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The 56th Annual Montagna Symposium on the Biology of Skin was held at Salishan Resort, Gleneden Beach, Oregon, USA, 11–15 October 2007.
*The 56th Annual Montagna Symposium on the Biology of Skin was held at Salishan Resort, Gleneden Beach, Oregon, USA, 11–15 October 2007.
was organized around a specific disease, starting with an introduction by the Session Chair, an expert in the disease, and ending with a breakout session guided by questions posed by the session chairs. (A list of the questions addressed and approaches and actions determined can be viewed in the Supplementary Information online.)
The Symposium began on Thursday evening with keynote talks by patient advocates from three disease foundations: Victoria Kalabokes (the National Alopecia Areata Foundation), Elizabeth Horn (the International Psoriasis Council), and Judy Jones (the Cutaneous Lymphoma Foundation). A particular highlight was the participation of Irene Crosby, who gave her view as a patient with atopic dermatitis. An eye opener for many of us was the enormous burden that patients carry in order to minimize stigmatization by the public, including washing bed linens every day and always wearing black or dark colors so that small blood spots do not show (eczema) or never wearing black so that skin flakes do not show (psoriasis). The advocates explained that many patients feel ignored by society, funding agencies, and doctors who “just gave them a tube of something to stop the itch.” We also learned that patient-based organizations not only are active in public education, they also support research, both financially and by maintaining databases of individuals willing to participate in research studies. The important take-home message was that researchers should contact these foundations to identify patients to participate in research studies.
The highlight of the Symposium came from Brian Nickoloff's opening remarks about psoriasis. When asked by a patient, “Why can't you figure out what causes this disease?,” he answered, “Well, it's tricky.” He went on to explain that you can't separate the epithelium from the immune system. He also noted that a family of diseases produce psoriasis-like plaques; thus, not all psoriasiform reactions mean that the patient has psoriasis per se. There are HLA-DR and T-cell subset differences. This theme was continued by Andrew Blauvelt, who described a psoriasis mouse model in which TH17 T cells induced keratinocytes to express receptors that attracted more TH17 T cells. A continuous interactive loop was thus formed. Kristina Duffin explained that psoriasis is also a genetic disease, as demonstrated by studies of twins, and that a phenotype often runs within a family. However, no single gene has been found to be causative for this disease. Using phenotypic classification, she clustered gene loci according to risk for psoriasis. Michelle Lowes discussed cellular phenotypes with psoriasis showing high levels of CD3+, HLA-DR+, and CD11c+ cells and low levels of BDCA cells. Continuing the theme of cellular phenotypes, Thomas McCormick demonstrated that T-regulatory cells did not function properly in psoriatic plaques; i.e., they did not suppress proliferation of T-memory/effector cells. Frank Nestle introduced psoriatic mouse models. He made a humanized model by grafting uninvolved psoriatic human skin to Rag knockout mice. These formed psoriatic plaques without additional T cells. Karin Scharffetter-Kochanek's psoriatic mouse model was made by knocking out CD18, which demonstrated that T-regulatory cells were not functioning properly, because T-reg cells from wild-type mice normalized the skin. Nicole Ward concluded the session with a short talk about a new mouse model made using an inducible TIE2.
In an overview of atopic dermatitis and other eczemas, Jon Hanifin informed us that atopic dermatitis comes on in childhood; that 80% of patients have increased IgE levels, which cause itching; and that most cases are also associated with asthma, hay fever, and other allergies, but that 20% are not. The current belief is that T cells arrive at the behest of the keratinocytes after the epidermal barrier has been compromised. Shinji Shimada explored the role of mast cells that reside in the skin. These cells are filled with dense granules and react via stimuli through Toll-like receptors, which likely cross-talk with IgE receptors. Julie Segre discussed the role of the residing local bacteria and the fact that different areas of the skin show different quantities of various bacteria that affect mutual local bacterial colonization. Thus, early atopic dermatitis could be an adaptive mode in reaction to nonsterile outside environs. She also mentioned that the understanding of the normal and diseased skin microbiome is an NIH Roadmap initiative. Lisa Beck agreed that atopic dermatitis could be an adaptive immune response but said it may also be an innate response. Her data suggest that atopic dermatitis may also have a genetic effector that may allow barrier compromise to occur. Mihail Iordanov explored released cytokines as causal for hyperproliferation of keratinocytes.
As Richard Sontheimer explained in his introduction, lichenoid tissue reactions (LTRs)/interface dermatitis represent a large number of diverse skin diseases with scaly plaques that are very itchy. They are currently classified according to the amount of lymphocytic infiltrate as cell rich or cell poor. The major challenges are that these conditions are not common and almost everything triggers the reaction. Jan Dutz introduced dendritic cells and explained their role in the circle of keratinocyte death induced by activated T-memory cells, an event possibly controlled by regulatory T cells. He reviewed several mouse models of lichenoid skin disease. A classic model was made by injecting autoreactive T-cell clones into the footpads of mice. Graft-vs.-host disease was proposed as a convenient model for studying LTRs. Continuing with the T-cell model, Jorg Wenzel described how T cells target defective keratinocytes following local type I interferon expression in humans. Stephan Meller added that local cytokines (e.g., the type I interferon, IFN-α) induced inflammatory chemokines, such as CXCL family members. He proposed that aberrant expression of CXCLs could indicate a propensity to disease. Miriam Merad presented her work on graft-vs.-host disease. She used a parabiotic animal model to prove that Langerhans cells move into the skin from the bone marrow during development, but that once there, Langerhans cells remain in the skin unless the skin is damaged, e.g., in lichenoid reactions. In such diseases, when the Langerhans cells are damaged or leave, they are replaced from the bone marrow. This turnover of Langerhans cells is proposed to modulate subsequent immune reactions.
