Tomoaki Yokoyama

Antigen-independent development of Foxp3+ regulatory T cells suppressing autoantibody production in experimental pemphigus vulgaris

The CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) play suppressive roles in various types of autoimmunity. It has been reported that Tregs develop in the thymus after high-affinity interaction of their TCR with self-peptide/MHC ligands mostly utilizing TCR-transgenic system. In this study, we examined whether the specific antigen is involved in the development of polyclonal Tregs in pemphigus vulgaris (PV), an autoimmune blistering disease caused by anti-desmoglein 3 (Dsg3) IgG antibodies, as a model system. Adoptive transfer of splenocytes of Dsg3(-)(/-) mice immunized with recombinant mouse Dsg3 to Rag2(-)(/-) recipient mice expressing Dsg3 resulted in the stable production of anti-Dsg3 IgG and the development of PV phenotypes. We show here that Tregs control anti-Dsg3 antibody production in PV model mice: the adoptive transfer of Tregs and the depletion of endogenous Tregs suppressed and augmented, respectively, the anti-Dsg3 antibody production. To examine whether the endogenous expression of Dsg3 is involved in the generation of these PV-relevant Tregs, we compared the potential of wild-type Tregs with that of Tregs from Dsg3(-)(/-) mice. Polyclonal Tregs from Dsg3(-)(/-) mice were more potent than that of wild-type mice, in both adoptive transfer and Treg-depletion experiments, while suppressive activities against IgG production against an irrelevant antigen were similar between Tregs from wild-type and Dsg3(-)(/-) mice. Our observation implies that Tregs capable of suppressing T(h) cells that drive autoantibody production can develop in the absence of the target antigen.

Immune dysregulation of pemphigus in humans and mice.

Pemphigus vulgaris is an autoimmune blistering disease of the skin and mucous membranes that is caused by immunoglobulin (Ig)G autoantibodies against the cadherin‐type adhesion molecule desmoglein (Dsg)3 expressed on stratified epithelial cells. Interaction between antigen‐specific T and B cells, which is selectively achieved through T‐cell receptor/major histocompatibility complex–peptide complex association and subsequently corroborated by co‐stimulatory molecules such as CD40/CD154, is required for production of pathological anti‐desmoglein 3 antibody. Some genetically and environmentally susceptible individuals harbor desmoglein reactive B and T cells, and anti‐desmoglein antibodies were detected in their serum. Analysis of the anti‐desmoglein antibody clones derived from pemphigus patients or pemphigus model mice revealed that pathogenic antibodies mostly react with conformational epitopes on mature form desmogleins, whereas non‐pathogenic ones tend to react with non‐conformational epitopes. Surprisingly, antibodies to the Dsg1 precursor pro‐protein are also cloned from individuals without pemphigus. These observations suggest that active suppression by regulatory cell subsets is dominant in these susceptible individuals. In fact, Dsg‐reactive T‐inducible regulatory type 1 (Tr1) cells are readily detected in healthy carriers of pemphigus‐related human leukocyte antigen haplotypes, but rarely in pemphigus patients. These Tr1 cells can be functionally converted to T‐helper 2‐like cells which secrete interleukin‐2 by inactivation of Foxp3 through antisense oligonucleotides. Thus, delicate balance between self‐reactive lymphocytes and regulatory T cells may be a key element in determining whether individuals produce pathogenic antibodies and develop pemphigus phenotypes or not.

An elderly patient with chronic active Epstein–Barr virus infection with severe hydroa vacciniforme-like eruptions associated with αβT-cell proliferation

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Blastic Plasmacytoid Dendritic Cell Neoplasm in a 7-year-old Girl with a Solitary Skin Lesion Mimicking Traumatic Purpura

© 2015 The Authors. doi: 10.2340/00015555-1903 Journal Compilation

Coexistence of acquired perforating dermatosis and bullous pemphigoid: three cases.

Both acquired perforating dermatosis (APD) and bullous pemphigoid (BP) are associated with a wide variety of systemic and cutaneous disorders [1, 2]. However, coexistence of APD and BP has never been reported. Herein, we describe three patients with coexisting BP and APD. The patients had several common features, suggesting that this condition is a new and unique clinical presentation associated with BP.Patient 1 was a 65-year-old male who presented with a three-month history of pruritic skin lesions [...]

Case of Rapid Progression of Hemiatrophy on the Face: A New Clinical Entity?

A lot of diseases, including lupus profundus, morphea, lipodystrophy, and Parry-Romberg syndrome, may manifest progressive hemifacial atrophy. These diseases usually progress slowly and rapid progression of atrophy is extremely rare. We report a case of elderly-onset rapid progression of hemifacial atrophy only in three weeks. Our case did not meet variable differential diagnoses. We discuss the clinical character of the patient against the past of literature and suppose it may be a new clinical entity.

