Takaya Komori

A microbial glycolipid functions as a new class of target antigen for delayed-type hypersensitivity

Delayed-type hypersensitivity (DTH) is marked by high levels of protein antigen-specific T cell responses in sensitized individuals. Recent evidence has revealed a distinct pathway for T cell immunity directed against glycolipid antigens, but DTH to this class of antigen has been undetermined and difficult to prove due to their insolubility in aqueous solutions. Here, glucose monomycolate (GMM), a highly hydrophobic glycolipid of the cell wall of mycobacteria, was dispersed in aqueous solutions in the form of octaarginine-modified liposomes and tested for its ability to elicit cutaneous DTH responses in bacillus Calmette-Guerin (BCG)-immunized guinea pigs. After an intradermal challenge with the GMM liposome, a significant skin induration was observed in BCG-immunized, but not mock-treated, animals. The skin reaction peaked at around 2 days with local infiltration by mononuclear cells, and therefore, the response shared basic features with the classical DTH to protein antigens. Lymph node T cells from BCG-immunized guinea pigs specifically increased IFN-γ transcription in response to the GMM liposome, and this response was completely blocked by antibodies to CD1 lipid antigen-presenting molecules. Finally, whereas the T cells increased transcription of both T helper (Th) 1-type (IFN-γ and TNF-α) and Th2-type (IL-5 and IL-10) cytokines in response to the purified protein derivative or tuberculin, their GMM-specific response was skewed to Th1-type cytokine production known to be critical for protection against tuberculosis. Thus, our study reveals a novel form of DTH with medical implications.

Glycerol monomycolate, a latent tuberculosis-associated mycobacterial lipid, induces eosinophilic hypersensitivity responses in guinea pigs

Dynamic changes in the lipid composition of the cell wall occur in pathogenic mycobacteria that are often intended for adaptation to the host environment. Dormant mycobacteria should have evolved efficient maneuvers for cohabitation, allowing the microbes to persist for years within the host. Glycerol monomycolate (GroMM) has been implicated as a specific immune target in human individuals with latent, but not active, tuberculosis, but the in vivo response to GroMM and the relevance of it to latent infection remain poorly understood. Here, we immunized guinea pigs with bacillus Calmette-Guerin (BCG) expressing high levels of GroMM and then, monitored skin reactions at the site of challenge with GroMM-containing liposome. We found that BCG-immunized guinea pigs mounted enhanced skin reactions to GroMM with prominent local infiltration by eosinophils. Consistent with this, GroMM-stimulated lymph node cells upregulated the expression of T helper (Th)2-type cytokines, such as interleukin (IL)-5 and IL-10, that could potentially counteract the microbe-eliminating Th1-type cytokine response. On the basis of these observations, we predict that the host response to GroMM produced by dormant mycobacteria would contribute to their long-term survival in the host.

Trehalose Dimycolate Elicits Eosinophilic Skin Hypersensitivity in Mycobacteria-Infected Guinea Pigs

Delayed-type hypersensitivity represents high levels of protein Ag-specific adaptive immunity induced by mycobacterial infection, and can be monitored in the Ag-challenged skin. Besides protein Ags, recent evidence has suggested that a substantial immunity directed against glycolipid Ags is also elicited in response to mycobacterial infection, but skin hypersensitivity to this class of Ags has not been fully assessed. To address this issue directly, glycolipid-specific skin reactions were evaluated in guinea pigs infected with Mycobacterium avium complex (MAC). Significant skin induration was observed in MAC-infected, but not mock-infected, guinea pigs, following intradermal administration of a mixture of MAC-derived glycolipids. Surprisingly, this glycolipid-specific skin response involved up-regulated expression of IL-5 mRNA in situ and marked local infiltration of eosinophils. Challenge experiments with individual glycolipid components detected an outstanding capability for trehalose dimycolate (TDM), but not a structurally related glycolipid, glucose monomycolate, to elicit the skin response. T lymphocytes derived from the spleen of MAC-infected, but not uninfected, guinea pigs specifically responded to TDM in vitro by up-regulating IL-5 transcription, and this response was not blocked by Abs that reacted to the known guinea pig group 1 CD1 proteins. Finally, the eosinophilic skin hypersensitivity to TDM was also elicited in guinea pigs vaccinated with bacillus Calmette-Guerin, which contrasted sharply with the classical delayed-type hypersensitivity response to the purified protein derivative. Therefore, the TDM-elicited eosinophilic response defines a new form of hypersensitivity in mycobacterial infection, which may account for local infiltration of eosinophils often observed at the site of infection.

