7 patients), and undifferentiated CTD (UCTD, 9 patients). Antinuclear matrix antibodies were detected using indirect immunofluorescence staining on HCl-treated HEp-2 cells. The antinuclear matrix antibody titer was significantly higher in serum from patients with MCTD or SSc than in serum from patients with SLE or UCTD. The antinuclear matrix antibody titer was significantly increased in serum from patients with sclerodactyly, pitting scars, contracture of the phalanges, and decreased carbon monoxide diffusion capacity. Thus, a higher titer of antinuclear matrix antibodies in serum from patients with anti-U1RNP antibodies may be associated with a clinical diagnosis of MCTD or SSc rather than a diagnosis of SLE or UCTD.

Background: The serum levels of soluble forms of vascular cell adhesion molecule 1 (sVCAM-1) and E-selectin (sE-selectin) can be used as a marker of endothelial activation. Objective: We investigated whether the serum level of sVCAM-1 and sE-selectin in patients with localized scleroderma (LSc) was correlated with the clinical or serologic features of this disease. Methods: Serum samples from 59 patients with LSc, 20 patients with systemic sclerosis (SSc) and 29 healthy controls were examined using specific enzyme-linked immunosorbent assays. Results: The serum levels of sVCAM-1 and sE-selectin in patients with LSc were significantly higher than those of the healthy controls. The serum levels of sVCAM-1 and sE-selectin were correlated with both the number of sclerotic lesions and the number of involved areas. Conclusion: These results indicate that the serum levels of sVCAM-1 and sE-selectin may reflect the extent of the skin involvement (ie, the disease severity) and may be useful for monitoring the in vivo states of endothelial activation in LSc. (J Am Acad Dermatol 2000;42:64-9.)

Anti-histone antibodies have been detected in the sera of patients with various autoimmune diseases. The existence of anti-histone antibodies in patients with polymyositis/dermatomyositis, however, has not been reported. We found anti-histone antibodies in eight (17%) of 46 sera from patients with polymyositis/dermatomyositis by an enzyme-linked immunosorbent assay. One serum was positive for both IgG anti-histone antibodies and IgM anti-histone antibodies. Six sera were positive only for IgG anti-histone antibodies. One serum was positive only for IgM anti-histone antibodies. An indirect immunofluorescence analysis using HEp-2 cells as the substrate showed that all sera positive for anti-histone antibodies produced homogeneous nuclear fluorescence. This immunofluorescence pattern disappeared after absorption of anti-histone activity with total histones. An immunoblotting analysis demonstrated that the anti-histone antibodies were predominantly directed against histone H1 in all seven sera with IgG anti-histone antibodies. Weak reactivity with H2B and H4 were also found in three sera from the patients with polymyositis/dermatomyositis. Sera from two patients with polymyositis/dermatomyositis displayed anti-H2A and H3 activity. One of the two sera showed IgM anti-histone antibodies in the enzyme-linked immunosorbent assay reacted with H1, H2A, H2B, H3, and H4, whereas the other serum reacted with no fractions of total histones. The activity of anti-histone antibodies disappeared in immunoblotting after absorption with total histones. All of the patients with anti-histone antibodies were free from lung fibrosis or internal malignancies. Thus, our data indicate that the presence of anti-histone antibodies is classified as one of the serologic abnormalities observed in polymyositis/dermatomyositis.

In the period 1994-2002, we saw 71 patients with sclerotic skin changes; 66 were diagnosed with systemic sclerosis (SSc) while five (7%) were diagnosed with pseudoscleroderma associated with various malignancies. The mean duration of disease in these five patients was significantly shorter than that of patients with SSc. The incidence of positive antinuclear antibodies, Raynaud's phenomenon or oesophageal involvement in patients with pseudoscleroderma was significantly lower than that in patients with SSc. The distributions of skin sclerosis varied in each case. Serum basic fibroblast growth factor (bFGF) levels in the five patients with pseudoscleroderma were very elevated compared with levels in controls. Elevated expression of bFGF was detected on fibroblasts of affected skin and in one lung-cancer tissue sample obtained by excision.

Background: Basic fibroblast growth factor (bFGF), a cytoplasmic polypeptide growth regulator that induces endothelial cell and fibroblast proliferation, is produced by endothelial cells and skeletal muscle. Objective: We hypothesized that this factor is involved in fibrotic changes in muscle and skin in collagen diseases. Methods: The serum level of bFGF was measured in 74 patients with systemic sclerosis, 12 with systemic lupus erythematosus, 33 with dermatomyositis, 13 with Raynaud's disease, and 20 control subjects. Results: bFGF was undetectable in the serum of normal persons, but detectable levels were found in 31 of 74 patients with systemic sclerosis and 7 of 33 patients with dermatomyositis. Elevated serum bFGF level was correlated with an elevated plasma endothelin level and anticentromere antibody in patients with systemic sclerosis. An elevated serum bFGF level correlated with lung fibrosis and an elevated creatine kinase level in the patients with dermatomyositis. Conclusion: Measurement of the serum bFGF level may be useful to detect vascular damage in patients with systemic sclerosis and muscule fibrosis in patients with dermatomyositis.

