Clinical and Serological Characterization of Orf-Induced Immunobullous Disease.

Importance: Ecthyma contagiosum, or orf, is a viral zoonotic infection caused by Poxviridae. Although human orf infection is considered to follow a self-limited course, various immunological reactions may be triggered, including immunobullous diseases. In the majority of the latter cases, the antigenic target remained enigmatic. Objective: To characterize the predominant autoantigen in orf-induced immunobullous disease and further describe this clinical entity. Design, Setting, and Participants: This multicenter case series sought to provide detailed clinical, histopathological and immunological characteristics of a patient with orf-induced pemphigoid. Based on this index patient, serological analyses were conducted of 4 additional patients with previously reported orf-induced immunobullous disease. Immunoblotting with extracellular matrix and a recently established indirect immunofluorescence assay for detection of serum anti-laminin 332 IgG were performed. Exposures: The disease course and clinical characteristics of orf-induced immunobullous disease were observed. Main Outcomes and Measures: Orf-induced immunobullous disease is primarily characterized by anti-laminin 332 autoantibodies, predominant skin involvement, and a self-limiting course. The study provides further details on epidemiological, clinical, immunopathological, diagnostic, and therapeutic aspects of orf-induced immunobullous disease. Results: In all 5 patients, IgG1 and/or IgG3 autoantibodies against laminin 332 were identified. The α3, ß3, and γ2 chains were recognized in 2, 4, and 1 patient(s), respectively. Conclusions and Relevance: In this case series, laminin 332, a well-known target antigen in mucous membrane pemphigoid, was a major autoantigen in orf-induced immunobullous disease, even though predominant mucosal lesions were lacking in this autoimmune blistering disease. Orf-induced anti-laminin 332 pemphigoid is proposed as distinct clinical entity.

Training Physician‒Scientists for Careers in Investigative Dermatology.

Physician‒scientists have made countless discoveries, and their dwindling numbers are a significant concern. Although dermatology has become an increasingly popular destination for physician‒scientist trainees, the proportion of trainees who pursue scientific research careers after training is among the lowest of all medical specialties. To investigate this problem, we surveyed a national cohort of dermatology educators, physician‒scientist track program directors, and National Institute of Arthritis and Musculoskeletal and Skin Diseases T32 directors for opinions regarding physician‒scientist training in dermatology. On the basis of these findings and to help address the issue, we propose a training practicum and provide a resource for funding opportunities to help guide trainees and institutions interested in supporting investigative dermatologists. We also discuss the important roles of department chairs and institutions in fashioning an environment conducive to physician‒scientist training. The information and recommendations provided in this paper may help to improve the recruitment, training, development, and retention of investigative dermatologists and future leaders in this field.

A cross-sectional survey and analysis of Dermatology Foundation Career Development Award recipients.

BACKGROUND: The Dermatology Foundation (DF) has a comprehensive career development award (CDA) program. OBJECTIVE: To assess the impact of this program, a cross-sectional survey of recipients receiving support between 1990 and 2012 was performed. METHODS: Award recipients completed a questionnaire concerning their career status and record of research funding. To verify the self-reported funding data, information about each awardee was extracted from the National Institutes of Health Research Portfolio Online Reporting Tools database and used to define funding acquired by CDA recipients. RESULTS: In all, 84% of CDA recipients responded to the survey. A total of 213 awardees (79%) hold full- or part-time positions in academic medicine. Approximately 70% of the award recipients in academic medicine have received federal research funding. The National Institutes of Health Research Portfolio Online Reporting Tools database and other sources indicated that the funding acquired by CDA recipients through 2015 and 2017 amounted to approximately $365.4 million and $451.8 million, respectively. Each dollar of DF CDA funding through 2015 (ie, $36.2 million) was linked to more than $10 in grant support through 2015 and $12 through 2017. LIMITATIONS: This cross-sectional survey was retrospective and (in part) self-reported. CONCLUSIONS: The DF has succeeded in supporting the career development of basic, translational, and clinical investigators and fostered the promotion and retention of these individuals in academic medicine.

Itch, eosinophils, and autoimmunity: a novel murine model of bullous pemphigoid.

Mice carrying a deletion in the NC14A domain of murine type XVII collagen begin scratching at age 2 months and then develop erosions, subepidermal vesicles, eosinophil-rich skin infiltrates, and autoantibodies directed against a 180 kDa skin protein that appears to be type XVII collagen. These mice represent a bullous pemphigoid animal model featuring pruritus in immunocompetent, mature, and largely unmanipulated animals.

Detection of Type VII Collagen Autoantibodies Before the Onset of Bullous Systemic Lupus Erythematosus.

