A possible role for CD8+ T lymphocytes in the cell-mediated pathogenesis of pemphigus vulgaris.

Pemphigus vulgaris (PV) is an autoimmune blistering disease whose pathogenesis involves both humoral and cell-mediated immune response. Though the pathogenetic role of autoantibodies directed against desmoglein 3 is certain, a number of other factors have been suggested to determine acantholysis in PV. In this study we examined the possible role of CD8+ T cells in the development of acantholysis by a passive transfer of PV autoantibodies using CD8 deficient mice, and we also studied the inflammatory infiltrate of PV skin lesions by immunohistochemical staining. The results of the immunohistochemical staining to study the expression of CD3, CD4, and CD8 in PV skin lesions showed that CD4+ are more expressed than CD8+ in the inflammatory infiltrate of PV lesions, confirming the data of the previous literature. The passive transfer study showed a lower incidence of pemphigus in the group of CD8 deficient mice compared to the control one of wild-type mice. These results suggest that CD8+ T cells may play a role in the pathogenesis of PV, perhaps through the Fas/FasL pathway.

Squamous cell carcinoma manifesting as cutaneous cystic lesions.

Squamous cell carcinoma (SCC), a malignancy of epidermal keratinocytes, is the second most common cause of skin cancer in the United States. Our case represents an unusual variant of this common tumor. We report a clinical presentation of a case of SCC occurring as cutaneous cystic lesions on the face of an 87-year-old white woman with a medical history of multiple SCCs.

Cytokine knockouts in contact hypersensitivity research.

Contact hypersensitivity (CHS) is a Langerhans cell (LC)-dependent, T cell-mediated cutaneous immune response. CHS reflects a culmination of LC activities in vivo: uptake of epicutaneous antigens, migration into lymph nodes, and presentation of antigens to naïve T cells. Although studies have suggested involvement of the cytokine network in LC migration and CHS initiation, the in vivo function of individual cytokines remains largely unknown. Gene targeting technology has made it possible to study in vivo functions of cytokines through gene-targeted knockout (KO) mice deficient in a given cytokine or its receptor. A variety of cytokine knockouts have been used to assign biological functions to specific cytokines in CHS. These studies have contributed significantly to our understanding of molecular mechanisms underlying CHS.

Photoaging: mechanisms and repair.

UNLABELLED: Aging is a complex, multifactorial process resulting in several functional and esthetic changes in the skin. These changes result from intrinsic as well as extrinsic processes, such as ultraviolet radiation. Recent advances in skin biology have increased our understanding of skin homeostasis and the aging process, as well as the mechanisms by which ultraviolet radiation contributes to photoaging and cutaneous disease. These advances in skin biology have led to the development of a diversity of treatments aimed at preventing aging and rejuvenating the skin. The focus of this review is the mechanism of photoaging and the pathophysiology underlying the treatments specifically designed for its prevention and treatment. LEARNING OBJECTIVES: At the conclusion of this learning activity, participants should be familiar with the mechanism of photoaging, the treatments for photoaging, and the data that supports the use of these treatments.

Pemphigus vulgaris induced by electrical injury.

Pemphigus refers to a group of autoimmune blistering diseases that affect the skin and mucous membranes. Pemphigus may be induced following exposure to various exogenous agents, including thermal burns, drugs, infectious agents, and neoplasms, as well as UV, ionizing, and x-ray irradiation. We report a case of a 28-year-old man with pemphigus vulgaris (PV) induced by a severe electrical injury. Approximately one month after the electrical injury, he began to develop recurrent painful oral ulcers; one year later, he began to develop cutaneous bullae. Results of a histopathologic examination and immunofluorescence studies were diagnostic of PV The primary mechanisms of high-voltage electrical injury involve electroporation, electroconformational protein denaturation, and both joule and dielectric heating. Cutaneous electrical injury ultimately results in the destruction of cells with release of their cellular constituents. Through these mechanisms, desmoglein 3 (Dsg3) may be released and become available to the immune system, which potentially leads to an autoantibody response and the subsequent development of PV.