A patient with lupus miliaris disseminatus faciei treated successfully with a combination of oral metronidazole and topical tacrolimus

Dear Editor, Lupus miliaris disseminatus faciei (LMDF) is a rare granulomatous, inflammatory dermatosis of unknown etiology. It is characterized by reddish yellowish brown papules on the central face, particularly on and around the eyelids. There is no established therapy for LMDF due to lack of controlled study. Although many therapies, including tetracycline, oral steroids, dapsone, and topical tacrolimus are reported to be effective, there is no report of treatment with oral metronidazole in English literature. Herein, we report the first case of LMDF treated successfully with oral metronidazole. A 37-year-old woman visited our department with a 2-month history of almost asymptomatic eruption of the central face. She had tiny (1–3 mm), dome-shaped reddish yellow papular lesions without rash and teleangiectasia on the face including the eyelids, perioral area, forehead, and chin (Fig. 1a). Dermoscopy revealed apple-jelly nodule-like appearance (Fig. 1b). Laboratory examination, including angiotensin-converting enzyme and lysozyme, was within normal limits and the T-SPOT tuberculosis test was negative. The histopathology of papules on the right cheek revealed granulation tissue composed of central caseation necrosis surrounded by epitheloid cells (Fig. 1c). There were multinucleate giant cells of the Langhans type (Fig. 1d). The tissue was negative for Ziel-Neelsen stain. A diagnosis of LMDF was made. We had treated the patient with oral roxithromycin (150 mg twice daily) and topical tacrolimus for 1 month, however, the eruption showed no improvement. Oral metronidazole (250 mg twice daily) was then administered, while topical tacrolimus was maintained. Two weeks later, a prominent improvement was achieved. The eruptions almost disappeared with no scarring (Fig. 1e). The medication was maintained and no recurrence and side effects have occurred at 4-month follow-up. Metronidazole is a nitroimidazole antimicrobial drug. It is used both systemically and topically for many cutaneous disease, including rosacea, acne and perioral dermatitis. However, the use of oral metronidazole for treatment of LMDF has never been reported in English literature. LMDF is a distinctive disease entity of a debatable pathophysiology, and a variety of treatments have been tried and reported with variable outcomes. There are some reports of the treatment for rosacea, one of similar conditions of LMDF, by oral metronidazole. Pye et al. conducted a double-blind trial in 29 patients with rosacea and showed that metronidazole was therapeutically superior to a placebo after 6 weeks’ treatment. No other patients presented side effects during the trial. Saihan et al. conducted a randomized double-blind trial in forty patients and showed the same effectiveness of oral metronidazole to rosacea as that of oral oxytetracycline after 6 and 12 weeks’ treatment. No side effects were reported. Although these trials provided only limited data, oral metronidazole might be a choice of treatment for rosacea and its relative conditions including LMDF. We treated the patient with oral metronidazole in combination with topical tacrolimus, therefore we can not rule out the possibility that topical tacrolimus is also effective. However, for 1 month before the introduction of metronidazole, we also had used topical tacrolimus, but the eruption showed no improvement. Therefore, we believe the oral metronidazole was most effective in our patient. Figure 1. (a) Clinical features on the first visit. (b) Dermoscopic images. Apple-jelly nodule-like appearance. (c) Granulation tissue with central caseation necrosis. (d) Langhans cells. (e) Clinical features after the treatment.

Traumatic neuroma on the digital tip: Immunohistochemical analysis of inflammatory signaling pathways.

Dear Editor, Traumatic neuromas (TN) are uncommon lesions that occur after nerve injury or resection. A typical clinical feature is a painful nodule on the margins of the palm or the fingers. Histologically, it is characterized by the irregular arrangement of nerve fascicles embedded in a fibrous stroma. Their etiology is hypothesized to be from nerve amputation after trauma. However, the detailed mechanism is yet to be clarified. Here, we report a case of TN that occurred on the digital tip. To obtain insight into the pathogenesis of TN, we performed immunohistochemical analysis of proteins related to inflammation. An 8-year-old Japanese girl presented with a nodule that had been on her digital tip for 5 years. It developed after she had accidentally got her fingertip caught in the door of a microwave oven. She had no significant medical or family histories. On physical examination, she had a dome-shaped, smooth, skin-colored and painless nodule measuring 6 mm 9 6 mm on the tip of her right fifth digit (Fig. 1a). The lesion was excised under local anesthesia. Histopathological finding showed an increased number of dermal S-100-positive nerve fibers in a tangle of fascicles embedded in fibrous stroma (Fig. 1b–d). These findings were compatible with those of TN. Immunohistochemical analysis of a-smooth muscle actin showed confined positive staining within the vascular wall but was negative for the neuroma lesion (Fig. 1e), the finding of which suggested the lack of myofibroblasts and is reported to be observed in the non-painful TN as shown in this case. No recurrence was observed after a year of surgical excision. Traumatic neuromas often occur on the digits, but TN on the digital tip has rarely been reported. The lack of such

Intramuscular myxoma on the forehead: An unusual localization with useful sonographic findings.

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