Sera from patients with localized scleroderma frequently produce cytoplasmic staining by indirect immunofluorescence, although the antigen remains to be determined. We studied the prevalence, antigen specificity and associated clinical characteristics of anti-cytoplasmic antibodies in localized scleroderma. Serum samples from 60 patients with localized scleroderma were examined by indirect immunofluorescence analysis and immunoblotting. By immunofluorescence analysis on HEp-2 cell substrate, seven of 60 (12%) patients were shown to be positive for anti-cytoplasmic antibodies. Among these, six patients with generalized morphea had anti-mitochondrial antibodies as shown by immunoblotting: they showed reactivity with the E2 component of pyruvate dehydrogenase complex (PDC), with protein X, and with the E2 component of α-oxo-glutarate dehydrogenase complex, while two of them showed reactivity with PDC-E1α. One of these patients who was positive for anti-PDC-E1α antibody showed laboratory abnormalities, suggesting the presence of primary biliary cirrhosis. The age of disease onset was significantly higher in these six patients than in those without anti-mitochondrial antibodies. Furthermore, five of them were classified into generalized morphea with multiple plaque lesions but without linear lesions (multiple plaque type). These observations suggest that major antigens for anti-cytoplasmic antibodies in patients with localized scleroderma are mitochondrial enzymes, 2-oxo-acid dehydrogenase complexes. Patients with anti-mitochondrial antibodies may comprise a unique subset of localized scleroderma designated multiple plaque type of generalized morphea of older onset.

This study investigated the prevalence and clinical significance of anti-ribosomal P protein (anti-P) antibodies in patients with systemic sclerosis (SSc). Serum samples from 150 patients with SSc were examined by indirect immunofluorescence, ELISA and immunoblotting. Anti-P antibodies were detected in four (3%) patients with SSc. Three of the four patients showed SSc/SLE (systemic lupus erythematosus) overlap syndrome, but psychiatric disorders were not observed in these patients. By longitudinal immunoblotting analysis one patient, who was initially diagnosed with SSc, later developed anti-P antibodies along with clinical manifestations of SLE. Our data suggest that anti-P antibodies are uncommon in SSc and that the presence of anti-P antibodies in patients with SSc indicates an overlap with SLE.

We investigated the responses of normal and scleroderma fibroblasts to various growth factors, especially transforming growth factor-beta 1 (TGF-beta 1). The effects of various growth factors on [3H]thymidine incorporation in normal and scleroderma fibroblasts were examined. [125I]-labeled platelet-derived growth factor (PDGF)-BB binding in scleroderma and normal fibroblasts was examined both in the presence and absence of TGF-beta 1 (1 ng/ml). Cytoplasmic protein was isolated and analyzed by Western blotting. Total RNA from fibroblasts was also isolated and analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) using specific primer sets. Mitogenic responses to TGF-beta 1 (0.33-1 ng/ml) in seven scleroderma fibroblast strains were significantly greater than those in normal controls. [125I]-PDGF-BB binding to scleroderma fibroblasts was increased after TGF-beta 1 stimulation. The increased response to TGF-beta 1 was shown to be mediated through PDGF-like protein induction; TGF-beta 1-treated scleroderma fibroblasts produced greater amounts of 36-kD PDGF-like protein, which was reported previously as connective tissue growth factor (CTGF), than did TGF-beta 1-treated normal fibroblasts. TGF-beta 1 treatment also upregulated PDGF-alpha receptor expression in scleroderma fibroblasts but not in normal dermal fibroblasts. mRNA expression of CTGF and PDGF-alpha receptor was correlated with the above protein expression. These observations suggest that the increased growth response to TGF-beta 1 in scleroderma fibroblasts is mediated through the induction of CTGF and PDGF-alpha receptor.

Background: Recently we demonstrated the presence of antihistone antibodies (AHA) in localized scleroderma. Objective: Our purpose was to determine clinical characteristics associated with AHA in patients with localized scleroderma. Methods: We examined 57 serum samples by an enzyme-linked immunosorbent assay in the following three subgroups: 15 patients with generalized morphea, 27 with linear scleroderma, and 15 with morphea, We classified the patients as having generalized morphea when they had four or more lesions on at least two areas of the body, irrespective of whether the lesions were of morphea or linear type. Results: AHA were detected in 42% of patients with localized scleroderma (24 of 57), and in 87% of patients with generalized morphea (13 of 15). The presence of AHA strongly correlated with the number of morphea lesions, the total number of lesions, and the number of involved areas of the body. However, AHA did not correlate with the presence or number of linear lesions. The presence of AHA showed a 87% sensitivity (13 of 15 patients) and a 74% specificity (31 of 42 patients) for generalized morphea. Conclusion: Our data suggest that AHA are a serologic marker for generalized morphea and that the validity of our new classification for generalized morphea is supported by the high frequency of AHA detection.