Using mouse models, Stuart Yuspa described the inflammatory mediators and receptors involved in the induction and maintenance of cutaneous squamous cell carcinoma. Continuing with mouse models, Michael Girardi examined the role of the immune system in spontaneous regression of tumors, specifically as related to Langerhans cells and different subsets of αβ T cells as well as γδ T cells. Sam Hwang introduced cutaneous T-cell lymphomas (CTCLs) as a rare group of diseases of mostly CD4+ T cells with yet unknown etiologies. The T cells preferentially home to cutaneous sites via cell surface chemokine receptors. The skin expresses a number of chemokine ligands that can attract T cells via these receptors Thus, therapies could target the receptors. James Campbell, using CCR4 knockout mice in a model of antigen-specific T-cell trafficking, demonstrated the requirement for the CCR4 receptor for homing of T cells to the skin. Alain Rook discussed the clinical aspects of CTCL, specifically introducing the mechanism by which several effective biological agents may target different aspects of the immune system. He emphasized that the increasing ability of the dendritic cell to present T-cell antigens may be the key in stimulating host antilymphoma responses in CTCL.
To end the symposium, Carl Baker and Cheryl Lapham, Program Directors at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, discussed new directions at NIAMS and the potential for funding via several mechanisms, such as K99/R00 and the new Roadmap initiatives.
David Norris, from the University of Colorado Health Sciences Center, showed pictures of past Symposia participants and gave a hilarious, fact-filled talk about what it was like to attend the Montagna Symposium first as an awe-filled young dermatologist and then as its Chair for 13 years. We are fortunate that David remains as Chair Emeritus. Summing up the heart of this long-standing forum on cutaneous biology, David was heard to say at the Sunday event, “I've totally changed the way I look at lichenoid disease after this session. I sat there thinking, ‘I needed to be here.’”
2007 SID Eugene M. Farber Travel Awards for Young Investigators and the MSBS Director's Award
As in the past, we helped nine young investigators to attend the Montagna Symposium through a generous donation from the Eugene M. Farber family:
Erin Fitch, BA
Department of Dermatology, Oregon Health & Science University, Portland, OR
“Inducible expression of TGFβ1 in basal keratinocytes causes psoriasis-like disease in transgenic mice: role of the IL-23/IL-17 inflammatory pathway”
Mehran Ghoreishi, MD, PhD
Departments of Dermatology and Medicine, University of British Columbia, Vancouver, BC, Canada
“Expansion of antigen-specific regulatory T cells with the topical vitamin D analogue calcipotriol”
Florent Ginhoux, PhD
Departments of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY
“Identification of a langerin expressing dermal dendritic cell population that differs from migrating epidermal Langerhans cells”
Karen Jonscher, PhD
Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, CO
“Toward the identification of proteins in activated human T cells that drive macrophage activation and proinflammatory cytokine production”
Daniel Kaplan, MD, PhD
Department of Immunology, University of Minnesota, Minneapolis, MN
“Autocrine/paracrine TGFβ is required for the development of epidermal Langerhans cells”
Li Li, PhD
Department of Dermatology, University of Colorado Health Sciences Center, Denver, CO
“Novel human T cell cytokine inducing surface molecules (TCISMs), including CD40 ligand, augments T-cell-driven macrophage activation to produce proinflammatory cytokines”
Anke Lonsdorf, PhD
Dermatology Branch, National Cancer Institute, Bethesda, MD
“Accumulation of epidermis-derived CCL27 in skin-draining lymph nodes following topical application of a contact sensitizer induces accumulation of CCR10-positive cells”
Francesca Mascia, PhD
Laboratory of Cancer Biology & Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD
“EGFR activation regulates the expression of GM-CSF in keratinocytes”
Julie Wolfram, BA
Departments of Dermatology and Pathology, Case Western Reserve University, Cleveland, OH
“Keratinocyte-specific overexpression of the angiopoietin receptor Tie2 leads to development of a psoriasiform phenotype”
Support for the symposium was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (5 R13 AR009431-42); the Eugene M. Farber family; Centocor, Inc.; Genentech; Johnson & Johnson, Consumer & Personal Products Worldwide; The Procter & Gamble Company; Amgen; the National Psoriasis Foundation; Stiefel Laboratories, Inc.; Therakos; AGIDermatics; the National Alopecia Areata Foundation; Orentreich Foundation for the Advancement of Science; and Taisho Pharmaceutical Co., Ltd.
Breakout Session Questions, Approaches, and Actions. Selected topics and conclusions from the Montagna Symposium.
Program Chairs: Kevin D. Cooper and Richard D. Sontheimer; Session Chairs: Jan Dutz, Sam T. Hwang, Brian J. Nickoloff, and Shinji Shimada; Symposium Chairs: Molly Kulesz-Martin and Jackie R. Bickenbach