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In March 2009, the course entitled “Immunology and Skin Disease 2009: Frontiers in Cutaneous Immunology” was held in Boston, Massachusetts.* 98 physicians and scientists from 13 countries attended. The course, organized by Robert Fuhlbrigge and Rachael Clark (Harvard University, Boston) covered the latest developments in cutaneous immunology. Attendees were welcomed by Rachael Clark and Thomas Kupper (Harvard University, Boston). Dr. Kupper quoted Albert Szent-Gyorgyi, saying “discovery is seeing what everybody else has seen, and thinking what nobody else has thought.”
Michael Zasloff (Georgetown University, Washington D.C.) presented a fascinating overview of antimicrobial peptides (AMP), small proteins produced by epithelial cells that provide front line protection against skin pathogens. The AMP repertoire varies at different body sites and reflects differing skin flora at these sites. Vitamin D induces production of the AMP LL-37 and this molecule together with TLR activation enhances the ability of macrophages to kill mycobacteria. Underproduction and overproduction of AMP are both associated with human diseases. Atopic dermatitis patients have decreased AMP and frequent skin infections. AMP are overproduced in psoriatic skin and individuals with increased copy numbers of beta-defensin AMP genes are at increased risk for developing the disease. A complex of self DNA and LL-37 stimulates activation of plasmacytoid dendritic cells (pDC), a critical event in the initiation of psoriatic lesions.
Antigen presenting cells (APC) are critical to the initiation and tuning of T cell responses. Georg Stingl (Medical University of Vienna, Austria) described three types of APC in the skin. Studies on genetically modified mice suggest that epidermal Langerhans’ cells (LC) actually suppress T cell responses and promote tolerance, contrary to earlier reports. Dermal dendritic cells, on the other hand, elicit potent immune reactions when antigen is taken up under conditions that induce DC maturation. pDC are scarce in normal skin, frequent in inflamed skin and, together with a subtype type of myeloid DC (mDC), accumulate in imiquimod-treated skin. Both Imiquimod-induced mDC and pDC express molecules of the lytic machinery, kill cancer cells in vitro and may be responsible for imiquimod-induced regression in basal cell carcinomas. Dr Stingl and his co-workers have recent evidence that TLR7 activated pDC may also contribute to apoptotic death of activated T cells in HIV infection.
APC and other cells sense pathogens via toll-like receptors (TLR), a set of pathogen receptors hardwired into the genome. Michael Schon (Georg August University, Germany) described how these highly conserved receptors signal through MyD88 and all have a double arch shape despite the differing structures of their ligands. TLR can induce both stimulatory and inhibitory signals and TLR signaling contributes to autoimmune diseases including lupus and inflammatory bowel disease. Stimulation of TLR9 from the apical surface of intestinal cells down modulates inflammatory NFκβ signaling but stimulation from the basal surface is pro-inflammatory. TLR7/8 agonists such as imiquimod are used to treat actinic keratoses and BCC; Dr. Schon showed striking photos of cutaneous metastases of malignant melanoma that cleared after topical imiquimod therapy. In addition to TLR7/8 signaling, imiquimod can activate cells via adenosine receptors and can induce tumor cell death directly.
DC travel to the lymph nodes to present antigens to T and B cells. Using intravital microscopy in anesthetized mice, Dr. Ulrich Von Andrian (Harvard University, Boston) observed that T cells interacting with antigen laden DC progressed through three stages. T cells first made brief serial contacts with many DC and became activated. T cells then formed stable long lasting contacts with a single DC and developed cytokine production and effector functions. Lastly, T cells again made brief contacts with multiple DC and proliferated. These stages -dating, mating and procreating - allowed T cells to scan multiple DC and integrate these signals into a single decision to respond or not. Dr. Von Andrian also discovered that macrophages present in the subcapsular sinus of lymph nodes trap particulates, including viruses, and then present these particles to lymph node B cells.
Regulatory T cells (Treg) and IL-17 producing T cells (Th17) are two recently described T cell subsets with reciprocal roles. Treg induce and maintain self tolerance. Th17 cells defend against extracellular pathogens but also contribute to inflammatory diseases such as arthritis and psoriasis. Estelle Bettelli (Harvard University, Boston) presented her studies of experimental autoimmune encephalomyelitis in mice, a Th17 and Th1 mediated disease. IL-6 promoted Th17 development and inhibited formation of Treg. TGFβ, IL-21 and IL-23 also drove pathogenic Th17 cells. Similar findings have been reported in psoriasis. DC and keratinocytes in psoriatic lesions overproduce IL-23, driving the development and proliferation of Th17 cells. These cells in turn produce IL-22 and other inflammatory mediators. IL-22 induces keratinocyte proliferation and acanthosis. These studies suggest that interruption of IL-23 signaling or Th17 effector function could benefit patients with many different inflammatory disorders.
Few topics have received more recent attention than vitamin D. Many studies show that the majority of the population is vitamin D deficient, especially in winter. Dermatologists have to walk a fine line in recommending sun protection for vulnerable patients while ensuring they obtain adequate vitamin D. Daniel Bikle (UCSF) spoke about recent findings that vitamin D plays a critical role in immune responses. Vitamin D stimulates the production of AMP by skin. Upon stimulation, macrophages can generate their own vitamin D, enhancing their ability to kill pathogens. Vitamin D also promotes the differentiation of Th2 cells and Treg, inhibits the differentiation of Th17 cells and helps to imprint T cells with skin homing addressins. Recent studies suggest that 2000 units of vitamin D may be required per day to obtain adequate blood levels but optimal dosage varies from patient to patient.
