岩田 洋平

Morphea is a type of localized scleroderma. It is a skin disease involving the development of fibrosis in the dermis and subcutaneous fat tissue beneath without a visceral lesion, and the cause is still unclear. An involvement of epithelial-mesenchymal transition (EMT) has been reported as a cause of tissue fibrosis, but this was mostly observed in pulmonary and hepatic fibrosis, and the involvement of EMT in a skin disease, morphea, has not been studied. Thus, we analyzed the involvement of EMT in skin fibrosis in morphea patients using pathological techniques. Skin lesions of six morphea patients were analyzed (five female and one male patient). As a control, non-light-exposed skin lesions of 11 healthy females were analyzed. Concretely, tissue samples were prepared from these subjects and subjected to immunostaining of transforming growth factor (TGF)-beta 1, alpha-smooth muscle actin (alpha-SMA) and fibronectin, which have been reported to be associated with fibrosis, and Snail1 and E-cadherin, which are considered to be involved in EMT, and expressions of these were analyzed. In morphea patients, dermal expression of TGF-beta 1, alpha-SMA and fibronectin, which are involved in fibrosis, was enhanced, and, at the same time, enhanced expression of Snail1 and reduced expression of E-cadherin, which are involved in EMT, were observed in the dermal eccrine glands. These findings suggested the progression of EMT in the dermal eccrine glands in morphea.

Backgroud: : More effective treatment strategies are needed for the chronic skin ulcers. Recently, it has been reported that clinical application of stem cells improve wound healing. Objective: We aimed to determine the dynamic time-course movement of epidermal stem cell markers especially p75 neurotrophin receptor (p75NTR) and Integrin beta-1 in wound healing process. Furthermore, we also investigated the presence of these markers in human. Methods: Epidermal Integrin beta-1(+) and p75NTR(+) cells were counted in wound healing process in mice. Both cells were also counted in human skin specimen obtained from chronic skin ulcers and healthy controls. Growth factor gene expression levels by purified mouse epidermal p75NTR. cells were also analyzed using real-time RT-PCR. Results: Integrin beta-1(+) and p75NTR(+) cells were proliferated from 3 days after wounding. Reepithelization was completed 7 days after wounding, and the numbers of cells were returned to the baseline levels by 14 days after wounding. Integrin beta-1(+) cells were proliferated in the basal layer, and p75NTR(+) cells were proliferated in the upper layer of epidermis. In human skin, Integrin beta-1(+) and p75NTR(+) cells were 81% +/- 12% and 36% +/- 15% of the basal cells, respectively. In patients with chronic skin ulcers, the percentage of Integrin beta-1(+) cells in the epidermis was identical to healthy controls. Surprisingly, p75NTR(+) cells were significantly decreased in chronic skin ulcer patients (1.2% +/- 2.6%; p < 0.0005) compared to healthy controls. Purified mouse epidermal p75NTR(+) cells expressed higher transforming growth factor-beta2 and vascular endothelial growth factor-alpha transcripts and lower epidermal growth factor transcripts than p75NTR(-) cells. Conclusion: These results suggest that Integrin beta-1(+) and p75NTR(+) cells play an important role in wound healing process, and that p75NTR may be a key molecule and a candidate for new therapeutic target besides preexisting molecules for chronic skin ulcer patients. (C) 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

症例1は35歳の男性。工場作業中,配電盤(440V,直流)の充電部に頭部が接触し前額部および臀部を受傷した。臀部は縫縮可能であったが,前額部は骨膜まで壊死に陥っており遊離前腕皮弁による再建を要した。症例2は63歳の男性。工業用電源(200V,交流)に電気工具を使用していた際に電気火花が発生し両手,頸部,胸部を受傷した。頸部,胸部は外用治療で上皮化したが,両手は極薄分層植皮術(Thiersch植皮術)を要した。2例とも経過中不整脈や腎障害などの重篤な合併症は認めず良好な経過を得ることが可能であった。電撃傷は皮膚のみでなく全身の合併症をきたしうるので,他科との密な連携および症例ごとの適切な管理が必須である。(著者抄録)