GM-CSF-Independent CD1a Expression in Epidermal Langerhans Cells: Evidence from Human CD1A Genome-Transgenic Mice

the primer-binding regions, our present study might underestimate the frequencies detectable in the skin cancer samples. Nevertheless, the copy number of the viruses per human genome within the positive tested samples was very low. In the representative examples depicted in Figure 1c, HPyV6 showed much higher cycle thresholds than the cellular gene control thyroid peroxidase, which is normally unaffected by gains and losses in MCC and thus should represent a curve for two copies per cell (Paulson et al., 2009). The more frequent presence of HPyV6 compared with HPyV7 among the skin tumor samples is in line with the serological data available for these viruses (Schowalter et al., 2010). The observations of a similar detection rate of HPyV6 and HPyV7 on the skin surface of healthy volunteers, the higher seropositivity for HPyV6, and an increased presence of HPyV6 in skin tumor samples are suggestive for either a broader cell tropism, a higher survival capability within the skin, or a more efficient skin entry mechanism of HPyV6. The low viral load presence of HPyV6 and HPyV7 in some of the cancer samples reflects the situation of MCV, which can also be detected at low quantities in different tissue specimens irrespective of the pathological status (Loyo et al., 2010). In summary, the low level presence of HPyV6 and HPyV7 within the 108 analyzed skin cancer samples, i.e., clearly lower than one viral copy per cell, does not deliver any evidence for a significant role of these polyomaviruses for the pathology of the respective skin cancers, but it certainly exclude a role of these viruses in the maintenance of the malignant phenotype of the analyzed skin cancers.

Lichen Planus in Irradiated Skin During Nivolumab Treatment.

Lichen planus (LP) is a T-cell-mediated chronic inflammatory disease that develops in skin and mucosa (1). LP is characterized by band-like lymphocyte infiltration in the subepithelium and necrosis of basal keratinocytes (1). Nivolumab is a monoclonal antibody to programmed death 1 (PD-1), an immune checkpoint molecule. Nivolumab facilitates T-cell activation by cancelling the suppressive effect of PD-1 signalling on T cells. It has been shown to have great efficacy in facilitating T cell activation in various cancers, including, but not limited to, melanoma and breast cancer (2). In addition, the combination of nivolumab with radiotherapy may have synergistic effects (3). We report here a case of LP that developed in the irradiated skin area during administration of nivolumab in a patient with breast cancer.

Oral lichen planus associated with candidiasis during secukinumab treatment.

Dear Editor, Oral lichen planus (OLP) is a chronic T-cell-mediated inflammatory disease of the oral mucosa. Although the pathogenesis of OLP remains unknown, some reports note the involvement of drug intake, virus infection and candidiasis in its development. Secukinumab is a monoclonal human immunoglobulin G1 antibody that can fully neutralize interleukin (IL)-17A and exhibits great efficacy in the treatment of psoriasis. Because IL-17A plays pivotal roles in host protection against fungal infections, patients treated with secukinumab sometimes develop oral candidiasis. Herein, we report a case of OLP accompanied by candidiasis during secukinumab treatment. A 74-year-old woman diagnosed with rheumatoid arthritis (RA) and psoriasis vulgaris had presented with persistent painful erosion of the oral mucosa for several months. She had received various systemic medications including cyclosporin, etretinate, adalimumab (an anti-tumor necrosis factor [TNF]-a antibody) and ustekinumab (an anti-IL-12/23p40 antibody) for psoriasis. Her skin symptoms gradually worsened, however, and secukinumab was thus prescribed. After secukinumab administration, her skin symptoms improved significantly, but 5 months after the administration, she developed painful whitish plaque on the left oral mucosa (Fig. 1a). The lesion repeatedly deteriorated with secukinumab administration. We suspected the lesion to be candidiasis or lichen planus, and performed a microscopic analysis of Candida and an oral mucosa biopsy. We detected abundant pseudohyphae of Candida by microscopy. Histological examination showed bandlike lymphocyte infiltration just beneath the mucosal epithelium with liquefaction and colloid body formation (Fig. 1b). In addition, aggregates of Candida, which was confirmed by periodic acid-Schiff staining, were observed on the epithelial surface (Fig. 1c,d). We diagnosed the lesion as OLP with candidiasis. Because secukinumab was suspected as the causal factor for the oral lesion, and as the psoriasis lesion had almost completely disappeared at this point, we discontinued secukinumab treatment. We also started oral amphotericin B (360 mg/day) syrup treatment after every meal for oral candidiasis for 2 months. The OLP and candidiasis diminished in 2 months, and have not relapsed since then. In this case, the development and exacerbation of OLP was closely related to the administration of secukinumab. Although the actual pathological relationship between OLP and secukinumab remains unknown, secukinumab might have contributed to the development of OLP by inducing oral candidiasis, a common side-effect of secukinumab.

