Publications

The epidermis regenerates continually to maintain a protective barrier at the body’s surface composed of differentiating keratinocytes. Maturation of this stratified tissue requires that keratinocytes undergo wholesale organelle degradation upon reaching the outermost tissue layers to form compacted, anucleate cells. Through live imaging of organotypic cultures of human epidermis, we find that regulated breakdown of mitochondria is critical for epidermal development. Keratinocytes in the upper layers initiate mitochondrial fragmentation, depolarization, and acidification upon upregulating the mitochondrion-tethered autophagy receptor NIX. Depleting NIX compromises epidermal maturation and impairs mitochondrial elimination, whereas ectopic NIX expression accelerates keratinocyte differentiation and induces premature mitochondrial fragmentation via the guanosine triphosphatase (GTPase) DRP1. We further demonstrate that inhibiting DRP1 blocks NIX-mediated mitochondrial breakdown and disrupts epidermal development. Our findings establish mitochondrial degradation as a key step in terminal keratinocyte differentiation and define a pathway operating via the mitophagy receptor NIX in concert with DRP1 to drive epidermal morphogenesis.

A  woman  in her 50s presented with a 7-month history of worsening pruritic papules and bullae on her face,  trunk,  arms,  and  axillae. Her medical history  was  significant  for  Meniere  disease and hyperthyroidism. At an outside clinic, an initial   skin   biopsy   from   the   arm   showed intraepidermal acantholysis with dyskeratosis and  she  was  diagnosed  with transient   acantholytic   dermatosis   (Grover disease). Treatments included triamcinolone ointment, doxycycline,  antihistamines, and short  courses  of  prednisone  without clinical improvement. Over the following two months,  her  eruption  worsened,  and  she developed   painful   oral   mucosal   erosions. Physical examination revealed   vegetative scale-crusts overlying  erosions  on  the  face, arms,  and  chest  in  an  armor-like  pattern as  well  as  flaccid  bullae  on  the back  and  erosions  of  the  gingival and  labial mucosae. A  shave  biopsy  of  the  skin  from the  upper  back  was  performed. Direct immunofluorescence showed intercellular epidermal deposition of IgG and C3.     Indirect     immunofluorescence was positive on monkey  esophagus  substrate  in an  intercellular  pattern  at  a  titer  of  1:5120 and  enzyme-linked   immunosorbent   assay (ELISA) quantified anti-desmoglein-1 (Dsg1) and  anti-desmoglein-3  (Dsg3)  antibodies  at 620 (negative<20) and 176 units (negative<20), respectively.

Symmetric cell division requires the even partitioning of genetic information and cytoplasmic contents between daughter cells. Whereas the mechanisms coordinating the segregation of the genome are well known, the processes that ensure organelle segregation between daughter cells remain less well understood1. Here we identify multiple actin assemblies with distinct but complementary roles in mitochondrial organization and inheritance in mitosis. First, we find a dense meshwork of subcortical actin cables assembled throughout the mitotic cytoplasm. This network scaffolds the endoplasmic reticulum and organizes three-dimensional mitochondrial positioning to ensure the equal segregation of mitochondrial mass at cytokinesis. Second, we identify a dynamic wave of actin filaments reversibly assembling on the surface of mitochondria during mitosis. Mitochondria sampled by this wave are enveloped within actin clouds that can spontaneously break symmetry to form elongated comet tails. Mitochondrial comet tails promote randomly directed bursts of movement that shuffle mitochondrial position within the mother cell to randomize inheritance of healthy and damaged mitochondria between daughter cells. Thus, parallel mechanisms mediated by the actin cytoskeleton ensure both equal and random inheritance of mitochondria in symmetrically dividing cells.

Medical education must prepare clinicians to care for diverse populations, which is especially important in dermatology, as cutaneous disorders present differently depending on skin pigmentation. Patients with nonwhite skin tones are underrepresented in the dermatologic literature and broader educational resources, a deficiency that is particularly problematic for rare disorders like autoimmune bullous diseases (AIBD). We present a case series of AIBD in patients with nonwhite skin tones, emphasizing differences in disease presentation and pigmentary sequelae.

Background: Access to dermatologists is limited for disadvantaged patients, who may receive suboptimal dermatologic care from nonspecialists. We assessed if teledermatology could improve primary care provider (PCP)-delivered care for cutaneous disease at a clinic serving uninsured patients.

