Akira Kasuya

IgG4‐related skin disease

IgG4‐related disease (IgG4‐RD) is a recently established clinical entity characterized by high levels of circulating IgG4, and tissue infiltration of IgG4+ plasma cells. IgG4‐RD exhibits a distinctive fibroinflammatory change involving multiple organs, such as the pancreas and salivary and lacrimal glands. The skin lesions of IgG4‐RD have been poorly characterized and may stem not only from direct infiltration of plasma cells but also from IgG4‐mediated inflammation. Based on the documented cases together with ours, we categorized the skin lesions into seven subtypes: (1) cutaneous plasmacytosis (multiple papulonodules or indurations on the trunk and proximal part of the limbs), (2) pseudolymphoma and angiolymphoid hyperplasia with eosinophilia (plaques and papulonodules mainly on the periauricular, cheek and mandible regions), (3) Mikulicz disease (palpebral swelling, sicca syndrome and exophthalmos), (4) psoriasis‐like eruption (strikingly mimicking psoriasis vulgaris), (5) unspecified maculopapular or erythematous eruptions, (6) hypergammaglobulinaemic purpura (bilateral asymmetrical palpable purpuric lesions on the lower extremities) and urticarial vasculitis (prolonged urticarial lesions occasionally with purpura) and (7) ischaemic digit (Raynaud phenomenon and digital gangrene). It is considered that subtypes 1–3 are induced by direct infiltration of IgG4+ plasma cells, while the other types (4–7) are caused by secondary mechanisms. IgG4‐related skin disease is defined as IgG4+ plasma‐cell‐infiltrating skin lesions that form plaques, nodules or tumours (types 1–3), but may manifest secondary lesions caused by IgG4+ plasma cells and/or IgG4 (types 4–7).

Attempts to accelerate wound healing

Wound healing is a well-orchestrated process, where numerous factors are activated or inhibited in a sequence of steps. Immediately after the infliction of damage, the repair of wound stars. The initial step is an inflammatory change with activation of innate immunity, which is followed by proliferation phase, including fibroplasia, angiogenesis and re-epithelialization. Pathological impairment of wound healing process may lead to persistent ulceration as seen in diabetic patients. Various signaling pathways are involved in wound healing. TGFβ/Smad pathway is a representative and well known to participate in fibroplasia, however, its comprehensive effect on wound healing is controversial. Experimental and clinical remedies have been being tried to promote wound healing. Advancement of cell engineering allows us to use stem cells and living skin equivalents.

Potential application of in vivo imaging of impaired lymphatic duct to evaluate the severity of pressure ulcer in mouse model

Ischemia-reperfusion (IR) injury is a cause of pressure ulcer. However, a mechanism underlying the IR injury-induced lymphatic vessel damage remains unclear. We investigated the alterations of structure and function of lymphatic ducts in a mouse cutaneous IR model. And we suggested a new method for evaluating the severity of pressure ulcer. Immunohistochemistry showed that lymphatic ducts were totally vanished by IR injury, while blood vessels were relatively preserved. The production of harmful reactive oxygen species (ROS) was increased in injured tissue. In vitro study showed a high vulnerability of lymphatic endothelial cells to ROS. Then we evaluated the impaired lymphatic drainage using an in vivo imaging system for intradermally injected indocyanine green (ICG). The dysfunction of ICG drainage positively correlated with the severity of subsequent cutaneous changes. Quantification of the lymphatic duct dysfunction by this imaging system could be a useful strategy to estimate the severity of pressure ulcer.

Biochemical, cytological, and immunological mechanisms of rhododendrol-induced leukoderma

Recently, an unexpected outbreak of patients with leukoderma occurred in Japan with the use of brightening/lightening cosmetics containing rhododendrol (RD). Patients developed leukoderma mostly on the skin sites repeatedly applied with RD, but some patients also had vitiligo-like lesions on the non-applied sites. RD is a tyrosinase-competitive inhibiting substance, thereby serving as an inhibitor of melanin synthesis. Upon inhibition of tyrosinase, RD is converted to new products such as tyrosinase-catalyzed hydroxyl-metabolite, which damage melanocytes. The melanocyte cell lysates seem to induce T-cell response. The frequencies of CD8+ T cells in both lesional skin and peripheral blood are significantly higher in the RD leukoderma as well as non-segmental vitiligo patients than in normal controls. In HLA-A*02:01 positive cases, circulating Melan-A-specific cytotoxic T cells can be detected at a high frequency. It is thus suggested that RD-induced leukoderma is induced by not only cytolysis of melanocytes but also subsequent immune reactions toward melanocytes.

Early diagnosis of recurrent diffuse large B-cell lymphoma showing intravascular lymphoma by random skin biopsy

A 66‐year‐old man was admitted to our hospital presenting 2 weeks’ history of fever of unknown origin with elevated levels of lactate dehydrogenase and C‐reactive protein. Six years before this episode, he had developed diffuse large B‐cell lymphoma, which had been successfully treated with chemoradiation. While recurrence of diffuse large B‐cell lymphoma was suspected, there was neither lymphadenopathy nor tumor formation by the imaging study. Random biopsy from normal‐appearing abdominal skin showed extensive infiltration of CD20+, CD79a+, CD3− atypical lymphoid cells in the lumen of vessels in subcutaneous tissues. These findings led us to the diagnosis of intravascular B‐cell lymphoma. Following rituximab plus cyclophosphamide, adriamycin, vincristine and prednisolone therapy, high fever subsided, and lactate dehydrogenase and C‐reactive protein levels returned to the normal range. In conclusion, random skin biopsy is useful for the early diagnosis of intravascular B‐cell lymphoma.

