Rosai‐Dorfman disease successfully treated with thalidomide: A case report

Rosai‐Dorfman disease (RDD) is a rare disease which characterized by proliferation and overproduction of histiocytes in the lymph nodes appearing as lymphadenopathy, however, it may also occur in extranodal sites. The occurrence of unusual manifestations of the disease such as the appearance of the mass in an unusual area may increase the probability of misdiagnosis. Herein, we describe a case of RDD in an old woman with an unusual appearance of RDD in the leg that was successfully treated by thalidomide.     

DAMP molecules S100A9 and S100A8 activated by IL‐17A and house‐dust mites are increased in atopic dermatitis

S100A9 and S100A8 are called damage‐associated molecular pattern (DAMP) molecules because of their pro‐inflammatory properties. Few studies have evaluated S100A9 and S100A8 function as DAMP molecules in atopic dermatitis (AD). We investigated how house‐dust mites affect S100A9 and S100A8 expression in Th2 cytokine‐ and Th17 cytokine‐treated keratinocytes, and how secretion of these molecules affects keratinocyte‐derived cytokines. Finally, we evaluated expression of these DAMP molecules in AD patients. S100A9 expression and S100A8 expression were strongly induced in IL‐17A‐ and Dermatophagoides (D.) farinae‐treated keratinocytes, respectively. Furthermore, co‐treatment with D. farinae and IL‐17A strongly increased expression of S100A9 and S100A8 compared with D. farinae‐Th2 cytokine co‐treatment. The IL‐33 mRNA level increased in a dose‐dependent manner in S100A9‐treated keratinocytes, but TSLP expression did not change. S100A8/A9 levels were also higher in the lesional skin and serum of AD patients, and correlated with disease severity. Taken together, S100A9 and S100A8 may be involved in inducing DAMP‐mediated inflammation in AD triggered by IL‐17A and house‐dust mites.     

S100阳性不典型幼年性黄色肉芽肿一例随访观察并文献复习

【摘要】 患者男,3岁,因躯干多发棕黄色丘疹3个月就诊。皮损组织病理学检查,见真皮较多单一核组织细胞、嗜酸性粒细胞及少量淋巴细胞浸润。免疫组化示S100阳性、CD1a部分阳性、CD68阳性。其后原发皮疹颜色渐变暗,部分变平消退,留色素沉着,但仍有新发皮疹。4个月后第2次组织病理学检查显示,除组织细胞、嗜酸性粒细胞外,真皮尚可见少许多核巨细胞。免疫组化示组织细胞S100阴性、CD1a阴性、CD68 阳性。诊断：幼年性黄色肉芽肿。     

寻常型银屑病患者及正常人S100A6、S100A8、S100A9基因的研究

目的：通过测定家族性寻常型银屑病患者和正常人中S100A6、S100A8和S100A9基因的外显子编码区序列，探索其与银屑病发病的关系。方法：从家族性寻常型银屑病患者和正常人的外周血中提取基因组DNA，用自动测序法测定S100A6、S100A8和S100A9基因的外显子编码区序列。结果：患者和正常对照组的S100A6、S100A8、S100A9基因外显子编码区序列均相同，未发现基因多态性。结论：S100A6、S100A8、S100A9基因的外显子编码区序列与家族性寻常型银屑病发病无相关性。     

A case of S‐100‐negative CD1a‐positive indeterminate cell histiocytosis

Histiocytoses are a group of rare disorders characterized by a proliferation of monocytes/macrophages and dendritic cells. We present a case of a 3‐year‐old girl with a diffuse papular eruption without systemic symptoms demonstrating a proliferation of strongly CD1a⁺ histiocytes, but negative for S‐100 and langerin on histopathology. Systemic work‐up including bone marrow biopsy was unremarkable, and the patient received a diagnosis of CD1a⁺ S^? 100‐indeterminate cell histiocytosis.     