Microarray profiles of human basal cell carcinoma: insights into tumor growth and behavior.

PURPOSE: Basal cell carcinoma (BCC) is the most common human neoplasm. Much interest lies in determining the genetic basis of BCC to explain the unique locally invasive phenotype and infrequent metastatic behavior of these skin tumors. OBJECTIVE: We sought to examine a gene expression profile for BCC to elucidate new molecules responsible for its unique growth characteristics. METHODS: We analyzed gene expression patterns of 50 BCC tumors using spotted cDNA microarrays of 1718 characterized human genes related to cancer and immunity. This is the largest and most comprehensive gene expression study ever performed for BCC. Nodular and sclerosing histological subtypes of BCC were examined and compared to normal control skin. After statistical filtering, 374 significantly dysregulated genes were sorted by hierarchical clustering to determine trends of gene expression and similarities between patient gene expression profiles. RESULTS: A total of 165 upregulated genes and 115 downregulated genes were identified. These covered a range of categories, including extracellular matrix, cell junctions, motility, metastasis, oncogenes, tumor suppressors, DNA repair, cell cycle, immune regulation and angiogenesis. Clusters of genes were either commonly dysregulated across the 50 patient sample, or selectively affected in subsets of tumors. Histological subtypes were not distinguishable by hierarchical clustering. Many of the genes elucidated, including collagen type IV subunits and other novel candidates, possess functions related to extracellular matrix remodeling and metastasis. CONCLUSION: These results suggest a gene profile which may explain the invasive growth yet rarely metastatic behavior of BCC. The genes identified may also be potential targets for therapeutics aimed at further controlling invasiveness and local destruction of BCC.

Topical immunotherapy: what's new.

Further understanding of the pathogenesis of dermatologic conditions at a molecular level has led to targeted therapies. The topical immune response modifiers have contributed significantly to the treatment of cutaneous diseases. New topical remedies, particularly the Toll-like receptor agonists and calcineurin inhibitors, have added to the clinical armamentarium and have further advanced clinicians' ability to treat a wide variety of benign, premalignant, and malignant conditions. Furthermore, these agents have contributed to the understanding of the disease process. The next decade will witness even greater advances in targeted immunotherapies for dermatologic disease.

Low-dose ultraviolet B rays alter the mRNA expression of the circadian clock genes in cultured human keratinocytes.

Current understanding of mammalian circadian rhythms suggests that they are regulated by light targeting signaling pathways in the hypothalamic suprachiasmatic nuclei. Recently, investigators have identified the existence of extraretinal photoreceptors and a potential role for the skin in this regulatory process has been implied. We demonstrated that mRNA of the circadian clock genes Per1, Clock, and bmal1/mop3 are expressed in normal human cultured keratinocytes. Low-dose ultraviolet B rays initially downregulate all circadian clock genes and then induce altered expression of the genes in keratinocyte cell cultures. Ultraviolet light targeting superficial layers of skin (keratinocytes) may therefore contribute to circadian rhythm modulation.

Contact hypersensitivity: the mechanism of immune responses and T cell balance.

The skin is the largest organ in the human body. It acts not only as an important structural barrier against injury but also as a peripheral arm of the immune system. Elucidating the characteristics of this latter function has taken on renewed importance in recent years. Exposure to chemicals in everyday life has increased exponentially over the past decades. This has been accompanied by an increased incidence of contact hypersensitivity (CHS), a dendritic cell-dependent, T cell-derived, cytokine-mediated skin inflammation. Cytokines derived from Langerhans cells (i.e., interleukin-12 [IL-12]) and from T cell (i.e., interferon-gamma [IFN-gamma], IL-4, and IL-10) play a pivotal role in the induction and initiation of CHS. Developments in immunology and molecular biology have improved our understanding of the molecular mechanisms underlying this immune response. However, the conflicting opinions that continue to characterize discussions of CHS supply clear testimony that our knowledge is as yet incomplete.