39歳、女性。初診の4ヵ月前に統合失調症で入院中の精神病院において、左大腿部内側の小皮下腫瘤を指摘された。経過観察していたところ4ヵ月間で急激に増大し当科転院となった。左股部から大腿部内側にかけて約20cm大の巨大な皮下腫瘤を認め、中央部は自壊し、著明な悪臭を伴っていた。腫瘍から多量の出血を繰り返しており、歩行不能な状態であった。画像検査では深部は薄筋まで浸潤していたため、筋肉を含めて全摘し遊離植皮術を施行した。腫瘍の全摘出により全身状態は改善し歩行も可能となるなどQOLの改善が得られた。現在術後8ヵ月で局所再発は認められていないが、肺転移を認めている。全摘標本の病理組織所見では小円形の腫瘍細胞が不均一に増殖しており、腫瘍細胞はMIC2およびPAS陽性であり、骨外性Ewing肉腫が最も考えられた。(著者抄録)

42歳、男性。初診の7年前から腹部に皮下結節が出現し、徐々に増大した。当科初診時、腹部に17×16×9cm大の紅色で弾性硬のカリフラワー状に隆起した広茎性巨大腫瘤を認めた。腫瘍表面は自壊し、潰瘍と壊死を認め、易出血性で悪臭を伴っていた。MRI画像所見では、腫瘍深部は腹直筋との境界が一部不明瞭であったため、腫瘍茎部辺縁より水平方向は5cm離し、深部は腹直筋前鞘を含めて切除し、メッシュ植皮術を施行した。全摘標本では腫瘍全体の約7割はCD34陰性の紡錘形の腫瘍細胞がherringbone patternを呈しており、残りの3割がCD34陽性の紡錘形の腫瘍細胞でstoriform patternを呈して増殖していた。腫瘍組織において、変異遺伝子を検索したところ、COL1A1-PDGFB融合遺伝子が検出された。以上から線維肉腫様変化を伴った隆起性皮膚線維肉腫と診断した。術後1年2ヵ月経過したが、明らかな再発や転移を認めていない。(著者抄録)

55歳、女性。初診の3ヵ月前より全身に紅斑が出現し、尋常性乾癬として近医で加療を続けるも難治であった。血液検査にて抗HTLV-1抗体陽性であったため成人T細胞白血病・リンパ腫(ATLL)を疑われ紹介受診した。初診時は乾癬性紅皮症様の臨床像を呈しており、皮膚生検を行ったが異型リンパ球の浸潤は認められなかった。1ヵ月後に右側腹部の腫瘤と表在リンパ節腫脹が出現し、病理組織所見で異型リンパ球の密な浸潤が認められた。さらに同時期より血液中にflower cellも出現し最終的に白血化した急性型ATLLと診断した。化学療法を開始するも奏効せず、初診より4ヵ月後に死亡した。紅皮症の原因疾患は多岐にわたるが、自験例のようにATLLの非特異診のことがある。紅皮症を呈するATLL患者は予後不良の急性型である可能性が高いので、紅皮症の鑑別の一つとして特に注意を要すると考えられた。(著者抄録)

61歳男性。NSAIDsとメトトレキサートの内服治療に抵抗性の関節症性乾癬に対してinfliximabを投与した。Infliximab投与により関節症状は劇的な改善を認めたが、2クール終了後にニューモシスチス肺炎(Pneumocystis pneumonia;以下PCP)を発症した。乾癬患者では、現在のところ生物学的製剤によるPCP発症のリスク評価とST合剤の予防投薬の明確なガイドラインがない。生物学的製剤の使用に際しては低頻度ではあるもののPCP発症の可能性について慎重に経過観察していく必要があると考えられる。(著者抄録)

Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin (IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5 + CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgV H mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice. © 2013 Macmillan Publishers Limited All rights reserved.

Recently, we have found that pressure-induced hemolysis is enhanced by inhibiting water transport via aquaporin-1 (AQP1), as seen in p-chloromercuribenzoate (pCMB)-treated erythrocytes. So, using this method we reinvestigated the functions as AQP1 inhibitors of drugs and chemicals such as acetazolamide, sodium nitroprusside, tetraethylammonium ions (TEA(+)), and dimethylsulfoxide (DMSO). The values of hemolysis at 200MPa were almost unaffected by acetazolamide or sodium nitroprusside, decreased by TEA(+), and increased significantly by DMSO. Furthermore, the erythrocytes were exposed to pCMB in the presence of TEA(+) or DMSO. The enhancement effect of pCMB on pressure-induced hemolysis was unaffected by TEA(+) but attenuated by DMSO. Taken together, these results suggest that, of drugs and chemicals examined here, DMSO only is an AQP1 inhibitor, but the effect of DMSO is small compared with pCMB.