Machiko Nishimura

Antibodies to Pathogenic Epitopes on Type XVII Collagen Cause Skin Fragility in a Complement-Dependent and -Independent Manner

In bullous pemphigoid (BP), the most prevalent autoimmune blistering disease, type XVII collagen (COL17) is targeted by circulating autoantibodies. BP is thought to be an autoantibody-mediated complement-fixing blistering disease, and a juxtamembranous noncollagenous 16A (NC16A) domain spanning Glu490 to Arg566 was proved to be the main pathogenic region on COL17, although precise pathogenic epitopes within NC16A have not been elucidated. In this study, we showed that injection of rabbit IgG Abs targeting Asp522 to Gln545 induced skin fragility associated with in vivo deposition of IgG and complement in neonatal COL17-humanized mice. Notably, immunoadsorption of rabbit anti-NC16A IgG Ab with this epitope (Asp522 to Gln545) or the anti-NC16A IgG administered together with the peptides of this epitope as a decoy ameliorated skin fragility in the injected neonatal COL17-humanized mice compared with the anti-NC16A IgG alone even though all of the mice showed both IgG and complement deposition. These results led us to investigate an additional, complement-independent mechanism of skin fragility in the mice injected with anti-COL17 Abs. The rabbit anti-NC16A IgG depleted the expression of COL17 in cultured normal human keratinocytes, whereas immunoadsorption of the same IgG with this epitope significantly suppressed the depletion effect. Moreover, passive transfer of F(ab′)2 fragments of the human BP or rabbit IgG Abs against COL17 demonstrated skin fragility in neonatal COL17-humanized mice. In summary, this study reveals the importance of Abs directed against distinct epitopes on COL17, which induce skin fragility in complement-dependent as well as complement-independent ways.

Circulating IgA and IgE autoantibodies in antilaminin-332 mucous membrane pemphigoid

Background  Antilaminin‐332 mucous membrane pemphigoid (MMP) is a chronic autoimmune bullous disease that is often associated with internal malignancy. IgG autoantibodies against laminin‐332 in patients with MMP are well documented; however, IgA and IgE autoantibodies against laminin‐332 have not yet been described.

Circumscribed palmar hypokeratosis: correlation between histopathological patterns and dermoscopic findings

acknowledgments within their content, authorship disclosure within advertising material was highly inconsistent and often made it difficult to determine if medical professionals were involved. In other specialities, reports have observed a similar low level of professional medical involvement in app design, and have found content containing misleading claims and a lack of academic reference. Certain apps, such as one that uses an automated system of photographic analysis to stratify a patient’s skin lesions as low, medium or high risk, provide many potential diagnostic risks. While such apps may promote beneficial skin-monitoring behaviour, the use and interpretation of an unknown, unvalidated risk stratification system by the untrained user is inadvisable and could lead to false reassurance. Other concerns include confidentiality and data storage. Some teledermatology apps use online forums where a large number of unknown users can view an individual’s clinical information. More general concerns include the risk of cross-contamination, where using mobile phones during clinical encounters could interfere with hand hygiene and provide a reservoir for pathogenic bacteria. In February 2011, the U.S. Food and Drug Administration published draft guidelines specifying that some apps constitute a ‘medical device’ and require regulation. Additionally, the U.S. Federal Trade Commission has addressed misleading marketing, in one case by outlawing an app claiming to provide a cure for acne. As some apps cross the divide from entertainment into a capacity as a medical device, increasing regulation is welcome; however, the future extent of regulation of medical apps is currently unknown. We propose that simple measures to improve accountability of app content, such as insistence by app providers of full authorship disclosure, listing of regulatory approval, recognized quality marks and external review, may lead to improvements in the reliability and quality of the content offered.

Primary cutaneous CD30+ anaplastic large‐cell lymphoma with generalized skin involvement and involvement of one peripheral lymph node, successfully treated with low‐dose oral etoposide

Primary cutaneous CD30+ anaplastic large‐cell lymphoma (PCALCL) in adults is rare, and the prognosis is generally excellent. Multifocal PCALCL tends to relapse after multiagent chemotherapy and is generally considered more prone to progress to extracutaneous involvement than is the localized disease. We report a 43‐year‐old woman with PCALCL who had generalized skin involvement accompanied by involvement of one peripheral draining lymph‐node region. Although the disease relapsed after multiagent chemotherapy regimens, the disease was successfully treated with low‐dose etoposide. We reviewed the previously reported cases of PCALCL treated with low‐dose etoposide. We suggest that oral etoposide might be a useful effective treatment for treatment of relapsed multifocal PCALCL.

Extracellular cleavage of collagen XVII is essential for correct cutaneous basement membrane formation

In skin, basal keratinocytes in the epidermis are tightly attached to the underlying dermis by the basement membrane (BM). The correct expression of hemidesmosomal and extracellular matrix (ECM) proteins is essential for BM formation, and the null-expression of one molecule may induce blistering diseases associated with immature BM formation in humans. However, little is known about the significance of post-translational processing of hemidesmosomal or ECM proteins in BM formation. Here we show that the C-terminal cleavage of hemidesmosomal transmembrane collagen XVII (COL17) is essential for correct BM formation. The homozygous p.R1303Q mutation in COL17 induces BM duplication and blistering in humans. Although laminin 332, a major ECM protein, interacts with COL17 around p.R1303, the mutation leaves the binding of both molecules unchanged. Instead, the mutation hampers the physiological C-terminal cleavage of COL17 in the ECM. Consequently, non-cleaved COL17 ectodomain remnants induce the aberrant deposition of laminin 332 in the ECM, which is thought to be the major pathogenesis of the BM duplication that results from this mutation. As an example of impaired cleavage of COL17, this study shows that regulated processing of hemidesmosomal proteins is essential for correct BM organization in skin.