A recombinant human hyaluronidase sustained release gel for the treatment of post-surgical edema.

BACKGROUND: Edema commonly accompanies surgical procedures and when excessive, can adversely affect surgical outcomes. The skin extracellular matrix, including one of its primary components, hyaluronan (HA), is a significant barrier to effective drainage of accumulated edematous fluid. Recombinant human hyaluronidase (rHuPH20) is a human hyaluronidase that acts transiently and locally to depolymerize HA. A non-liposomal gel formulation that provides a sustained release of rHuPH20 was tested in vivo in a preclinical murine model of acquired lymphedema. METHODS: Lymphedemic mice were injected 24 hours before surgery, and at 2 and 12 days following surgery with rHuPH20 sustained release gel (PH20 SR gel). Quantitative assessment of treatment response indicated that a single dose of PH20 SR gel resulted in accelerated resolution and reduced severity of post-surgical edema as compared to the gel vehicle (control). RESULTS: Statistically significant enzymatic degradation of HA was demonstrated up to 5 mm from the injection site, and histological analysis confirmed removal of HA up to 72 hours following PH20 SR gel administration. CONCLUSIONS: These results demonstrate sustained hyaluronidase enzymatic activity that promotes diffusion of accumulated post-surgical edematous fluid, suggesting that PH20 SR gel may be a useful adjuvant in promoting postoperative edema resolution.

Novel use of polymethyl methacrylate (PMMA) microspheres in the treatment of infraorbital rhytids.

AIM: To demonstrate safely with the use of polymethyl methacrylate (PMMA) microspheres in the infraorbital eyelid area using a deliberate conservative injection in the treatment of rhytids. METHODS: A retrospective case series of 289 patients in an outpatient cosmetic dermatology clinic evaluated and treated by one senior provider (NM) of infraorbital rhytids with PMMA from December 2010 to March 2011. Statistical analysis was performed for race, skin type, history of hypertrophic scar, autoimmunity, history of "sensitive skin" and history of prior procedures such as prior facelift, rhinoplasty, and blepharoplasty. RESULTS: Two hundred ninety-one patients underwent at least 1-6 injections of PMMA microspheres into bilateral under eye area. Early complications were edema and ecchymosis. Late complications were identified in 4 of 289 patients who developed small granulomas. All patients who developed granulomas had had a previous lower blepharoplasty (P = 0.00). A history of "sensitive skin" was approaching statistical significance (P = 0.15). CONCLUSION: This study has shown that PMMA microsphere injection is a safe subdermal technique in the correction of infraorbital rhytids. Safety was demonstrated in 289 patients with only 4 minor complications of small lateral granuloma which all resolved within 4 weeks after intralesion triamcinolone injection. However, this is an off-label use of a permanent filler not approved for use in the infraorbits and significant caution must be taken with full disclosure to the patient leading to informed consent. Caution in PMMA microsphere injection should be given in the patient with prior blepharoplasty. The advantage of PMMA microsphere is that the result seems to be predictable and natural.

Nested, non-parametric, correlative analysis of microarrays for heterogenous phenotype characterization.

We present a non-parametric approach for qualitatively selecting candidate genes to characterize several criteria that are nested among genes selected on the basis of their individual, similar effects upon an array-wide closeness measure. In this setting, a goal is to obtain a reliable characterization of phenotypes, based on very high-dimensional data from a few samples. As opposed to a distance-based approach, the proposed measure defines closeness based on gene signal profiles (functionals) rather than on isolated (numerical) differences in each gene between samples. By using such a measure to characterize intensity differences, we effectively separate biological from artifactual variation in expression, due to tissue effects or signal calibration. Based on this measure, we successively examine the significance of the following: a set of similarly behaved genes relative to all arrayed genes, a set of candidate genes relative to similarly behaved genes, individual candidate genes relative to non-candidates, and the direction, as over- or under-expressed, of candidate genes. In each setting, sample pairs are the units of analysis, with U-statistics the theoretical framework. We illustrate the method on a microarray experiment, where the goal is to select sets of genes that characterize a type of skin cancer and its histological subtypes.

