Background Atopic dermatitis (AD) is a common inflammatory skin disease with a Th2 and “T22” immune polarity. Despite recent data showing a genetic predisposition to epidermal barrier defects in some patients, a fundamental debate still exists regarding the role of barrier abnormalities versus immune responses in initiating the disease. In order to explore whether there is an intrinsic predisposition to barrier abnormalities and/or background immune activation in AD patients an extensive study of non-lesional AD (ANL) skin is necessary. Objective To characterize ANL skin by determining whether epidermal differentiation and immune abnormalities that characterize lesional AD (AL) are also reflected in ANL skin. Methods We performed genomic and histologic profiling of both ANL and AL skin lesions (n=12 each), compared to normal human skin (n=10). Results We found that ANL is clearly distinct from normal skin with respect to terminal differentiation and some immune abnormalities, and it has a cutaneous expansion of T-cells. We also showed that ANL skin has a variable immune phenotype, which is largely determined by disease extent and severity. Whereas broad terminal differentiation abnormalities were largely similar between involved and uninvolved AD skin, perhaps accounting for the “background skin phenotype,” increased expression of immune-related genes was among the most obvious differences between AL and ANL skin, potentially reflecting the “clinical disease phenotype.” Conclusion Our study implies that systemic immune activation may play a role in alteration of the normal epidermal phenotype, as suggested by the high correlation in expression of immune genes in ANL skin with disease severity index.

Background Atopic dermatitis (AD) is a common inflammatory skin disease exhibiting a predominantly Th2/“T22” immune activation and a defective epidermal barrier. Narrow-band UVB (NB-UVB) is considered an efficient treatment for moderate-to-severe AD. In psoriasis, NB-UVB has been found to suppress the Th1/Th17-polarization with subsequent reversal of epidermal hyperplasia. The immunomodulatory effects of this treatment are largely unknown in AD. Objective To evaluate the effects of NB-UVB on immune and barrier abnormalities in AD, aiming to establish reversibility of disease and biomarkers of therapeutic response. Methods 12 moderate-to-severe chronic AD patients received NB-UVB phototherapy 3 times weekly for up to 12 weeks. Lesional and non-lesional skin biopsies were obtained before and after treatment and evaluated by gene-expression and immunohistochemistry studies. Results All patients had at least a 50% reduction in SCORing of AD (SCORAD) index with NB-UVB phototherapy. The Th2, “T22,” and Th1 immune pathways were suppressed and measures of epidermal hyperplasia and differentiation normalized. The reversal of disease activity was associated with elimination of inflammatory leukocytes, Th2/“T22”- associated cytokines and chemokines, and normalized expression of barrier proteins. Conclusions Our study shows that resolution of clinical disease in patients with chronic AD is accompanied by reversal of both the epidermal defects and the underlying immune activation. We have defined a set of biomarkers of disease response that associate resolved Th2 and “T22” inflammation in chronic AD patients with reversal of barrier pathology. By showing reversal of the AD epidermal phenotype with a broad immune-targeted therapy, our data argues against a fixed genetic phenotype.

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The porphyrias are a group of disorders characterized by defects in the heme biosynthesis pathway. Many present with skin findings including photosensitivity, bullae, hypertrichosis, and scarring. Systemic symptoms may include abdominal pain, neuropsychiatric changes, anemia, and liver disease. With advances in DNA analysis, researchers are discovering the underlying genetic causes of the porphyrias, enabling family members to be tested for genetic mutations. Here we present a comprehensive review of porphyria focusing on those with cutaneous manifestations. In Part I, we have included the epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Treatment and management options will be discussed in Part II. IntroductionThe porphyrias are a group of disorders characterized by defects in heme production, resulting in buildup of toxic heme precursors (Table 1). Cutaneous findings are common and include photosensitivity, painful burning, bullae, and scarring. Diagnosis requires laboratory measurement of heme precursors in plasma, urine, stool, and erythrocytes.Heme is made from glycine and succinyl-coenzyme A in eight steps (Fig. 1). Heme synthesis is ubiquitous throughout the body, but 85% occurs in bone marrow, becoming hemoglobin.1 Porphyrias are classified into two categories based on whether heme precursors build up in the liver (hepatic porphyrias) or bone marrow (erythropoietic porphyrias). Hepatic porphyrias are subdivided into acute and chronic subtypes, and tend to have secondary triggers (e.g., drugs, alcohol, hormone fluctuation, infection, and fasting). Acute hepatic porphyrias present with episodes (acute attacks) of abdominal or neurological symptoms caused by a genetic predisposition with a secondary metabolic trigger. Porphyria cutanea tarda (PCT), the only chronic hepatic porphyria, has a prolonged course of liver damage and photosensitivity. Erythropoietic porphyrias present in childhood with photosensitivity. While the main defect lies in the erythrocytes, the liver may also be involved. Materials and methodsA comprehensive literature search was initially performed using PubMed. Broad searches were performed using the terms "porphyria," "coproporphyria," and "protoporphyria" in the title, and "skin diseases, genetic" in the medical subject heading, but excluding for medical subject heading "acute intermittent." Articles

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