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.

Humanization of autoantigen.

Transmissibility of characteristic lesions to experimental animals may help us understand the pathomechanism of human autoimmune disease. Here we show that human autoimmune disease can be reproduced using genetically engineered model mice. Bullous pemphigoid (BP) is the most common serious autoimmune blistering skin disease, with a considerable body of indirect evidence indicating that the underlying autoantigen is collagen XVII (COL17). Passive transfer of human BP autoantibodies into mice does not induce skin lesions, probably because of differences between humans and mice in the amino acid sequence of the COL17 pathogenic epitope. We injected human BP autoantibody into Col17-knockout mice rescued by the human ortholog. This resulted in BP-like skin lesions and a human disease phenotype. Humanization of autoantigens is a new approach to the study of human autoimmune diseases.

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.

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.

A retrospective analysis of the Dermatology Foundation's Career Development Award Program.

BACKGROUND: To provide research support that develops and retains leaders, educators, and investigators in dermatology and cutaneous biology, the Dermatology Foundation (DF) has designed and implemented a comprehensive Career Development Award (CDA) Program. OBJECTIVE: To assess the impact of the DF's 3-year CDA, a comprehensive survey of recipients who received this mechanism of support between 1990 and 2007 was performed. METHODS: Of 196 individuals receiving a DF CDA, 181 were identified and asked to complete a comprehensive questionnaire concerning their career status, employment history, professional rank, and record of independent research funding (private foundation, federal, other). A personal assessment of the impact of this funding on these individuals' career trajectory was also requested. RESULTS: Eighty percent of 181 CDA recipients identified currently hold full- or part-time positions in academic medicine. The faculty rank of 112 survey respondents included 46 assistant professors (41%), 41 associate professors (37%), 18 professors (16%), and 7 division or departmental chairs (6%). Of respondents, 84% reported that they have received subsequent independent research funding; 95 of these individuals (86%) have received funding from a federal agency (235 federal grants awarded to date with funding >$318M). LIMITATIONS: The study was retrospective and self-reported; some awardees did not respond to the survey. CONCLUSIONS: The DF's CDA Program has succeeded in supporting the early career development of talented investigators, educators, and leaders; fostered the promotion and retention of these individuals in academic medicine; and nucleated numerous investigative careers that have successfully acquired independent research funding.

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.

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.

A novel humanized neonatal autoimmune blistering skin disease model induced by maternally transferred antibodies.

All mammal neonates receive maternal Abs for protection against pathogenic organisms in the postnatal environment. However, neonates can experience serious adverse reactions if the Abs transferred from the mother recognize self-molecules as autoAgs. In this study, we describe a novel model for autoimmune disease induced by transferred maternal Abs in genetically transformed Ag-humanized mice progeny. Bullous pemphigoid is the most common life-threatening autoimmune blistering skin disease that affects the elderly, in which circulating IgG autoAbs are directed against epidermal type XVII collagen (COL17). We have established a genetically manipulated experimental mouse model in which maternal Abs against human COL17 are transferred to pups whose skin expresses only human and not mouse COL17, resulting in blistering similar to that seen in patients with bullous pemphigoid. Maternal transfer of pathogenic Abs to humanized neonatal mice is a unique and potential experimental system to establish a novel autoimmune disease model.

Bullous pemphigoid and related subepidermal autoimmune blistering diseases.

The pemphigoid group of autoimmune blistering diseases includes distinct entities (bullous pemphigoid, mucous membrane pemphigoid, pemphigoid gestationis, linear IgA dermatosis and lichen planus pemphigoides) that are characterized by relatively consistent clinical, histologic and immunopathologic findings. Patients with these disorders have antibasement membrane autoantibodies that often display pathogenic (blister-forming) activity following passive transfer to experimental animals. Interestingly, such autoantibodies target important structural proteins that promote adhesion of epidermis to epidermal basement membrane in human skin. Autoimmune blistering diseases are characterized by substantial morbidity (for example pruritus, pain, disfigurement) and in some instances mortality. Treatment with systemic immunosuppressives has reduced morbidity and mortality in patients with these diseases.

The pathophysiology of autoimmune blistering diseases.

Knowledge of the pathophysiology of immunobullous diseases has been advanced by the demonstration that passive transfer of antibodies against skin autoantigens can induce blisters in experimental animals with clinical, histologic, and immunopathologic features similar to those seen in human patients. In this issue of the JCI, Liu et al. extend their earlier observations regarding an experimental murine model of bullous pemphigoid by showing that the plasminogen/plasmin signaling cascade synergizes with MMP-9 during the early phase of antibody-induced blister formation in vivo. In a separate study, Sitaru et al. show for the first time to my knowledge that passive transfer of experimental antibodies against type VII collagen create subepidermal blisters in mice that mimic those seen in patients with epidermolysis bullosa acquisita (see the related article beginning on page 870). While the articles by Liu, Sitaru, and their colleagues identify pathways of inflammation and tissue injury that, if interrupted, may abrogate blister formation, in a third study, Payne et al. utilized phage display technologies to isolate human anti-desmoglein monoclonal antibodies from a patient with pemphigus vulgaris and show that such antibodies have restricted patterns of heavy and light chain gene usage - findings suggesting that autoantibodies may represent an additional target for therapeutic interventions in patients with immunobullous diseases (see the related article beginning on page 888).

IgG anti-laminin-332 autoantibodies are present in a subset of patients with mucous membrane, but not bullous, pemphigoid.

BACKGROUND: Antiepiligrin cicatricial pemphigoid is a mucosal-predominant subepidermal blistering disease associated with an increased relative risk of cancer. In contrast to prior reports showing that anti-laminin (L)-332 autoantibodies are a reliable marker for patients with antiepiligrin cicatricial pemphigoid, a recent report suggested that as many as 40% of patients with bullous pemphigoid (BP) have IgG reactive with this laminin isoform. OBJECTIVE: We sought to determine whether patients with BP possess circulating IgG anti-L-332 autoantibodies. METHODS: Sera from 100 adults with BP were analyzed by indirect immunofluorescence testing of intact skin, immunoblot studies of human keratinocyte (HK) extracts, and a new L-332 enzyme-linked immunosorbent assay. Sera showing reactivity suggestive of anti-L-332 autoantibodies in these assays were further analyzed in immunoblot studies of HK extracellular matrix and immunoprecipitation studies of biosynthetically radiolabeled HK extracts. RESULTS: IgG from all patients with BP bound intact epidermal basement membrane by indirect immunofluorescence microscopy and immunoblotted bullous pemphigoid antigen-1, -2, or both in HK extracts. None of these sera immunoblotted L-332 in HK extracts, although 13 did score above the cut point of a new IgG(4) L-332 enzyme-linked immunosorbent assay (sensitivity = 0.91, specificity = 0.98, Youden index = 0.89). Further analysis of sera from these 13 patients found: (1) all had IgG that bound the epidermal side of 1 mol/L NaCl split skin by indirect immunofluorescence microscopy; (2) none immunoblotted L-332 purified from HK extracellular matrix; and (3) none immunoprecipitated L-332 from biosynthetically radiolabeled HK extracts. LIMITATIONS: The basis of false-positive enzyme-linked immunosorbent assay determinations for anti-L-332 IgG among patients with BP is unknown. CONCLUSION: Anti-L-332 autoantibodies remain a reliable marker for patients with antiepiligrin cicatricial pemphigoid.