Downregulation of NDUFA1 and other oxidative phosphorylation-related genes is a consistent feature of basal cell carcinoma.

Basal cell carcinoma (BCC) is the most common cutaneous malignancy that, like other tumours, possesses a heterogeneous genetic composition. In order to select genes with consistent changes in expression among these tumours, we analysed BCC microarray expression data by using a novel approach, termed correlative analysis of microarrays (CAM). CAM is a nested, non-parametric method designed to qualitatively select candidates based on their individual, similar effects upon an array-wide closeness measure. We applied the CAM method to expression data generated by two-channel cDNA microarray experiments, where 21 BCC and patient-matched normal skin specimens were examined. Fifteen candidate genes were selected, with six overexpressed and nine underexpressed in BCC vs. normal skin. Five of the nine consistently downregulated genes in the tumour samples are involved in mitochondrial function and the oxidative phosphorylation (OXPHOS) pathway. One of these genes was the 7.5-kDa subunit, NADH dehydrogenase (ubiquinone) alpha subcomplex-1 (NDUFA1), an accessory component of OXPHOS complex-I that is essential for respiratory activity. These findings support the hypothesis that irregularities in mitochondrial function are involved in neoplasia. Suppression of NDUFA1 expression could represent a key pathogenic mechanism in the development of BCC.

Mechanism of action and emerging role of immune response modifier therapy in dermatologic conditions.

Immune response modifiers (IRMs) are agents that target the body's immune system (i.e., cytokines, receptors, and inflammatory cells) to combat disease. Topical IRM therapies, which encompass both proinflammatory and immunosuppressive therapeutics, have been used to successfully treat a number of dermatologic conditions. Proinflammatory treatments include Toll-like receptor agonists (e.g., imiquimod 5% cream) and interferon (e.g., interferon-alpha) therapies, which have been used in the treatment of external genital warts, basal cell carcinoma, and other dermatologic diseases. Immunosuppressive therapies include topical and intralesional corticosteroids, anti-tumor necrosis factor agents (e.g., infliximab and etanercept), and anti-CD4+ T-cell agents, including calcineurin inhibitors and mycophenolate. These agents have been used to treat a number of conditions, including atopic and seborrheic dermatitis and psoriasis. This article reviews the mechanism of action of IRMs and the application of IRMs in several dermatologic diseases.

Understanding the new clinical landscape for psoriasis: a comparative review of biologics.

BACKGROUND: Encouraging results from clinical trials suggest that biologic therapies are effective treatments for psoriasis. OBJECTIVE: The aim of our study was to evaluate the scientific evidence for the efficacy and safety of biologic drugs for psoriasis. METHODS: The studies reviewed include data on the biologies alefacept, efalizumab, etanercept, and infliximab. This article reviews all data published in the dermatology literature listed in the MEDLINE database, as well as data presented as abstracts and posters at dermatology society meetings, including the annual meetings of the American Academy of Dermatology. RESULTS: The majority of the studies used an improvement from baseline of 75% or more in the psoriasis area and severity index (PASI 75) as the primary measure of efficacy. CONCLUSIONS: Overall, biologics represent an important addition to the psoriatic therapies and have a great impact on the disease course and life quality of those afflicted with psoriasis.

Immunotherapy of basal cell carcinoma: evolving approaches.