TNFα‐ and IL‐17A‐mediated S100A8 expression is regulated by p38 MAPK

The antimicrobial peptide S100A8 is known to be upregulated in lesional psoriatic skin compared with non‐lesional psoriatic skin and is believed to play a role in the pathogenesis of psoriasis. However, little is known about the signalling pathways involved in the regulation of S100A8 expression. Using quantitative real‐time RT‐PCR analysis, we demonstrated that stimulation with TNFα and IL‐17A in combination resulted in a significant and synergistic induction of S100A8 mRNA in human keratinocytes. TNFα and IL‐17A also induced the S100A8 promoter activity synergistically. This was demonstrated by a gene reporter assay in cells transfected with a luciferase plasmid construct, consisting of 3502 base pairs of the human S100A8 promoter. The TNFα‐ and IL‐17A‐mediated induction of S100A8 mRNA and protein was mediated by a p38 MAPK‐dependent mechanism, as demonstrated by the use of a p38 MAPK inhibitor. Finally, adalimumab treatment for patients with psoriasis significantly decreased S100A8 mRNA at day fourteen after start of treatment, but not at day four. Taken together, this study demonstrates that the p38 MAPK signalling pathway plays a key role in the TNFα‐ and IL‐17A‐induced expression of S100A8 in cultured human keratinocytes.     

S100A7 acts as a dual regulator in promoting proliferation and suppressing squamous differentiation through GATA‐3/caspase‐14 pathway in A431 cells

S100A7 is expressed in many squamous cell carcinomas (SCCs), such as SCC of the skin, and well‐differentiated SCC always displays stronger staining of this protein. A431 cells, an epidermal cancer cell line, were selected as a cell model to investigate the roles and mechanism of S100A7 in SCC of the skin. In this study, we demonstrated that the overexpression of S100A7 in A431 cells significantly promoted cell proliferation in vitro and tumor growth in vivo, whereas it suppressed the expression of GATA‐3, caspase‐14 and three squamous differentiation markers, keratin‐1, TG‐1 and involucrin. Conversely, the overexpression of caspase‐14 not only significantly decreased cell proliferation and delayed tumor growth but also markedly induced the expression of three squamous differentiation markers, whereas S100A7 and GATA‐3 were not influenced. Further evidence showed that silencing GATA‐3 greatly inhibited the expression of caspase‐14 and three differentiation markers, while the expression of S100A7 was not changed; contrary results were obtained when overexpressing GATA‐3. Importantly, restoring the expression of GATA‐3 and caspase‐14 in A431‐S100A7 cells could bypass the ability of S100A7 to increase cell viability and repress squamous differentiation. These data suggested that S100A7 expression in SCC may play an important role in the maintenance of SCC cell dedifferentiation, at least in SCC of the skin.     

寻常型银屑病患者皮损中白介素-22和S100A7,A8,A9mRNA的表达及关系

目的研究白介素-22(IL-22)和S100A7,A8,A9mRNA在寻常型银屑病皮损中的表达及关系。方法采用逆转录聚合酶链反应(RT-PCR)技术对35例寻常型银屑病患者皮损和16例正常人皮肤中IL-22,S100A7,A8,A9mR-NA进行检测。结果①IL-22和S100A8,A9mRNA在寻常型银屑病皮损中呈阳性表达,而在正常皮肤中为阴性;S100A7mRNA在寻常型银屑病皮损中的表达水平为1.133±0.0403,较正常对照组0.744±0.0371明显升高,差异有显著性(P<0.01)。②IL-22mRNA与S100A7,A8,A9mRNA的表达呈显著正相关r1=0.543,r2=0.774,r3=0.621,P均<0.01。结论IL-22和S100A7,A8,A9与银屑病的发生和发展中明确相关,可能成为银屑病治疗新的靶位点。     

Aberrantly differentiated cells in benign pilomatrixoma reflect the normal hair follicle: immunohistochemical analysis of Ca-binding S100A2, S100A3 and S100A6 proteins

BACKGROUND: Pilomatrixoma is a common benign cutaneous tumour containing differentiated hair matrix cells. This tumour is mainly composed of basophilic, transitional, shadow and squamoid cells. Although some S100 proteins are expressed in a tissue-specific manner in the hair follicle (e.g. S100A2 in the outer root sheath, S100A3 in the cortex and cuticle, and S100A6 in the inner root sheath), little information is available concerning their distribution in the aberrantly differentiated tissues of pilomatrixoma. OBJECTIVES: To characterize the disordered epithelial elements of pilomatrixoma by localizing S100A2, S100A3 and S100A6 proteins. METHODS: Immunohistochemistry and dual-immunofluorescence microscopy were performed on 22 pilomatrixoma specimens using antibodies specific to the three proteins. RESULTS: Tissue-specific distribution of the S100 proteins investigated was preserved in the morphologically disordered tumour tissues. Anti-S100A2 antibody stained squamoid cells and putative outer root sheath cells; basophilic and potential hair matrix cells were occasionally stained. S100A3 staining was found in transitional cells and putative cortical cells, and was strong in both dispersed cells and hair-like structures surrounding cells which were presumably cuticular cells. Anti-S100A6 antibody labelled some S100A3-negative transitional cell strands, potentially inner root sheath cells. CONCLUSIONS: The epithelial elements of pilomatrixoma can be characterized using S100 proteins as biochemical markers. Our results show that pilomatrixomas retain a certain degree of differentiation indicative of distinct hair-forming cells.     