Effects of transforming growth factor beta (TGF-beta) on proliferative responses to basic fibroblast growth factor (bFGF) were studied in human diploid fibroblasts cell strains derived from three different sources: adult skin, scleroderma, and newborn foreskin. All three types of cell strains were similarly responsive to TGF-beta, whereas adult skin fibroblasts were significantly more responsive to bFGF. Incubation of cells with TGF-beta prior to bFGF addition substantially increased responsiveness of adult skin fibroblasts to this latter cytokine, slightly increased that of scleroderma fibroblasts, and decreased that of foreskin fibroblasts. Modulation of bFGF receptors by TGF-beta correlated positively with these mitogenic effects. Adult skin fibroblasts showed increases of both high- and low-affinity receptors and scleroderma fibroblasts showed small increases of high-affinity receptors only, whereas foreskin fibroblasts showed no changes. Heparitinase treatment of adult skin fibroblasts during TGF-beta pre-incubation resulted in reduced bFGF binding to low-affinity receptors and reduced mitogenic response to bFGF, suggesting that the TGF-beta-stimulated increase of low-affinity receptors in these cells contributes to the observed enhanced mitogenic effects of bFGF. Abnormal responses of scleroderma fibroblasts to TGF-beta/bFGF stimulation, particularly failure to synthesize low-affinity receptors in response to TGF-beta, adds a new characteristic to the fibrotic phenotype of scleroderma fibroblasts.

Extramammary Paget's disease (EMPD) is regarded as a malignancy most likely derived from or differentiated into apocrine sweat duct and gland. The tumor cells in EMPD usually have abundant pale cytoplasm and large pleomor- phic nuclei. We present a case with EMPD where the tumor included many signet ring cells, cells with intracytoplasmic lumen formation and glandular formation. This case is interesting in that the tumor included many cells with intracytoplasmic lumen formation. Signet ring cells and glandular formation support the traditional speculation that EMPD is derived from apocrine sweat gland and intracytoplasmic lumen formation may mimic the intrafollicular apocrine duct.

Necrolytic migratory erythema (NME) is an uncommon inflammatory dermatosis with a distinctive clinical and histological appearance. It shows irregular erythema, bullae, erosion, crusts and pigmentation. While it is typically associated with glucagonoma, some cases of NME without glucagonoma have been reported. Herein, we report a case of necrolytic migratory erythema associated with malabsorption 30 years after ileocolectomy. She presented erosive erythema with scale or partly flaccid bullae on her intergluteal cleft, buttock and extremities. Her laboratory data revealed essential amino acid deficiency and a slightly decreased serum zinc level, while her plasma glucagon level was low. With diagnosis of non-glucagonoma-associated NME with malabsorption due to short-bowel syndrome, she was treated and improved by i.v. amino acid supplement. Histological findings of NME include necrotic changes of keratinocytes in the upper epidermis, proliferation of those in the lower epidermis and inflammatory cell infiltration of upper dermis. We also examined the expression pattern of epidermal keratins (K6, K10) and Ki-67, one of the markers of proliferative activity, to assess the proliferation and differentiation of keratinocytes in a NME lesion by immunostaining. The findings with these immunostainings support the characteristics of HE-staining, and suggest hyponutrition may induce changing differentiation/proliferation of keratinocytes.

Aberrant methylation of promoter CpG islands (CGI) is involved in silencing of tumor suppressor genes and is also a potential cancer biomarker. Here, to identify CGIs aberrantly methylated in human melanomas, we did a genome-wide search using methylation-sensitive representational difference analysis. CGIs in putative promoter regions of 34 genes (ABHD9, BARHL1, CLIC5, CNNM1, COL2A1, CPT1C, DDIT4L, DERL3, DHRS3, DPYS, EFEMP2, FAM62C, FAM78A, FLJ33790, GBX2, GPR10, GPRASP1, HOXA9, HOXD11, HOXD12, HOXD13, p14ARF, PAX6, PRDX2, PTPRG, RASD1, RAX, REC8L1, SLC27A3, TGFB2, TLX2, TMEM22, TMEM30B, and UNC5C) were found to be methylated in at least 1 of 13 melanoma cell lines but not in two cultured normal melanocytes. Among these genes, Peroxiredoxin 2 (PRDX2) was expressed in normal melanocytes, and its expression was lost in melanomas with methylation. The loss of expression was restored by treatment of melanomas with a demethylating agent 5-aza-2′-deoxycytidine. In surgical melanoma specimens, methylation of PRDX2 was detected in 3 of 36 (8%). Furthermore, immunohistochemical analysis of PRDX2 showed that disappearance of immunoreactivity tends to associate with its methylation. PRDX2 was recently reported to be a negative regulator of platelet-derived growth factor signaling, and its silencing was suggested to be involved in melanomas. On the other hand, 12 CGIs were methylated in ≥9 of the 13 melanoma cell lines and are considered as candidate melanoma biomarkers. (Cancer Res 2006; 66(12): 6080-6)