Multiple erosive lichen planus preceded by solitary lichen planus after combination therapy with nivolumab and radiation

thema multiforme. Cytomegalovirus blood PCR became positive at 3922 UI/mL. Oral valganciclovir was started with no improvement of skin lesions and fever. All other analyses for opportunistic and viral infections were negative. On day 29 of ART, the syphilis serology was repeated and showed a TPHA titre of 1 : 10 240 and VDRL titre of 1 : 64. A prozone phenomena had been eliminated on the first serology. Cerebrospinal fluid (CSF) analysis was normal, and TPHA and VDRL were negatives on it. Syphilis nPCR was positive in the synovial fluid but negative in the skin biopsy. Immunohistochemistry of the skin biopsy showed treponema in the papillary dermis and epidermis. By day 29 of ART, CD4 cell count increased to 329/mm (30%), whilst plasma HIV RNA decreased by 3 log10 copies/mL. After 2 weeks of benzathine penicillin infusions, the arthritis and the skin lesions resolved completely, and the patient was discharged. We conclude it was not just syphilis because of the severe and atypical presentation with arthritis and the speed of apparition after the serology became positive. We diagnosed an unmasking IRIS linked to syphilis in the setting of rapid increase in CD4 and important reduction in viral load quickly after ART introduction, persistent high-grade fever, very high non-treponemal titres with a negative serology 1 month prior, severe infection quickly after the serology became positive. Although polyarthralgia is described in around 10% of secondary syphilis cases, infectious arthritis have rarely been reported. We found two reported cases of knee arthritis and skin rash related to secondary syphilis, which were diagnosed only by serological tests. In one of these cases, serological tests were negative at admission despite the presence of arthritis. Documentation of syphilis by PCR on the synovial fluid has not been previously reported. In the case of tabetic arthropathy described by Bernard et al., the PCR was positive on the bone biopsy. The latest European guidelines on the management of syphilis (2014) recommend that PCR can be performed in tissues, CSF and blood in cases of negative serology. IRIS due to ART might have contributed to the acute and atypical presentation of this case. Funding: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

A case of chilblain lupus erythematosus with lupus erythematosus/lichen planus overlap syndrome

Chilblain lupus erythematosus (CHLE) is an acral erythema with cutaneous lesion of lupus erythematosus (LE) that is exacerbated during the winter (1). LE/lichen planus (LP) overlap syndrome is a rare cutaneous disorder characterized by mixed histological features of LE and LP at the same lesion (2). Although both CHLE and LE/LP overlap syndrome are immune mediated diseases (3), there is no indication that the same lymphocyte subset induces two distinct cutaneous lesions. This article is protected by copyright. All rights reserved.

Acantholytic dyskeratotic acanthoma: a possible skin adverse event of vemurafenib treatment

Acantholytic dyskeratotic acanthoma (ADA) is a solitary small papule that is pathologically characterized by dyskeratosis with acantholytic acanthosis (1). Vemulafenib is a specific inhibitor of BRAF protein kinase with V600E mutation and is administered to treat metastatic melanoma. Various skin adverse events associated with vemurafenib, including acantholysis and flare up of Dariers disease, have been reported (2, 3). Here we report a case of ADA that developed during vemulafenib treatment for metastatic melanoma. Our case suggests a possibility that vemurafenib may affect epidermal structures which induces acantholysis and dyskeratosis. This article is protected by copyright. All rights reserved.

Efficacy of intravenous immunoglobulins for the treatment of mucous membrane pemphigoid-like epidermolysis bullosa acquisita

Mucous membrane pemphigoid (MMP)-like epidermolysis bullosa acquisita (EBA) is a severe and intractable phenotypic variant of EBA [1, 2]. We report a case of oral-predominant MMP-like EBA (oral EBA) successfully treated with intravenous immunoglobulins (IVIg).A man in his seventies developed oral pain and blistering. The aphthae and blisters were localized in the oral cavity, lips, tongue, and flexor sides of the wrists (figure 1A-C). No other mucous lesions were observed. Fibroscopic examination [...]