Elevated serum levels of calcium-binding S100 proteins A8 and A9 reflect disease activity and abnormal differentiation of keratinocytes in psoriasis

BACKGROUND: The expression of calcium-binding S100 molecules organized within the epidermal differentiation complex on chromosome 1q21 is disturbed in hyperproliferative skin diseases such as psoriasis. OBJECTIVES: We studied whether serum levels of S100 proteins A8 (S100A8) and A9 (S100A9) are elevated in psoriasis, correlated their amounts with disease activity and identified potential cellular sources. METHODS: Serum obtained from psoriasis patients or from healthy individuals was studied for S100A8 and S100A9 levels by enzyme-linked immunosorbent assay. Data were correlated to disease activity as reflected by the Psoriasis Area and Severity Index (PASI). Cellular sources of S100A8 and S100A9 were identified by in situ hybridization and immunohistochemistry of lesional psoriatic and nonlesional, nonpsoriatic skin. RESULTS: A significant increase of S100A8/S100A9 serum levels was found in patients with psoriasis compared with healthy controls. Grading the patients into two groups of severity, individuals with a PASI of <15 showed serum levels of 705+/-120 ng mL-1 (mean+/-SEM, n=18), those with a PASI of >or=15 showed levels of 1315+/-150 ng mL-1 (n=32) while controls presented with 365+/-50 ng mL-1. Performing in situ hybridization of lesional psoriatic skin we detected a dramatic induction of both S100A8 and S100A9 mRNA and protein primarily in the suprabasal layers of the epidermis while expression was negligible in nonlesional, nonpsoriatic interfollicular epidermis. CONCLUSIONS: Our data demonstrate that hyperproliferation and abnormal differentiation of psoriatic skin is associated with a massive upregulation and secretion of S100A8 and S100A9, suggesting not only a prominent role of these molecules during intracellular calcium-dependent signalling but also implying distinct extracellular functions.     

Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi‐institutional retrospective study

Vitiligo is occasionally seen in melanoma patients. Although several studies indicate a correlation between vitiligo occurrence and clinical response in melanoma patients receiving immunotherapy, most studies have included heterogeneous patient and treatment settings. The aim of this study is to investigate the correlation between the occurrence of vitiligo and clinical benefit of nivolumab treatment in advanced melanoma patients. We retrospectively reviewed unresectable stage III or IV melanoma patients treated with nivolumab. Of 35 melanoma patients treated with nivolumab, 25.7% (9/35) developed vitiligo during treatment. The time from the start of nivolumab treatment to occurrence of vitiligo ranged 2–9 months (mean, 5.2). Of nine patients who developed vitiligo, two (22.2%) had a complete response to nivolumab and two (22.2%) had a partial response. The objective response rate was significantly higher in patients with vitiligo than in patients without vitiligo (4/9 [44.4%] vs 2/26 [7.7%]; P = 0.027). The mean time to vitiligo occurrence in patients achieving an objective response was significantly less than that in patients who showed no response (3.1 vs 6.8 months, P = 0.004). Vitiligo occurrence was significantly associated with prolonged progression‐free and overall survival (hazard ratio, 0.24 and 0.16; 95% confidence interval, 0.11–0.55 and 0.03–0.79; P = 0.005, and 0.047, respectively). At the 20‐week landmark analysis, however, vitiligo was not associated with a statistically significant overall survival benefit (P = 0.28). The occurrence of vitiligo during nivolumab treatment may be correlated with favorable clinical outcome.     

Cutaneous S100‐negative,CD1a‐positive histiocytosis successfully treated with combination therapy of oral methotrexate and corticosteroid

S100‐negative, CD1a‐positive histiocytosis is a rare histiocytic disorder characterized by proliferation of histiocytic cells possessing a phenotype of epidermal Langerhans cells except for the lack of S100 expression and Birbeck granules. We report the case of a Japanese man suffering from S100‐negative, CD1a‐positive histiocytosis. The patient showed numerous smooth erythematous 5–10‐mm papules/nodules on most of his body. The key histopathological feature was the presence of dermal infiltrates of non‐epidermotropic S100‐negative CD1a‐positive mononuclear cells. No systemic involvement was detected. Initially bath‐psoralen plus ultraviolet A therapy was effective, but the lesions became recalcitrant to this treatment. Methylprednisolone pulse therapy followed by low‐dose methotrexate (up to 30 mg/week) in combination with prednisolone (15 mg/day) effectively controlled the skin lesions.     