Macropinocytosis of type XVII collagen induced by bullous pemphigoid IgG is regulated via protein kinase C

Macropinocytosis is an endocytic pathway that is involved in the nonselective fluid uptake of extracellular fluid. Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with autoantibodies to type XVII collagen (COL17), which is a component of hemidesmosome. When keratinocytes are treated with BP-IgG, COL17 internalizes into cells by way of the macropinocytosis. We investigated the mechanism of COL17 macropinocytosis using DJM-1 cells, a cutaneous squamous cell carcinoma cell line. First, non-hemidesmosomal COL17 was preferentially depleted by stimulation with the BP-IgG in the DJM-1 cells. To investigate the signaling involved in COL17-macropinocytosis, the inhibition of small GTPase family members Rac1 and Cdc42 was found to strongly repress COL17 internalization; in addition, the Rho inhibitor also partially blocked that internalization, suggesting these small GTPases are involved in signaling to mediate COL17-macropinocytosis. Western blotting using Phostag-SDS-PAGE demonstrated high levels of COL17 phosphorylation in DJM-1 cells under steady-state condition. Treatment with BP-IgG increased the intracellular calcium level within a minute, and induced the overabundant phosphorylation of COL17. The overabundant phosphorylation of COL17 was suppressed by a protein kinase C (PKC) inhibitor. In addition, PKC inhibitor repressed COL17 endocytosis using cell culture and organ culture systems. Finally, the depletion of COL17 was not observed in the HEK293 cells transfected COL17 without intracellular domain. These results suggest that COL17 internalization induced by BP-IgG may be mediated by a PKC pathway. In summary, BP-IgG initially binds to COL17 distributed on the plasma membrane, and COL17 may be internalized by means of a macropinocytic pathway related to the phosphorylation of the intracellular domain by PKC.

Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning for mycosis fungoides and Sezary syndrome.

Advanced‐stage mycosis fungoides and Sezary syndrome (MF/SS) have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT), particularly using a reduced‐intensity conditioning (RIC) regimen, is a promising treatment for advanced‐stage MF/SS. We performed RIC‐HSCT in nine patients with advanced MF/SS. With a median follow‐up period of 954 days after HSCT, the estimated 3‐year overall survival was 85.7% (95% confidence interval, 33.4–97.9%) with no non‐relapse mortality. Five patients relapsed after RIC‐HSCT; however, in four patients whose relapse was detected only from the skin, persistent complete response was achieved in one patient, and the disease was manageable in other three patients by the tapering of immunosuppressants and donor lymphocyte infusion, suggesting that graft‐versus‐lymphoma effect and ‘down‐staging’ effect from advanced stage to early stage by HSCT improve the prognosis of advanced‐stage MF/SS. These results suggest that RIC‐HSCT is an effective treatment for advanced MF/SS. Copyright

Loss of interaction between plectin and type XVII collagen results in epidermolysis bullosa simplex

Plectin is a linker protein that interacts with intermediate filaments and β4 integrin in hemidesmosomes of the epidermal basement membrane zone (BMZ). Type XVII collagen (COL17) has been suggested as another candidate plectin binding partner in hemidesmosomes. Here, we demonstrate that plectin–COL17 binding helps to maintain epidermal BMZ organization. We identified an epidermolysis bullosa (EB) simplex patient as having markedly diminished expression of plectin and COL17 in skin. The patient is compound heterozygous for sequence variants in the plectin gene (PLEC); one is a truncation and the other is a small in‐frame deletion sequence variant. The in‐frame deletion is located in the putative COL17‐binding domain of plectin and abolishes the plectin–COL17 interaction in vitro. These results imply that disrupted interaction between plectin and COL17 is involved in the development of EB. Our study suggests that protein–protein binding defects may underlie EB in patients with unidentified disease‐causing sequence variants.

Thymoma-associated multi-organ autoimmunity: two cases and a review of the literature.

Thymoma-associated multi-organ autoimmunity (TAMA) is defined as a disease of the liver, intestine, and skin, which histopathologically resembles graft-versus-host disease (GVHD).1,2 Several sporadic cases imply that cutaneous manifestations of TAMA are associated with a poor prognosis.2-5 However, it is difficult to examine the association because of the rarity of the disease. Herein we describe two cases of TAMA with cutaneous lesions and fatal courses, and review the literature with a focus on the prognosis. This article is protected by copyright. All rights reserved.

Portable negative-pressure wound therapy for pyoderma gangrenosum: Report of two cases

Pyoderma gangrenosum is a chronic non‐infectious neutrophilic dermatosis that causes undermining ulcers. Topical therapies for the deep ulcers of pyoderma gangrenosum have not been established. To investigate whether negative‐pressure wound therapy is effective for a pyoderma gangrenosum ulcer, we used the PICO single use negative‐pressure wound therapy system (Smith & Nephew, London, UK) for two pyoderma gangrenosum patients. In these cases, the ulcers decreased in size and necrolytic tissue was removed notably. Moreover, there were no secondary infections nor was there Koebner phenomena. Our cases suggest that portable negative‐pressure wound therapy can be a treatment option for deep, intractable ulcers caused by pyoderma gangrenosum. Because portable negative‐pressure wound therapy devices afford increased mobility to patients, they can give the patient a better quality of life than standard negative‐pressure wound therapy systems do.