Structural and immunological effects of skin cryoablation in a mouse model.

Cryoablation is therapeutically applied for various disorders in several organs, and skin diseases are typical targets as this cryotherapy has been widely used for viral warts, benign tumors, and actinic keratosis. The main mechanisms of cryoablation consist of direct freezing effect on skin constituents, thrombosis formation in microcirculation, and subsequent immunological responses. Among them, however, the immunological mechanism remains unelucidated, and it is an issue how the direct freezing injury induces immunological consequences. We established a mouse cryoablation model with liquid nitrogen applied to the shaved back skin, and used this system to study the immunological excitement. After application of liquid nitrogen, the thermal decrease ratio was -25°C/sec or less and the lowest temperature was less than -100°C, which was sufficient to induce ulceration. Destruction of cornified layer and necrosis of epidermal cells were observed in transmission electron microscopy image, and increased transepidermal water loss and skin permeability were detected by the functional measurements. By flow cytometry, antigen-presenting dendritic cells (DCs), including PDCA1+B220+CD19- plasmacytoid DCs (pDCs) and CD11c+ myeloid DCs, as well as neutrophils and macrophages were increased in subcutaneous tissue. In parallel, the mRNA expressions of interferon α1 which are known as pDC-producing cytokines, was elevated. We also found marked degranulation of mast cells, providing a possibility that released histamine attracts pDCs. Finally, FITC migration assay revealed that pDCs and CD11c+ DCs emigrated from the cryoablated skin to the draining lymph nodes. Our study suggests that cryoablation induces destruction of the barrier/epidermis, accumulation of pDCs and CD11c+ DCs to the skin, and migration of DCs to regional lymph nodes. Viral elements or tumor cell lysates released from damaged keratinocytes may stimulate the DCs, thereby leading to antiviral or antitumor effect.

TIF1γ-overexpressing, Highly Progressive Endometrial Carcinoma in a Patient with Dermato myositis Positive for Malignancy-associated Anti-p155/140 Autoantibody

Anti-pl 55/140 autoantibody-positive dermatomyositis is a distinct subgroup with internal malignancies and characteristic clinical features, e.g. prominent cutaneous manifestation and lack of interstitial pneumonia ( 1 ). The target antigens ofp 155/140 have recently been identified as transcriptional intermediary factor ly (TIFly) and TIFla, respectively (2). It is thus speculated that TIFly is expressed in malignant tumour cells, leading to the development of anti-pl 55/140 autoantibody and the resultant occurrence of dermatomyositis. We report here the first case of anti-pl 55/140 antibody-positive dermatomyositis that shows the coexistence of a TIFly-overexpressing malignant neoplasm.

Histiocytoid Sweet’s syndrome associated with t(9;22)(q34;q11)-positive chronic myelogenous leukemia: immature granulocytic origin of histiocytic cells

and functional analysis of a chimeric protein COL1A1PDGFB generated by the translocation t(17;22)(q22;q13.1) in dermatofibrosarcoma protuberans (DP). Oncogene 2001; 20: 2965–2975. 6 Bague S, Folpe AL. Dermatofibrosarcoma protuberans presenting as a subcutaneous mass: a clinicopathological study of 15 cases with exclusive or near-exclusive subcutaneous involvement. Am J Dermatopathol 2008; 30: 327–332.

Raynaud phenomenon, digital gangrene and hypergammaglobulinaemic purpura occurring in a patient with IgG4-related disease.

1 Purnak T, Purnak S. Porphyria cutanea tarda and glucose metabolism alterations. Br J Dermatol 2011; 165:1363–65. 2 Muñoz-Santos C, Guilabert A, Moreno N et al. The association between porphyria cutanea tarda and diabetes mellitus: analysis of a long-term follow-up cohort. Br J Dermatol 2011; 165:486–91. 3 Perseghin G. Lipids in the wrong place: visceral fat and nonalcoholic steatohepatitis. Diabetes Care 2011; 34 (Suppl. 2):S367–70. 4 Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011; 332:1519–23.

Successful differentiation of herpes zoster-associated erythema multiforme from generalized extension of herpes by rapid polymerase chain reaction analysis.

The polymerase chain reaction (PCR) assay for varicella zoster virus (VZV), herpes simplex virus (HSV)‐1 and HSV‐2 is available for use. Sometimes the differential diagnosis of the generalized herpes zoster (HZ), HSV1/2, and drug eruption is difficult. We report a case of HZ followed by the vesicular erythema multiforme (EM)‐like lesion. In this case the use of PCR was of great assistance. A 78‐year‐old Japanese man without any significant previous history of disease was admitted to our hospital complaining of zosteriform vesicle on an erythematous base from his right shoulder to the upper arm. We diagnosed him with HZ at the level of right Th2. In spite of the prompt start of antiviral therapy, a secondary new vesiculous erythema developed on his trunk. Clinically, it was quite difficult to differentiate the lesion from the generalized HZ. Rapid PCR assay of effusion and crust for VZV was performed. A PCR assay of VZV was positive for the crust taken from the primary lesion, while it was negative for the effusion and crust of the secondary widespread lesion. We diagnosed the secondary widespread lesion as an EM‐type drug eruption induced by acyclovir, or an EM associated with herpes zoster. We then stopped the use of acyclovir and applied steroid ointment of a very strong class for the secondary lesions, which improved after a few days. A PCR assay for VZV was useful for ruling out the generalized HZ in our case with secondary developed vesiculous lesions.