Immunoglobulin G4‐related disease presenting with prurigo: Circulating T‐helper 2 cells may be involved in the pathogenesis

We report a case of immunoglobulin G4‐related disease (IgG4‐RD) which presented with prurigo on the trunk and extremities. A 66‐year‐old man had a 2‐month history of itchy erythematous papules on his trunk and extremities. Bilateral eyelid swelling and enlargement of the submandibular and parotid glands were also observed. Computed tomography revealed pleural thickening and diffuse pancreatic enlargement. Serum levels of IgG4 were markedly increased. A biopsy specimen obtained from an erythematous papule showed a perivascular inflammatory infiltrate of lymphocytes with eosinophils in the dermis, whereas a parotid gland biopsy revealed an infiltrate of abundant IgG4‐positive plasma cells. Treatment with prednisolone resulted in improvement of the skin and other lesions along with a decrease in IgG4 serum levels. A flow cytometric assay revealed that percentages of interleukin (IL)‐4‐ and IL‐13‐producing CD4⁺ T cells were markedly higher in the circulation of the IgG4‐RD patient than in that of healthy subjects. Moreover, those populations dramatically decreased after treatment. Thus, prurigo may be a skin manifestation of IgG4‐RD and T‐helper 2 cells may contribute to the pathogenesis.     

S100A7 (psoriasin) inhibits human epidermal differentiation by enhanced IL‐6 secretion through IκB/NF‐κB signalling

Psoriasin (S100A7), a member of the S100 protein family, is a well‐known antimicrobial peptide and a signalling molecule which regulates cellular function and is highly expressed in hyperproliferative skin conditions such as atopic dermatitis (AD) and psoriasis with disrupted skin barrier function. However, its role in epidermal differentiation remains unknown. We examined the effect of S100A7 on epidermal differentiation in normal human keratinocytes (NHKs) and on a reconstituted human epidermis model. When NHKs were exposed to disruptive stimuli such as Staphylococcus aureus, ultraviolet irradiation and retinoic acid, the secretion of S100A7 into the culture medium increased and the expression of epidermal differentiation markers decreased. Treatment of NHKs with S100A7 significantly inhibited epidermal differentiation by reducing the expression of keratin 1, keratin 10, involucrin and loricrin and by increasing the expression of abnormal differentiation markers (keratin 6 and keratin 16). We verified that the MyD88‐IκB/NF‐κB signal cascade was activated via RAGE after S100A7 treatment, resulting in the upregulation of interleukin‐6. Finally, we confirmed that S100A7 is a negative regulator of epidermal differentiation using a reconstituted human epidermis model. This study suggests that S100A7‐related signalling molecules could be potent targets for recovering skin barrier function in AD and psoriasis where S100A7 is accumulated excessively.     

Disseminated cutaneous Mycobacterium kansasii infection presenting with Rosai–Dorfman disease‐like histological features in a patient carrying anti‐interferon‐γ autoantibodies

Typical cutaneous non‐tuberculous mycobacteria (NTM) infections show a histopathology pattern of granulomas with admixed Langhans giant cells, and abscesses may be observed in acute lesions. Herein, we describe a patient carrying a high titer of autoantibodies to interferon (IFN)‐γ with disseminated Mycobacterium kansasii infection presenting with emperipolesis and Rosai–Dorfman disease (RDD)‐like histopathological features characterized by remarkable, large, pale‐staining “RD cells”, which were CD68 and S100 positive and CD1a negative. The patient was misdiagnosed with RDD initially, but exhibited a poor response to all interventions. A re‐biopsy revealed Langhans‐type multinucleated giant cells; multiple definite acid‐fast bacilli were also found. M. kansasii was isolated from cultured tissues. Anti‐NTM treatment was initiated. After treatment, all lesions resolved almost completely within the following month. High‐titer anti‐IFN‐γ autoantibodies were detected during follow up, leading to the diagnosis of adult‐onset immunodeficiency syndrome. In conclusion, patients carrying high‐titer autoantibodies to IFN‐γ who also have a disseminated cutaneous M. kansasii infection may present with RDD‐like histopathological features, which may be a pitfall in the diagnosis of disseminated cutaneous NTM infections.