Materials and Methods: Utilizing the American Academy of Dermatology’s free AccessDerm program, we offered store-and-forward teledermatology to PCPs, who initiated consultations at will during clinical care independent of the study. We retrospectively analyzed all consultations from 2013 to 2017 and collected patient age/sex, teledermatologist diagnosis, time to teledermatologist reply, time to next dermatology appointment, as well as PCP- and teledermatologist-proposed care plans.

Results: Retrospective analysis of 131 consults revealed a 37-h mean teledermatology response-time versus a 14-day appointment wait (p < 0.00001). Teledermatologists provided a definitive care plan without in-person evaluation for 82 (65%) of completed consults and recommended interim treatments while awaiting appointments in 15 cases, thus accelerating care plan delivery in 97 cases (76%). The triage decision rate differed among diagnostic categories; deferral to in-person evaluation was more frequent for neoplasms (p < 0.0001). When PCPs specified preconsult treatment plans, 82% differed from teledermatologist-advised management. Following teledermatologist recommendations would have changed the clinical course in 70% of cases, potentially avoiding suboptimal care, including inappropriate corticosteroids, antimicrobials, and emergency room referrals.

Conclusions: We found teledermatology can effectively guide PCPs in resource-limited settings by accelerating delivery of dermatologist-recommended care plans for uninsured patients. Expanding teledermatology for PCPs in under-resourced clinics has the potential to improve treatment of cutaneous disease by nonspecialists and to mitigate suboptimal care for disadvantaged patients.

Background: Bullous pemphigoid (BP), the most common autoimmune blistering disease, may be diagnostically challenging. Direct immunofluorescence (DIF), indirect immunofluorescence (IIF), enzyme-linked immunosorbent assay (ELISA), and recently, C3d immunohistochemistry (IHC), are used as adjuncts to diagnosis.

Objective: To compare C3d IHC to DIF, IIF, and ELISA testing in BP diagnosis.

Methods: C3d IHC was performed on skin biopsy specimens from 51 patients (27 with BP and 24 with other blistering diseases) and compared to DIF and IIF, with anti-BP180 or anti-BP230 ELISA results used as the gold standard.

Results: We found C3d IHC, DIF, and IIF had similar sensitivity (74.1%, 63.1%, and 70.4%), specificity (95.8%, 100%, and 100%), positive predictive value (95.2%, 100%, and 100%), and negative predictive value (76.7%, 70.6%, and 75%) for BP. Cases with positive C3d IHC, DIF, and IIF had significantly higher anti-BP180 and anti-BP230 by ELISA than cases with negative testing (P < .0001). False-negative IIF results were associated with lower BP230 compared with true-positive results (P = .03).

Limitations: This was a single-center, retrospective study.

Conclusion: Our study compared C3d IHC to DIF and IIF in BP diagnosis, demonstrating C3d IHC on fixed tissue provides similar diagnostic utility to immunofluorescence and ELISA.

Keywords: C3d immunohistochemistry; ELISA; bullous pemphigoid; diagnosis; direct immunofluorescence; indirect immunofluorescence.

Self-renewing somatic tissues depend upon the proper balance of chromatin-modifying enzymes to coordinate progenitor cell maintenance and differentiation, disruption of which can promote carcinogenesis. As a result, drugs targeting the epigenome hold significant therapeutic potential. The histone demethylase, LSD1 (KDM1A), is overexpressed in numerous cancers, including epithelial cancers; however, its role in the skin is virtually unknown. Here we show that LSD1 directly represses master epithelial transcription factors that promote differentiation. LSD1 inhibitors block both LSD1 binding to chromatin and its catalytic activity, driving significant increases in H3K4 methylation and gene transcription of these fate-determining transcription factors. This leads to both premature epidermal differentiation and the repression of squamous cell carcinoma. Together these data highlight both LSD1’s role in maintaining the epidermal progenitor state and the potential of LSD1 inhibitors for the treatment of keratinocyte cancers, which collectively outnumber all other cancers combined.

A man in his 60s presented with a subcutaneous nodule on the right side of the chest. Due to impaired mental status, he was unable to describe the precise age of the lesion, but his wife reported it had been present at least several weeks. She recently noted a new, bright red growth on top of the nodule. The lesion was asymptomatic but seemed to be growing in size. Physical examination revealed a 3-cm firm fixed nodule on the right side of the chest with an overlying, exophytic bright red papule. No similar lesions were found elsewhere on physical examination. A punch biopsy of the lesion was performed.