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Research aimed at understanding the host-microbial interface in atopic dermatitis is ongoing but already providing insights for novel therapeutic strategies.
The skin of patients with atopic dermatitis (AD) is prone to colonization and infection by pathogenic microbes, which can act as a major trigger for atopic dermatitis (AD). Now, research aiming to elucidate the immune and molecular pathways underlying these associations is suggesting novel approaches for intervention, said Donald Y. M. Leung, M.D., Ph.D., speaking at the 2nd Inflammatory Skin Disease Summit (November 2016, New York).
Dr. Leung“These investigations may also be the foundation for precision medicine. Ultimately, however, personalized treatment strategies for AD will require more accurate genotyping and immune profiling of patient subsets, and those studies are also underway,” says Dr. Leung, Edelstein Family Chair of Pediatric Allergy-Immunology, National Jewish Health, Denver.
It has been recognized for some time that people with AD are prone to microbial infection, particularly with Staphylococcus aureus and herpes simplex virus (HSV). Abnormal skin barrier function has been considered to be a primary factor. It has also been shown in animal models that S. aureus can induce AD, by expressing virulence factors that damage the skin barrier and activate skin inflammatory responses. In addition, S. aureus colonization and reduction of antimicrobial peptide production has been shown to be promoted by cytokines expressed in the Th2 immune pathway response of the skin that is characteristic of AD.
“Interleukin-4 (IL-4) and IL-13 inhibit terminal differentiation of keratinocytes and change the skin to favor binding of S. aureus. Furthermore, IL-4 and IL-13 inhibit synthesis of antimicrobial peptides, thereby impairing S. aureus killing by epidermal keratinocytes in AD skin,” Dr. Leung explains.
“These findings are relevant because blockade of IL-4 and IL-13 has been shown in vitro and in animal models to improve host defense against S. aureus. Further research, using biologics that inhibit the action of IL-4 and IL-13 will directly test the hypothesis that this pathway is relevant in human AD.”
Abnormalities in the skin microbiota of people with AD may be another factor promoting S. aureus overgrowth and infection. In a paper accepted for publication by Science Translational Medicine, Richard L. Gallo, M.D, and coauthors reported that skin of healthy controls was colonized by a high frequency of coagulase-negative staphylococcal isolates with antimicrobial activity whereas bacteria isolated from the skin of AD patients had significantly less antimicrobial activity.
Dr. Leung says this finding supports the idea of transplanting “good bacteria” onto the skin of AD patients as a potential strategy to fight S. aureus overgrowth. In a preclinical study, application of the antimicrobial staphylococcal organisms to human skin reduced colonization by S. aureus.
Dr. Leung is the principal investigator of The Atopic Dermatitis Research Network (ADRN) that is planning clinical trials investigating mechanisms of skin infection in AD and introducing new treatments. The studies include transplantation of beneficial bacteria in a topical cream and examination of the effects of IL-4/IL-13 blockade on the host-microbial interface. These studies are being funded by the National Institute of Allergy and Infectious Diseases.
There is also a subset of patients with AD who are unable to control viral replication, and both reduced IFNγ expression and an excessive Th2 response appear to underlie their susceptibility to HSV infection. The ADRN is funding research that is aiming to develop a better understanding of why certain AD patients develop eczema herpeticum, and National Jewish Health, in Denver, is the lead site for the investigation.
Dr. Leung notes that this project has important ramifications.
“Due to concern about the development of eczema vaccinatum, smallpox vaccination is contraindicated in anyone who has ever been diagnosed with AD. However, only about 3% of the AD population that is predisposed to develop eczema herpeticum are at risk for that severe complication,” Dr. Leung says.
“Understanding the mechanisms of susceptibility for eczema herpeticum could enable the vast majority of AD patients to be safely vaccinated. These studies also have important implications for the development of new biomarkers to identify patients at risk for disseminated viral skin infection and new therapies to approach this devastating complication of AD.”
Disclosure: Dr. Leung is a consultant to Novartis, Regeneron, and Sanofi-Aventis and has received research grants from the National Institutes of Health, ADRN, MedImmune, and Pfizer.