A case of IgA pemphigus with acantholysis in oral mucosal lesions.

IgA pemphigus is an autoimmune bullous disease caused by anti-keratinocyte cell surface IgA autoantibodies. Mucous membrane involvement is rare in IgA pemphigus. We report a case of IgA pemphigus with oral mucosal lesions, in which acantholysis was pathologically confirmed. A 31-year-old woman presented with skin erythema with small pustules and oral mucosal erosions. Histopathological examination of the erosions on her oral mucosa and papules on her back revealed acantholysis and intraepidermal infiltration of neutrophils. Direct immunofluorescence tests showed intercellular deposition of IgA, but not IgG, mainly in the lower, but not entire, layer of the epidermis. C3 was linearly present in the basement membrane zone (BMZ), but not in the intercellular space. Enzyme-linked immunosorbent assay revealed that both anti-desmoglein (Dsg) 3 IgA and IgG were positive. Neither IgA nor IgG against desmocollin 1-3 were detected. This case was clinically and histologically compatible with IgA pemphigus, but immunologically anti-BMZ autoimmunity was additionally observed. IgA pemphigus is classified into two major types: subcorneal pustular dermatosis type and intraepidermal neutrophilic dermatosis type. This case was not typical in terms of rarely observed oral lesions and predominant deposition of IgA in the lower layer of the epidermis. Instead, this case could be considered a rare subtype of IgA pemphigus, IgA-pemphigus vulgaris. Oral lesions in IgA pemphigus may be clinical clue of having anti-Dsg3 IgA that cannot be routinely examined.

Attenuation of OX40 signaling suppression by age disrupts peripheral deletion of CD4+ T cells specific for the epidermal autoantigen desmoglein 3.

Various autoimmune responses increase with age, but the underlying mechanism is not clear. In this study, we used CD4+ T cells expressing a transgenic T cell receptor specific for desmoglein 3 (Dsg3), which is the target antigen of the autoimmune bullous disease pemphigus vulgaris, to examine how peripheral immunological tolerance against pathogenic autoreactive CD4+ T cells changes with age. Dsg3-specific T cells were deleted within 14 days after adoptive transfer into young mice (8 weeks old), while they escaped deletion when transferred into older mice over 42 weeks old. Dsg3-specific T cells produced higher levels of the proinflammatory cytokine IFN-γ in aged mice than in young mice. In addition, the expression levels of both OX40 and Birc5, which are important for cell survival in T cell clonal proliferation, were higher in aged than in young mice. The dysfunction in suppressing proinflammatory cytokine secretion and Birc5 upregulation in Dsg3-specific autoreactive T cells may reflect an aspect of the preliminary steps in autoimmune disease development in the aged population. Understanding this mechanism may lead to better risk evaluation of autoimmune disease development and to onset prevention.

Two sporadic cases of childhood-onset Hailey-Hailey disease with superimposed mosaicism.

A prenatal second-hit genetic change that occurs on the wild-type allele in an embryo with a congenital pathogenic variant allele results in mosaicism of monoallelic and biallelic defect of the gene, which is called superimposed mosaicism. Superimposed mosaicism of Hailey-Hailey disease (HHD) has been demonstrated in one familial case. Here, we report two unrelated HHD cases with superimposed mosaicism: a congenital monoallelic pathogenic variant of ATP2C1, followed by a postzygotic copy-neutral loss of heterozygosity. Uniquely, neither patient had a family history of HHD at the time of presentation. In the first case, the congenital pathogenic variant had occurred de novo. In the second case, the father had the pathogenic variant but had not yet developed skin symptoms. Our cases showed that superimposed mosaicism in HHD can lack a family history and that genetic analysis is crucial to classify the type of mosaicism and evaluate the risk of familial occurrence.

T cell autoimmunity and immune regulation to desmoglein 3, a pemphigus autoantigen.

Pemphigus is a life-threatening autoimmune bullous disease mediated by anti-desmoglein IgG autoantibodies. Pemphigus is mainly classified into three subtypes: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. The pathogenicity of autoantibodies has been extensively studied. Anti-human CD20 antibody therapy targeting B cells emerged as a more effective treatment option compared to conventional therapy for patients with an intractable disease. On the other hand, autoreactive T cells are considered to be involved in the pathogenesis based on the test results of human leukocyte antigen association, autoreactive T cell detection, and cytokine profile analysis. Research on the role of T cells in pemphigus has continued to progress, including that on T follicular helper cells, which initiate molecular mechanisms involved in antibody production in B cells. Autoreactive T cell research in mice has highlighted the crucial roles of cellular autoimmunity and improved the understanding of its pathogenesis, especially in paraneoplastic pemphigus. The mouse research has helped elucidate novel regulatory mechanisms of autoreactive T cells, such as thymic tolerance to desmoglein 3 and the essential roles of regulatory T cells, Langerhans cells, and other molecules in peripheral tissues. This review focuses on the immunological aspects of autoreactive T cells in pemphigus by providing detailed information on various related topics.

Severe graft-versus-host disease-like enterocolitis accompanied with cytomegalovirus-reactivation in drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms.

Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug adverse reaction with skin eruption and visceral organ involvement. The characteristic clinical features of DIHS/DRESS are reactivation of human herpesviruses (HHV) and the development of autoimmune diseases, but their pathogenesis and associations are not yet understood. Here, we report a 66-year-old man who presented with fever, generalized erythema, diffuse lymphadenopathy, and diarrhea after 3 weeks of treatment with zonisamide. Reactivation of HHV-6 and cytomegalovirus (CMV) was detected during the clinical course. The patient was diagnosed with DIHS/DRESS and treated with systemic prednisolone, i.v. immunoglobulin therapy, and ganciclovir. However, severe enterocolitis persisted for 6 months. A series of examinations revealed features of both CMV enterocolitis, as indicated by identification of a few CMV-positive cells on immunohistochemical analysis, and graft-versus-host disease (GVHD)-like enterocolitis indicated by orange-peel appearance on endoscopic examination and histopathological loss of goblet cells. Intractable enterocolitis continued and the patient finally died of pneumonia. An autoimmune predisposition in DIHS/DRESS patients in combination with CMV reactivation was considered to trigger the severe enterocolitis of this case that showed GVHD-like features of the gastrointestinal tract. GVHD-like organ damage is a pathological condition rarely observed in DIHS/DRESS but should be recognized as one of the most severe complications of the disease.

Diagnostic utility of the basophil activation test in natto-induced hypersensitivity.

BACKGROUND: Natto (fermented soybeans)-induced hypersensitivity is characterized by delayed symptom onset that hampers diagnosis. We aimed to clarify the clinical utility of the basophil activation test (BAT) in the diagnosis of natto-induced hypersensitivity. METHODS: Five patients with a history of anaphylaxis and chronic urticaria suspected of natto-induced hypersensitivity and seven with chronic spontaneous urticaria clinically unrelated to natto were enrolled in the patient and control groups, respectively. The BAT was performed with two incubation times, 15 min and 1 h, in combination with various concentrations of natto-mucilage extract. RESULTS: In controls, CD203c levels in basophils remained low in the 15-min incubation but were significantly increased in the 1-h incubation. In the patient group, in the 15-min condition, basophil CD203c was significantly upregulated by natto mucilage but not by soybean vs controls (P = 0.001). Low concentrations of natto mucilage were sufficient to upregulate basophil CD203c in the anaphylaxis cases, but high concentrations were required to induce the same effect in the urticaria cases. Finally, the dose-dependent pattern of the BAT results differed significantly between the anaphylaxis and urticaria cases (P = 0.006). Thus, a strong background reaction was observed in the BAT with 1 h incubation; 15 min of incubation was sufficient to identify patients with natto-induced hypersensitivity and may distinguish the clinical phenotype of natto-induced hypersensitivity, i.e., anaphylaxis or urticaria. CONCLUSIONS: The BAT with a 15-min incubation period is useful in diagnosing natto-induced hypersensitivity.

A Case of an Ex Vivo Onychomycosis Model Introduced with a Cultured Colony of Kocuria koreensis from a Diabetic Ingrown Toenail.

A 57-year-old male patient with >10-year history of type 2 diabetes presented with a left big toenail deformity and pain. A physical examination revealed a white and yellow-to-brown patch on the nail as well as thickening and ingrowth of the nail plate. The nail plate was opened using nippers, and a fungal culture revealed Trichophyton interdigitale with yellow yeast. The yeast isolate was identified as Kocuria koreensis, a Gram-positive aerobic coccoid with keratinolytic properties that is part of the normal flora of the skin. We created an ex vivo onychomycosis model of T. interdigitale infection of the human nail by placing a sterilized normal nail on the cultured slant. K. koreensis initially spread over the normal nail, and T. interdigitale then penetrated the nail plate. After one year and six months, a spiral ingrown nail developed. A histopathological examination of the spiral revealed onychomycosis with superficial and deep abscesses of Gram-positive cocci infection. We performed PCR from paraffin-embedded material, and the sequences obtained were identical to those of T. interdigitale and K. koreensis. These results suggest that the development of onychomycosis by T. interdigitale is introduced and accelerated by K. koreensis, and the symbiosis of these microorganisms is suspected in the nail. This ex vivo model has a number of limitations. Therefore, further research on co-infected cases is needed to confirm this hypothesis.

Usefulness of Wood's Lamp for the Diagnosis and Treatment Follow-up of Onychomycosis.

Wood's lamp was demonstrated to be useful in three cases of dermatophytoma treated during clinical dermatological practice. Clinical signs of onychomycosis are longitudinal yellow and white striae on the nail plate and are diagnosed by KOH direct microscopic examination. For its treatment, surgical debridement is recommended. Usefulness of the Wood's lamp for diagnosis of tinea capitis caused by Microsporum canis is standard. In the first and second cases, we used Wood's lamp (Woody™) to make a clear margin for debridement of onychomycosis. In the third case, onychomycosis was unsuccessfully treated using topical 5% luliconazole nail solution for 1 year and 10 months with yellow nail discoloration. Under Wood's lamp, we were able to distinguish luliconazole crystal staining from onychomycosis. This method is simple and quick, and useful for nail observation in dermatology clinics.

Metastatic Cutaneous Squamous Cell Carcinoma in Liver Successfully Treated With Partial Hepatectomy and Adjuvant Irinotecan Chemotherapy.

BACKGROUND: The management of distant metastatic cutaneous squamous cell carcinoma (cSCC) relies mainly on chemotherapies and radiotherapy. Management of patients with cSCC with surgically resectable distant metastatic lesions is not clear. CASE REPORT: A 59-year-old male had 4×10 cm-sized cSCC on the perianal skin with inguinal lymph node metastasis. Surgical resection was performed followed by radiation and adjuvant carboplatin and farmorubicin combination therapy. Six months later, 25 mm-sized solitary metastatic nodule arose on the liver. Base on his favorable overall condition fulfilling the criteria of tumor resectability for the treatment of tumors in liver and having good performance status, laparoscopic partial hepatectomy and six courses of adjuvant irinotecan therapy were performed. The surgical margin was negative and the patient has maintained complete remission for over 3 years. CONCLUSION: The clinical course of the present case suggests that surgical approaches should also be considered as candidate additional therapy for resectable distant metastatic cSCC.