Over 125 pigmentation-related genes have been identified to date. Of those, PMEL17/GP100 has been widely studied as a melanoma-specific antigen as well as a protein required for the formation of fibrils in melanosomes. PMEL17 is synthesized, glycosylated, processed, and delivered to melanosomes, allowing them to mature from amorphous round vesicles to elongated fibrillar structures. In contrast to other melanosomal proteins such as TYR and TYRP1, the processing and sorting of PMEL17 is highly complex. Monoclonal antibody HMB45 is commonly used for melanoma detection, but has the added advantage that it specifically reacts with sialylated PMEL17 in the fibrillar matrix in melanosomes. In this study, we generated mutant forms of PMEL17 to clarify the subdomain of PMEL17 required for formation of the fibrillar matrix, a process critical to pigmentation. The internal proline/serine/threonine-rich repeat domain (called the RPT domain) of PMEL17 undergoes variable proteolytic cleavage. Deletion of the RPT domain abolished its recognition by HMB45 and its capacity to form fibrils. Truncation of the C-terminal domain did not significantly affect the processing or trafficking of PMEL17, but, in contrast, deletion of the N-terminal domain abrogated both. We conclude that the RPT domain is essential for its function in generating the fibrillar matrix of melanosomes and that the luminal domain is necessary for its correct processing and trafficking to those organelles.

Aberrant methylation and demethylation of promoter CpG islands lead to silencing of tumor-suppressor genes and abnormal expression of normally methylated genes, respectively. Here, we analyzed human melanomas for their methylation and demethylation profiles. Methylation status of core regions in promoter CpG islands was examined for 20 (candidate) tumor-suppressor genes, 4 genes that are not considered as tumor-suppressors, but are frequently silenced in human cancers, and 6 normally methylated melanoma antigen genes (MAGEs). Analysis of 13 melanoma cell lines and 2 cultured normal human epidermal melanocytes (HEMs) showed that 9 tumor-suppressor genes and all 4 non-tumor-suppressor genes were methylated in at least 1 cell line, but never in HEMs, and that all 6 MAGE genes were demethylated in 3 to 13 cell lines. Interestingly, we detected no methylation of MGMT, PTEN, MTAP and p27, which were previously reported as silenced in melanomas. Furthermore, 3 genes that were frequently methylated in the cell lines and 6 MAGE genes were analyzed in 25 surgical melanoma samples. RARB, RASSF1A and 3-OST-2 were methylated in 5 (20%), 9 (36%) and 14 (56%) samples, respectively. MAGE-A1, A2, A3, B2, C1 and C2 were demethylated in 9 (36%), 22 (88%), 20 (80%), 7 (28%), 21 (84%) and 16 (64%) samples, respectively. At least 1 gene was methylated in 18 (72%) samples and at least 1 was demethylated in 24 (96%) samples. No correlation between frequent methylation and frequent demethylation was observed. These profiles showed that both aberrant methylation and demethylation occur widely in human melanomas.

Background: Fusion of the collagen type I α 1 ( COL1A1 ) gene with the platelet-derived growth factor B-chain ( PDGFB ) gene has been pointed out in dermatofibrosarcoma protuberans (DFSP). Various exons of the COL1A1 gene have been shown to be involved in the fusion with exon 2 of the PDGFB gene. Objective: We studied the breakpoints of the COL1A1 gene using the tumor specimens from three patients with DFSP. Methods: Reverse transcriptase-polymerase chain reaction (PCR) was performed using cultured DFSP tumor cells or frozen tissue. Nucleotide sequence analysis was carried out using the PCR products to identify the breakpoints. Results: Cases 1, 2 and 3 were diagnosed as ordinary DFSP, DFSP with fibrosarcomatous lesion (DFSP-FS) and lung metastasis of DFSP-FS, respectively. The COL1A1-PDGFB fusion transcripts were detected from the tumor specimens. Sequence analysis revealed that the ends of exons 42, 29 and 38 in the COL1A1 gene were fused with the start of exon 2 in the PDGFB gene in case 1, 2 and 3, respectively. Conclusion: This study identified a novel COL1A1 breakpoint, namely, exon 42 of the COL1A1 gene. Detection of the aberrant fusion transcript seems to be useful at differential diagnosis both in primary and metastatic lesions.

To assess whether the functional disability in Japanese patients with systemic sclerosis (SSc) can be adequately evaluated by the Health Assessment Questionnaire (HAQ) developed in the United States.The HAQ was completed by 121 Japanese patients with SSc, in whom SSc-specific physical examinations and laboratory tests were performed at the same time. Clinical findings associated with the disability index (DI) and individual components of the HAQ were examined using Student's t tests and Pearson's correlation tests. Logistic regression analysis was used to identify clinical findings that independently contributed to the increase in the HAQ-DI score.Japanese patients with SSc had significant functional disability, especially in the categories of eating and gripping, but the degree of disability was much less than was reported in previous studies carried out in the US. The increase in the HAQ-DI score was strongly correlated with increased total skin score, reduced oral aperture, reduced hand extension, increased finger flexion, subcutaneous calcinosis, flexion contractures, increased erythrocyte sedimentation rates, decreased percent vital capacity, and vascular involvement (p0.001 for all correlations). Multivariate logistic regression analysis showed that hand extension was the most important and an independent correlate of the HAQ-DI.Our multicenter, cross-sectional study has demonstrated that the self-administered HAQ is a valuable assessment tool of functional disability in Japanese SSc patients, who have social customs different from Americans, but functional disability measured by the HAQ is potentially influenced by ethnic variability.