IMPORTANCE: Anti-type VII collagen autoantibodies are often detectable in patients with bullous systemic lupus erythematosus (BSLE). However, the timing of their appearance preceding the onset of disease is unknown to date. OBSERVATIONS: We report the case of a 50-year-old woman with a history of SLE who was seen with vesicles and bullae around her lips, trunk, axillae, arms, and thighs. Histologic analysis and immunofluorescence and immunoblot studies confirmed the diagnosis of BSLE. Immunoblotting and enzyme-linked immunosorbent assay studies of the patient's serum obtained 3 months before the onset of BSLE showed the presence of anti-type VII collagen autoantibodies. Levels of anti-type VII collagen IgG increased after bullous lesions appeared. Within 1 month after initiating dapsone therapy and increasing the dosage of prednisone, skin lesions promptly resolved. One year after the onset of BSLE, the anti-type VII collagen IgG decreased below levels observed before the inception of the bullous lesions. CONCLUSIONS AND RELEVANCE: Anti-type VII collagen autoantibodies can precede the clinical appearance of BSLE. The subsequent increase and decrease in levels of circulating anti-type VII collagen autoantibodies, which mirrored skin disease activity, support a potential role in their initiation of disease.

IgG, IgM, and IgA antinuclear antibodies in discoid and systemic lupus erythematosus patients.

IgG antinuclear antibodies (ANAs) are elevated in patients with systemic lupus erythematosus (SLE) compared with patients with discoid lupus erythematosus (DLE). To provide an expanded immunologic view of circulating ANAs in lupus patients, we compared the expressions of IgG, IgM, and IgA ANAs in DLE and SLE patients. In this cross-sectional study, sera from age-, gender-, and ethnic-matched SLE (N = 35), DLE (N = 23), and normal patients (N = 22) were tested for IgG, IgM, and IgA ANAs using enzyme-linked immunosorbent assays (ELISAs) and indirect immunofluorescence (IIF) with monkey esophagus as substrate. ELISAs showed elevated levels of IgG ANA, IgM ANA, and IgG/IgM ANA ratios in SLE patients compared with DLE and normal patients. IgA ANA expression was higher in SLE and DLE patients versus normal patients. IIF studies showed higher percentages of patients positive for IgG, IgM, and IgA ANAs in the SLE group. Higher IgG/IgM ANA ratios in SLE than DLE show enhanced class-switching and a more sustained humoral response in SLE. They also suggest a potential connection of IgM ANAs with disease containment.

Differential expression of BAFF and its receptors in discoid lupus erythematosus patients.

BACKGROUND: B-cell activating factor of the TNF family (BAFF) promotes the maturation and survival of B cells. Because BAFF levels are elevated in systemic lupus erythematosus (SLE) patients, BAFF has been the target of emerging therapies for SLE, such as belimumab. Levels of BAFF and its receptors in discoid lupus erythematosus (DLE) patients are unknown. OBJECTIVE: To compare skin and blood mRNA and protein levels of BAFF and its receptors BAFF-R, TACI, and BCMA in DLE subjects with (DLE+/SLE+ (N=28)) and without SLE (DLE+/SLE- (N=35)), psoriasis subjects (N=11), and normal subjects (N=42). METHODS: We used quantitative real-time PCR to measure blood and skin BAFF, BAFF-R, TACI, and BCMA mRNA, sandwich ELISAs to measure sera BAFF, and immunohistochemistry to evaluate BAFF and BAFF-R skin protein expression. RESULTS: BAFF mRNA and protein levels were highest in DLE+/SLE+blood, followed by DLE+/SLE-, psoriasis, and normal blood. BAFF protein also correlated with anti-nuclear antibodies, and autoantibodies against double-stranded DNA, single-stranded DNA, and ribonucleoprotein, and Systemic Lupus Erythematosus Disease Activity Index scores in DLE patients. While showing no difference between DLE+/SLE+ and DLE+/SLE- skin, BAFF and its receptors mRNA were up-regulated in DLE skin vs. normal and psoriasis skin. DLE skin had higher percentages of BAFF-R⁺ inflammatory cells, likely T cells and macrophages, than psoriasis and normal skin. CONCLUSIONS: BAFF may be a serologic marker of systemic disease in DLE patients. BAFF and its receptors are elevated in DLE skin, suggesting that targeted therapies against these proteins could treat refractory DLE patients.

Anti-laminin-332 mucous membrane pemphigoid in a 9-year old girl.

Mucous membrane pemphigoid (MMP), an autoimmune subepithelial blistering disease that predominantly affects the mucous membranes, is usually diagnosed in elderly adults. Early diagnosis of MMP is crucial because it tends to run a chronic and progressive course with the potential for devastating scarring of the mucous membranes that may lead to blindness and airway compromise. A subtype of MMP, anti-laminin-332 MMP, is a rare blistering disorder in which autoantibodies are directed against laminin-332 (formerly epiligrin), a structural protein of the epidermal basement membrane. Herein we report what we believe to be the youngest patient diagnosed with anti-laminin-332 MMP, a 9-year-old girl with disease affecting only the oral, pharyngeal, and laryngeal mucosa, with no skin involvement.