Nonmelanoma skin cancer (NMSC) is one of the most common types of cancer in the world. There is strong evidence that ultraviolet (UV) light plays a central role in the molecular pathogenesis of NMSC development. UV light causes DNA damage and loss of activity of tumor suppressor genes and overexpression of oncogenes and other genes related to enhanced growth and survival as well as tissue invasion. Also, UV light impairs the cutaneous immune response, especially Langerhans cell antigen-presenting function, resulting in immune tolerance to developing tumor cells. Standard treatments for NMSC include surgical excision, curettage and electrodessication, and Moh's micrographic surgery. Immunotherapy of NMSC has been attempted in the form of dinitrobenzene sensitization followed by topical application on the tumor, intralesional interferon injections, or perilesional interleukin-2. These treatments, although showing promise, have not been developed because of lower efficacy compared with surgical approaches, morbidity associated with treatments, as well as the expense of using recombinant cytokine treatments. The topical immune response modifier imiquimod is being developed as a novel local treatment for selected NMSC. Studies of the mechanism of action of imiquimod in NMSC indicate the presence of activated, natural killer cells (innate immunity), T-lymphocytes (adaptive immunity), antigen-presenting cells, and cytokines consistent with a delayed-type hypersensitivity reaction (Th1-lymphocyte cytokine pattern). This agent has been associated with a high response rate for the treatment of superficial basal cell carcinoma, with clearance rates ranging from 70% to 90% in a number of clinical trials. This novel immunotherapy represents a new, nonsurgical treatment option in the care of patients with NMSC.

Adhesion and virulence properties of epidemic Canadian methicillin-resistant Staphylococcus aureus strain 1: identification of novel adhesion functions associated with plasmin-sensitive surface protein.

Epidemic Canadian methicillin-resistant Staphylococcus aureus strain 1 (CMRSA-1) comprises related subtypes that differ in phenotype and prevalence, with subtypes 1A, 1B, and 1D representing 1%, 71%, and 18%, respectively, of total CMRSA-1 isolates. The predominant CMRSA-1B subtype possesses a variant of the staphylococcal cassette chromosome mec, harboring pls, which encodes plasmin-sensitive surface protein (Pls). CMRSA-1B cells that express Pls exhibited poor adhesion to keratinocyte extracellular matrix. However, CMRSA-1B and purified Pls adhered to cellular lipids and glycolipids, and Pls promoted bacterial cell-cell interactions. Although exoprotein expression was restricted to a precursor form of lipase in CMRSA-1B, it was not attenuated in virulence relative to CMRSA-1A, which exhibits normal exoprotein expression. In contrast, CMRSA-1D exhibited a pleiotropic defect in exoprotein expression and attenuated virulence relative to CMRSA-1A. These data indicate that the high transmissibility of CMRSA-1B was not achieved at the expense of attenuated virulence and that Pls confers a novel adhesion mechanism.

Topical imiquimod 5% cream as an effective treatment for external genital and perianal warts in different patient populations.

BACKGROUND: Genital infection with human papillomavirus, the cause of genital warts, is one of the most common sexually transmitted diseases. GOAL: The aim of this analysis was to determine whether patients' demographic variables affect the efficacy of imiquimod 5% cream versus vehicle cream for the treatment of external genital and perianal warts. STUDY DESIGN: Male and female immunocompetent patients applied imiquimod 5% cream topically to external genital warts 3 times a week until wart clearance or for up to 16 weeks. RESULTS: As previously published, the intent-to-treat (ITT) clearance rate was 50% (54/109) in the imiquimod-treated group and 11% (11/100) in the vehicle-treated group ( P< 0.0001). The ITT clearance rate in the imiquimod-treated group was higher in females (72%) than in males (33%). We have examined the clearance rates for subgroups based on variables of gender, baseline wart area, duration of current outbreak of warts, previous wart treatment, and tobacco use. For each of these subgroups, imiquimod was statistically more effective than vehicle in eradicating external genital and perianal warts. CONCLUSION: Imiquimod 5% cream is an effective treatment for external genital and perianal warts and provides a significant benefit in comparison with vehicle cream, independent of gender, initial wart size, duration of current outbreak of warts, previous wart treatment, or tobacco use.