Background: Platelet-derived growth factor BB (PDGF-BB) and transforming growth factor β are known to enhance the growth of neurofibroma-derived cells from neurofibromatosis type 1 (NF-1) patients. Objective: This study aims to elucidate whether these growth factors and their receptors are up-regulated in NF-1 patients. Methods: Tissues and culture cells from neurofibroma in NF-1 patients, nontumor lesions in NF-1 patients, and the skin of normal controls were collected. To evaluate the expressions of growth factors and their receptors, reverse-transcriptase polymerase chain reaction and immunohistochemistry were performed. Results: PDGF-β receptor subunit was expressed in the neurofibroma tissues from NF-1 patients, but not in the nontumorous tissues from NF-1 patients or skin from normal controls. As for the other factors, there were no significant differences among these tissues. Neurofibroma sections also stained positive for the PDGF-β receptor subunit. Conclusions: The interaction of PDGF and PDGF-β receptor subunit may be important in the tumorigenesis of NF-1.

We investigated the capacity of skin fibroblasts, derived from 9 patients with systemic sclerosis (SSc), to contract collagen lattices in a three-dimensional culture system. In comparison with control fibroblasts (N = 8), more than 30% of SSc fibroblasts exhibited markedly impaired ability to contract collagen lattices. The expression of alpha2beta1 integrins and integrin-mediated signals were not significantly different between normal and SSc fibroblasts. Although the underlying mechanisms remain to be determined, our present data provide evidence that certain aspects of interaction with collagen are impaired in SSc fibroblasts.

The serum tissue inhibitor of metalloproteinases 1 (TIMP-1) level was reported to be a useful indicator of disease activity, especially of lung fibrosis in patients with systemic sclerosis. TIMP-2 is also an important inhibitor of matrix metalloproteinases (MMPs), such as interstitial collagenase, gelatinase, and stromelysin, which control the metabolism of the extracellular matrix. However, serum levels of TIMP-2 in patients with systemic sclerosis (SSc) have not been investigated.We sought to determine the clinical significance of serum levels of TIMP-2 and MMP-2 in patients with SSc.Serum samples were obtained from 128 patients with SSc (68 with limited cutaneous SSc and 60 with diffuse cutaneous SSc). Twenty-seven serum samples from healthy age- and sex-matched individuals were also examined as controls. The TIMP-2 and MMP-2 levels were determined by means of sandwich enzyme-linked immunosorbent assays.The serum TIMP-2 levels were elevated in 29 (22.7%) of the 128 patients with SSc and were significantly higher than those of the healthy control subjects. The serum TIMP-2 levels were significantly correlated with the extent of skin sclerosis in the patients with SSc. The incidence of decreased percentage of the diffusing capacity of lung for carbon monoxide (DLCO ) and that of an elevated erythrocyte sedimentation rate were significantly greater in the patients with elevated TIMP-2 levels compared with the patients with normal TIMP-2 levels (P.05). When these patients were classified into 2 groups by disease activity, TIMP-2 levels were significantly more elevated in the high active group than in those low active group (P.001). The serum MMP-2 levels of the patients with SSc were not significantly higher than those of the healthy control subjects.These findings suggest that the serum TIMP-2 level is a useful marker of the extent of skin sclerosis and disease activity in patients with SSc. The balance of TIMP-2 and MMP-2 may play an important role in patients with SSc. Furthermore, TIMP-2 may be thought to contribute to the development of disease in patients with SSc.

Background: Yellow oculocutaneous albinism (OCA) that is caused by tyrosinase gene mutations shows two characteristics: extreme hypopigmentation at birth and the eventual development of yellow or blond hair. Objective: We studied a Japanese girl who had brown hair, a lighter skin color than her unaffected family and brown eyes at 9 months of age. Methods: We performed direct sequencing analyses of the tyrosinase gene in her genomic DNA. Results: The patient was a compound heterozygote for the +ΔC310 mutation (known to result in absent melanogenic activity) and a second t→a transition at the 3′ end of intron 2. Conclusion: The t→a transition has previously been reported as a splicing mutation in other Caucasian patients with a typical yellow OCA phenotype. However, this patient showed much more pigmentation than that reported in Caucasians. Therefore, we estimate that the mild phenotype results from her genetic pigment background.

A patient presented with a solitary large subcutaneous tumor homogeneously composed of loose fibroblasts interspersed with abundant mucinous material. The literature was reviewed, and the origin, pathogenesis and clinical course of this rare neoplasm were briefly discussed.

