Faculty Bibliography

The classical Th1/Th2 paradigm previously defining atopic dermatitis (AD) and psoriasis has recently been challenged with the discovery of Th17 T cells that synthesize IL-17 and IL-22. Although it is becoming evident that many Th1 diseases including psoriasis have a strong IL-17 signal, the importance of Th17 T cells in AD is still unclear. We examined and compared skin biopsies from AD and psoriasis patients by gene microarray, RT-PCR, immunohistochemistry, and immunofluorescence. We found a reduced genomic expression of IL-23, IL-17, and IFN-gamma in AD compared with psoriasis. To define the effects of IL-17 and IL-22 on keratinocytes, we performed gene array studies with cytokine-treated keratinocytes. We found lipocalin 2 and numerous other innate defense genes to be selectively induced in keratinocytes by IL-17. IFN-gamma had no effect on antimicrobial gene-expression in keratinocytes. In AD skin lesions, protein and mRNA expression of lipocalin 2 and other innate defense genes (hBD2, elafin, LL37) were reduced compared with psoriasis. Although AD has been framed by the Th1/Th2 paradigm as a Th2 polar disease, we present evidence that the IL-23/Th17 axis is largely absent, perhaps accounting for recurrent skin infections in this disease

Basal cell carcinoma (BCC), the most common human cancer, undergoes spontaneous regression in certain circumstances, which is potentially immune-mediated. To understand the immune response surrounding BCCs, we characterized the genomic, protein, and cellular microenvironment associated with BCC in comparison to normal skin. Our results demonstrated the following: (1) CD4+ CD25+ Foxp3+ surround epithelial tumor aggregates; (2) Immature dendritic cells (DCs) were abundant in the tumor microenvironment; (3) BCC showed increased expression of IL-4, IL-10, and CCL22 and increased expression of interferon-associated genes (IFI27, IRF1, IRF7, and G1P2) and IL-12/23, gene indicating a Th2 dominant microenvironment. Our findings suggest a dynamic state within the immune microenvironment associated with BCC. The finding of phenotypic T regs, in conjunction with immature DCs and Th2 cytokines, suggests an attenuated state of immunity to human BCC. In contrast, abundant CD8+ T cells, an interferon signal, and IL-12/23 suggest partial host antitumor response. A better understanding of these opposing forces within the immune microenvironment may facilitate development of more potent immune-based treatment for BCC and other human carcinomas

BACKGROUND: Since its inception in 1985, the American Academy of Dermatology (AAD) National Melanoma/Skin Cancer Screening Program has strived to enhance early detection of cutaneous malignant melanoma (MM) by providing nationwide skin cancer education campaigns in combination with free skin cancer screenings. OBJECTIVE: To analyze the AAD screening data from 2001 to 2005 in order to identify factors associated with MM detection, and thereby derive a model of increased likelihood for MM detection through visual skin examinations at screenings. MATERIALS AND METHODS: Patients completed a standardized AAD pre-screening form with historical and phenotypic information. Clinicians then recorded suspected clinical findings noted at visual skin examination. Statistical analyses were conducted using SPSS 14 (SPSS Inc., Chicago, Ill). RESULTS: Five factors, which can be remembered with the acronym HARMM, independently increased the likelihood of suspected MM being found in the 362,804 persons screened: History of previous melanoma (odds ratio [OR] = 3.3; 95% confidence interval [CI], 2.9-3.8); Age over 50 (OR = 1.2; 95% CI, 1.1-1.3); Regular dermatologist absent (OR = 1.4; 95% CI, 1.3-1.5); Mole changing (OR = 2.0; 95% CI, 1.9-2.2); and Male gender (OR = 1.4; 95% CI, 1.3-1.5). Individuals at highest risk (4 or 5 factors) comprised only 5.8% of the total population, yet accounted for 13.6% of presumptive MM findings, and were 4.4 times (95% CI, 3.8-5.1) more likely to be diagnosed with suspected MM than individuals at lowest risk (0 or 1 factor). Receipt of a total skin examination at screening independently increased the likelihood for identifying suspected MM (OR = 1.4; 95% CI, 1.3-1.6). However, significantly fewer screenees in the highest risk group versus those in the lowest risk group underwent total skin examinations (53.7% vs 62.5%). LIMITATIONS: Risk factors studied limited to variables collected in screenee enrollment form. CONCLUSIONS: A higher-risk subgroup of the skin cancer screening population can be identified through assessment of MM risk factors using the HARMM criteria. Refocusing efforts to provide a total skin examination to those individuals with multiple risk factors has the potential to both reduce costs and increase yields for suspected MM in future mass screening initiatives

BACKGROUND: Atopic dermatitis (AD) and psoriasis represent contrasting poles of the T(H)1 versus T(H)2 paradigm. Both diseases have been associated with increased numbers of dendritic cells (DCs) in the skin, but the similarities and differences in DC populations need to be established. OBJECTIVE: We aimed to characterize the specific DC subsets, as well as chemokine and cytokine environment in chronic AD compared with psoriasis. METHODS: Skin biopsies were obtained from patients with acute exacerbation of chronic AD (n = 18), psoriasis (n = 15), and healthy volunteers (n = 15) for microarray analysis, RT-PCR, immunohistochemistry, and double-label immunofluorescence. RESULTS: Myeloid DCs upregulate CCL17 and CCL18 in AD, as opposed to TNF-alpha and inducible nitric oxide synthase (iNOS) in psoriasis. In our study, we identified cells phenotypically identical to the inflammatory dendritic epidermal cells in the dermis in both diseases, although to a lesser extent in psoriasis. We found substantially higher numbers of dermal CCL22 producing plasmacytoid DCs in AD. The thymic stromal lymphopoietin receptor showed significantly higher expression in AD, whereas the thymic stromal lymphopoietin ligand was upregulated more in psoriasis. CONCLUSION: There are major differences in myeloid and plasmacytoid subsets of cutaneous DCs and the chemokine/cytokine environment between AD and psoriasis. Distinct subsets within the CD11c(+) population may influence polarization through the production of regulatory mediators, including iNOS, TNF, CCL17, and CCL18. Plasmacytoid DCs may also influence T(H)2 polarization, having a more important role in AD than previously appreciated. CLINICAL IMPLICATIONS: Dermal inflammatory dendritic cells in AD and TNF and iNOS-producing DCs in psoriasis, and/or their regulatory products, may be potential targets for future therapeutic interventions