OBJECTIVES—The aim of the study was to determine the prevalence and clinical significance of antibodies to individual histone components in systemic sclerosis (SSc). METHODS—Serum samples from patients with limited cutaneous SSc (lSSc; n=42) and diffuse cutaneous SSc (dSSc; n=28) were examined for IgG and/or IgM antibodies to individual histone components and complexes by enzyme linked immunosorbent assay (ELISA). RESULTS—The level of IgG antibody to total histones was significantly higher in lSSc and dSSc than in normal controls. The level of IgM antibody to total histones was significantly higher in lSSc, but not in dSSc, than in normal controls. IgG antibody to total histones tended to be increased in dSSc when compared with that in lSSc. On the other hand, IgM antibody to total histones tended to be increased in lSSc when compared with that in dSSc. Although SSc showed various antihistone specificities, H2B, H2A-H2B, (H2A-H2B)-dsDNA were main antigens recognised by IgG antibodies in both lSSc and dSSc. Although IgM antibodies to H2B and H2A-H2B were also detected in both lSSc and dSSc, serum samples from lSSc patients exhibited highest IgM reactivity with H1. CONCLUSION—SSc may be included among conditions in which heterogeneous antihistone antibodies are produced. IgM antibodies to the most accessible histone H1 may be related to mild clinical features (lSSc) and IgG antibodies to the inner core molecules of native histone such as H2B or complexes including H2B may be associated with severe clinical features (dSSc) in Ssc. Keywords: histone; antibody; systemic sclerosis; enzyme linked immunosorbent assay

Serum levels of carboxyterminal propeptide of type I procollagen (PICP) and aminoterminal propeptide of type I procollagen (PINP) have been used as indices of collagen synthesis in patients with various fibrotic diseases during the active stages. One of the suggested contributory factors to the development of tissue fibrosis is a decrease in collagenase activity, which may be related to levels of serum tissue inhibitors of metalloproteinases-1 (TIMP-1). In this study, the serum levels of PICP and PINP in 20 patients with dermatomyositis and 29 control subjects and of TIMP-1 in 29 patients with dermatomyositis and 29 control subjects were measured using an enzyme-linked immunosorbent assay (ELISA) or a radioimmunoassay (RIA). We found that the mean PICP level in patients with dermatomyositis was significantly higher than that in normal controls (mean +/- SD 326+/-76 ng/ml vs 135+/-88 ng/ml; P < 0.001). In 60% of dermatomyositis patients, the serum PICP level was elevated (more than 311 ng/ml, i.e. 2 x SD above the mean control value). Elevated serum PICP levels were correlated with the incidence of elevated serum creatine kinase levels in patients with dermatomyositis. The serum concentration of PINP was not elevated in comparison with that of the normal control subjects (mean +/- SD 36+/-30 ng/ml vs 63+/-34 ng/ ml). The mean TIMP-1 level in the patients with dermatomyositis was also significantly higher than in the normal control subjects (mean +/- SD 438+/-328 ng/ml vs 163+/-63 ng/ml; P < 0.001). In 59% of dermatomyositis patients, the mean serum TIMP-1 level was elevated (more than 289 ng/ml, i.e. 2 x SD above the mean control value). Serum PICP and TIMP-1 levels might be useful for detecting disease activity or severity in dermatomyositis.

Dermatofibrosarcoma protuberans is not a difficult tumor to recognize because of its characteristic clinical appearance, although some unusual variants have been reported. We describe the atrophic variant of dermatofibrosarcoma protuberans in a 21-year-old female. The lesion was a smooth-surfaced, oval depression on the left subclavicular area, with a violaceous plaque at the center. The suspected clinical diagnosis did not include fibrous tumors, although histological examination showed the typical picture of dermatofibrosarcoma protuberans. Positive CD34 staining was also helpful in the diagnosis. We review 14 cases of the atrophic variant of dermatofibrosarcoma protuberans in the literature. Dermatologists should be aware of this uncommon but characteristic appearance of atrophic dermatofibrosarcoma protuberans.

We report a case of papillary tubular adenoma, arising on the knee joint. The overall histologic structure of the tumor is consistent with that of papillary tubular adenoma with slight interluminal papillary changes, but most of the tumor cells present vacuolization outlined by carcinoembryonic antigen staining, suggesting that this adenoma may have resulted from microlumen formation. This is, to our knowledge, the first reported case of a papillary tubular adenoma with marked tubular vacuolization.

Localized scleroderma has been shown to be accompanied by various immunologic abnormalities. To obtain functional information on activated CD4+ or CD8+ T cells, we studied the levels of soluble CD4 (sCD4) and soluble CD8 (sCD8) in serum from patients with localized scleroderma. Serum samples were examined by enzyme-linked immunosorbent assay. The samples were obtained from 49 patients in the following three subgroups: 15 patients with generalized morphea, 22 with linear scleroderma, and 12 with morphea. The levels of sCD4 and sCD8 were significantly elevated in patients with generalized morphea. Furthermore, these patients showed significantly higher levels of sCD4 than those with systemic sclerosis (SSc). The frequency of positivity for IgG anti-single-stranded DNA (ssDNA) antibody was significantly higher in localized scleroderma patients with elevated sCD4 levels than in patients with normal sCD4 levels. The frequency of positivity for antinuclear antibodies, IgM antihistone antibodies, IgG anti-ssDNA antibody and rheumatoid factor, and elevated sCD23 levels were significantly higher in localized scleroderma patients with elevated sCD8 levels than in patients with normal sCD8 levels. Our findings suggest that both CD4+ and CD8+ T cells are activated in vivo in generalized morphea and that the immunologic events in generalized morphea are different from those in SSc.

Soluble CD23 (sCD23) is closely related to B-cell activation and elevated serum levels of sCD23 have been reported in several autoimmune disorders. This study investigated the serum levels of sCD23 and determined the correlation of sCD23 with other immunologic abnormalities and clinical features in localized scleroderma. We examined 49 serum samples by an enzyme-linked immunosorbent assay in the following three subgroups: 15 patients with generalized morphoea, 22 with linear scleroderma, and 12 with morphoea. The serum levels of sCD23 were significantly elevated in patients with localized scleroderma, compared with those in healthy individuals. Of the three subgroups of localized scleroderma, patients with generalized morphoea had the highest levels of serum sCD23. The frequency of IgM antihistone antibody (AHA) and IgM rheumatoid factor (RF), the number of linear lesions, and the frequency of muscle involvement were significantly higher in patients with elevated sCD23 levels than in those with normal levels of sCD23. A significant correlation between the serum sCD23 level and the number of involved areas of the body was observed. Our data suggest that the activation of virgin B cells, which is reflected by elevated sCD23 levels, is closely associated with the production of IgM autoantibodies in localized scleroderma and furthermore that the serum levels of sCD23 are a new serological indicator of the severity of localized scleroderma.

The role of some growth factors and cytokines in the pathogenesis of systemic sclerosis (SSc) has been suggested. In particular, the contribution of transforming growth factor beta in the progression of skin sclerosis is suspected. Connective tissue growth factor (CTGF) was originally identified in human umbilical vein endothelial cells, and a recent study has revealed that human skin fibroblasts produce CTGF after stimulation with transforming growth factor beta. In the present study, the distribution of CTGF gene expression in tissue sections from patients with SSc was investigated by digoxigenin-labeled in situ hybridization. Strong CTGF mRNA signals were observed in the fibroblasts in sclerotic lesions, especially in the deep dermis, of the skin specimens from patients with SSc, whereas there was no expression in the skin from normal controls. The number of fibroblasts with positive hybridization signals was more abundant in the dermis from the sclerotic stage than in that from the inflammatory stage. Our findings indicate a correlation between CTGF gene expression and skin sclerosis and support the hypothesis that transforming growth factor-beta plays an important role in the pathogenesis of SSc, because transforming growth factor beta is the only inducer for CTGF identified to date.

Cell adhesion to extracellular matrix proteins is a dynamic process leading to dramatic changes in the cell phenotype. Integrins are one of the major receptor families that mediate cell-matrix contact. Evidence that integrins can act as signal transducing molecules has accumulated over the past few years. We report here that p44erk-1 and p42erk-2 mitogen-activated protein (MAP) kinases are rapidly phosphorylated on tyrosine residues upon adhesion of human skin fibroblasts to fibronectin or upon cross-linking of beta 1 integrins with antibody. The tyrosine phosphorylation of both kinases is associated with increased enzymatic activity. Pretreatment of the cells with cytochalasin D, which selectively disrupts the network of the actin filaments, completely inhibits this adhesion-mediated MAP kinase activation. Thus, our findings indicate that ligation of beta 1 integrins induces an increase in both tyrosine phosphorylation and enzymatic activity of p44erk-1 and p42erk-2 MAP kinases, and that the integrity of the actin cytoskeleton is essential in this process. Since MAP kinase behaves as a convergence point for diverse receptor-initiated signaling events at the plasma membrane, this serine/threonine kinase plays a key role and helps to account for the diversity of integrin-dependent cell functions.

Localized scleroderma has been reported to be accompanied by immunological abnormalities related to B cells, but little is known about T-cell activation in this disease. In this study, serum levels of interleukin-2 (IL-2), interleukin-4 (IL-4) and interleukin-6 (IL-6), which are known to be released by activated T cells, were determined using a sensitive enzyme-linked immunosorbent assay in 48 patients with localized scleroderma and 20 with systemic sclerosis, and in 20 healthy control subjects. IL-2, IL-4 and IL-6 were detected in serum from patients with localized scleroderma but not in that from healthy controls. The presence of antihistone antibodies correlated significantly with elevated IL-4 and IL-6 levels. Decreased serum levels of IL-2, IL-4 and IL-6 paralleled improvement in cutaneous sclerosis. Frequent detection of these lymphokines in serum from patients with localized scleroderma reflects T-cell activation in this disorder.

We recently reported that the serum concentration of procollagen type I carboxyterminal propeptide (P1CP) in patients with systemic sclereosis (SSc) was elevated. In the present study, we investigated collagen metabolism in in vitro cultured scleroderma fibroblasts by measuring P1CP levels in the culture medium.Spontaneous P1CP production was 4.2 times higher in fibroblast cultures from patients with SSc (n = 11) than in those from healthy controls (n = 10). P1CP production in fibroblasts derived from diffuse cutaneous SSc patients was significantly greater than that from limited cutaneous SSc patients. The serum P1CP level in SSc patients was correlated with the P1CP production of cultured fibroblasts (r = 0.815, p0.005). Transforming growth factor beta increased P1CP production, and gamma-interferon decreased P1CP production similarly in both SSc and normal fibroblasts. In contrast, histamine dihydrochloride increased P1CP production only in SSc fibroblasts but not in controls.These findings suggest that P1CP production in SSc fibroblasts is relevant to in vivo collagen synthesis in SSc patients.

Localized scleroderma is generally considered to be limited to the skin and to the subcutaneous tissue beneath the cutaneous lesions. Previous studies have revealed that this disease is accompanied by various immunologic abnormalities. Recently, we discovered that the major antigens of antinuclear antibodies (ANA) detected in localized scleroderma are nuclear histones. 1 In addition, we found that the serum levels of interleukin (IL) 2, IL-4, IL-6, and soluble IL-2 receptor were significantly elevated in patients with localized scleroderma, which suggests that T-cell activation is also involved in its pathogenesis. 2 Interleukin 8 is known to be chemotactic for neutrophilic granulocytes and T lymphocytes and is produced by a variety of cell types, such as epithelial cells, fibroblasts (including dermal fibroblasts), and endothelial cells. 3,4 Recently Reitamo et al 5 reported that IL-8 was detected in 21 (19%) of 108 serum samples of patients with systemic sclerosis (SSc) but not in

Background and Design: Recently, we detected antihistone antibodies (AHAs) in patients with localized scleroderma. However, the exact antigen specificity of AHAs in this disease is still unknown. Therefore, we determined the reactivity of AHAs with five individual histones and the correlation of AHAs with rheumatoid factor in localized scleroderma by means of enzyme-linked immunosorbent assay. Twenty patients with localized scleroderma who had IgG and/or IgM AHAs, as determined by enzyme-linked immunosorbent assay, were examined. These patients were classified into the following three subgroups: patients with generalized morphea (n=11), patients with linear scleroderma (n=6), and patients with morphea (n=3). Results: In generalized morphea, IgG AHAs strongly reacted with histones H1, H2A, and H2B; and IgM AHAs strongly reacted with HI and H2B, as determined by means of enzyme-linked immunosorbent assay. The pattern of reactivity in linear scleroderma and morphea was similar to that in generalized morphea. A homogeneous immunofluorescent pattern on HEp-2 cells, which was produced by localized scleroderma sera, was completely abolished by absorption with total histones. By employing a latex agglutination test, IgM rheumatoid factor was detected in 60% of the 20 patients with localized scleroderma and at a frequency of 82% in those with generalized morphea. However, an absorption test of rheumatoid factor activity with human IgG revealed no cross-reactivity of AHAs with rheumatoid factor. Conclusions: Our data suggest that AHAs in localized scleroderma are directed against native chromatin, since H1, H2A, and H2B occupy a relatively exposed portion of chromatin. (Arch Dermatol. 1994;130:1273-1277)

Background: Intercellular adhesion molecule-1 (ICAM-1) is important in immune-mediated mechanisms, and its circulating form (cICAM-1) may be an indicator of immune activation. Localized scleroderma is accompanied by various immunologic abnormalities. Objective: We investigated whether the serum level of cICAM-1 in patients with localized scleroderma was elevated and was correlated with the clinical or serologic features of this disease. Methods: Serum cICAM-1 levels were determined by an enzyme-linked immunosorbent assay in 48 patients with localized scleroderma, in 20 patients with systemic sclerosis, and in 20 healthy control subjects. Results: Serum levels of cICAM-1 were significantly higher in patients with localized scleroderma than in the healthy control subjects. These levels correlated with the number of lesions, the number of involved areas, levels of antihistone antibody IgM, and levels of soluble interleukin 2 receptor. Conclusion: The results suggest that immune activation may be a factor in localized scleroderma.

Background and Design: Recently, we reported that the serum procollagen type I carboxyterminal propeptide (P1CP) level of patients with systemic sclerosis was elevated and correlated with disease severity. In this study, the serum level of P1CP was measured using the enzymelinked immunosorbent assay in 39 patients with localized scleroderma and in 30 control subjects. Results: The mean P1CP level in the patients was significantly higher than that in the normal control subjects. In 30% of the patients with localized scleroderma, the serum P1CP level was considered to be elevated (>305 ng/mL; ie, 2 SDs above the mean control value). The mean serum P1CP level in the patients with generalized morphea was significantly higher than in the pa- tients with morphea or linear scleroderma. In addition, the serum P1CP level in the patients with localized scleroderma was correlated with the number of sclerotic lesions, and it was negatively correlated with the duration of the disease. Anti—single-stranded DNA antibody and antihistone antibody were detected significantly more frequently in the patients with elevated P1CP than in the patients with normal P1CP. Conclusion: These findings suggest that the serum P1CP level is a useful indicator of disease severity in patients with localized scleroderma, as it has been found to be in those with systemic sclerosis. (Arch Dermatol. 1994;130:1269-1272)

Objective. To study the prevalence and antigen specificity of antihistone antibodies (AHA) in localized scleroderma. Methods. Forty-nine serum samples from patients with localized scleroderma were examined by an enzyme-linked immunosorbent assay (ELISA) and by immunoblottin. Results. By ELISA, AHA were demonstrated in 47% (23 of 49) of patients with localized scleroderma and in 87% (13 of 15) of patients with generalized morphea. Immunoblotting revealed that the predominant antigens were histones H1 and H3. The presence of AHA correlated with that of anti–single-stranded DNA antibody. Conclusion. Some of the major antigens for antinuclear antibodies in patients with localized scleroderma are histones.