Hilde Cheroutre (LIAI, San Diego) next presented evidence that retinioic acid (RA), a derivative of vitamin A, plays a critical role in gastrointestinal immunity. RA produced by gut DC induces T cell expression of gut homing addressins. RA promotes the development of Treg, suppresses IL-17 production and together with TGFβ, can re-polarize Th17 cells to a regulatory phenotype. Thus, under normal conditions RA helps to drive T cell immunity towards the formation of tolerogenic Treg. In mice, a population of CD4 T cells coexpresses CD8αα after exposure to the gut microenvironment. Under normal conditions, the activity of these cells is suppressed but they can become highly cytotoxic when exposed to inflammation. Thus, reprogramming of T cells at peripheral tissue sites supports the generation of tolerogenic T cells at baseline but mechanisms exist that allow these T cells to become highly cytotoxic if necessary.
In his Keynote address, Dr. David Altshuler (Harvard University, Boston) described how genome-wide genetic mapping allows the linkage of disease states to genetic alleles expressed by affected individuals. Technology driven improvements have allowed a shift from hypothesis testing to hypothesis generation. Instead of confirming the role of previously identified gene products, these screens allow identification of previously unsuspected molecules that can then be tested as drug targets. Small population variations in a clinical measurement such as blood lipids can allow the identification of gene products that, if inhibited completely, may have a much more dramatic clinical effect. This is because population studies determine the effect of a particular allele on a clinical parameter, not the effect of complete inhibition of a particular gene product. Lastly, new developments in sequencing technology will lead to rapid increases in the reach and explanatory power of these approaches.
Dr. Jiali Han (Harvard University, Boston) presented his work on genome-wide genetic mapping of polymorphisms conferring susceptibility to skin cancer. Dr. Han gathered data from the Nurses Health Study, a cohort of over 120,000 women followed since 1976. Risk factor data was collected prior to disease development. Blood samples from women who developed skin cancer were compared to age-matched controls. Polymorphisms in the MC1R gene associated with pheomelanin (red hair) conferred increased risk for both melanoma and non-melanoma skin cancers. Addition of MC1R genetic variant information significantly increased the ability to predict the development of melanoma and BCC in patient populations. Dr. Han’s work illustrates how genome-wide genetic mapping can be used to both study the underlying biology of a disease and to better predict disease development in a patient population.
Dr. Gregory Lanza (Washington University, Saint Louis) described exciting work with fluorocarbon nanoparticles. These particles are highly visible by MRI or ultrasound. Proteins can be added to target particles specifically, for instance, to areas of angiogenesis in tumors or at sites of inflammation. Medications can be incorporated for specific delivery to targeted cells. αvβ3-integrin targeted nanoparticles filled with the angiogenesis inhibitor fumagillin inhibited angiogenesis in rabbit breast cancers and clinically improved arthritis in mouse models. Nanoparticles can be used to visualize angiogenesis, inhibit it and then monitor response to therapy. Dr. Lanza also described an exciting new technology called photoacoustic tomography, in which a laser pulse excites skin or another tissue and resultant vibrations are detected by ultrasound. Using gadolinium enhanced nanoparticles, this method allowed noninvasive sentinel lymph node mapping in rats and has many promising applications in the field of dermatology.
Psoriasis and atopic dermatitis, two common inflammatory skin diseases, were addressed next. Dr. Brian Nickoloff (Loyola University, Chicago) presented an overview of how the focus of research has changed over the years in the field of psoriasis. Beginning with a focus on keratinocytes, the field of psoriasis has evolved to the current understanding that plasmacytoid DC and Th17 T cells play a critical role in the pathogenesis of this disease. Thomas Bieber (University of Bonn, Germany) then presented an elegant discussion of atopic dermatitis (AD) with an emphasis on personalized medicine. AD is a clinically and genetically heterogeneous disease. Genes predisposing to AD fall into two broad categories: skin related genes that affect barrier function and atopy related genes that affect the tendency of an individual to be allergic. Polymorphisms in the fillagrin gene that impair skin barrier function and changes in the gene for IL-4 and its receptor are all associated with AD. Knowledge of an individual’s risk alleles could be used to tailor therapy and to identify individuals at risk for progressive sensitization, allowing early intervention to improve barrier function. Epigenetic changes may explain why some individuals develop AD later in life and environment also plays a critical role. AD skin still shows signs of inflammation between flares. Proactive intermittent usage of steroids or calcineurin inhibitors significantly decreases the frequency and severity of flares.
Rachael Clark (Harvard University, Boston) noted that a minority of patients with cutaneous T-cell lymphoma (CTCL) develop rapid and fatal disease progression. Discriminating these patients from the majority who do well is difficult. CTCL has a constellation of findings difficult to fit into a single cohesive hypothesis. Clonal T cells with chromosomal abnormalities are present in both early and advanced CTCL, suggesting genetic damage is a common feature. Marked loss of T cell diversity often occurs, indicating widespread T cell death on a par with HIV disease. Neutrophils are activated and Staph Aureus driven inflammation of T cells worsens the disease. Extracorporeal photopheresis (ECP) improves CTCL but evidence suggests it does so by inducing tolerance. New findings in skin T cell biology explains some but not all features of the disease and a unifying hypothesis remains elusive.
Smallpox vaccination, which involves scarification of the skin, is the most effective vaccination in history. Luzheng Liu (Harvard University, Boston) described how scarification provided enhanced systemic immunity and protection against skin and respiratory challenge in vaccinia immunized mice. Following scarification, T cells entered the skin draining lymph node and generated effector cells expressing skin homing receptors. Early on, antigen specific cells also seeded other lymph nodes and gave rise to additional effector populations able to access other tissues. Thus, immunization in the skin gives rise to widespread and disseminated immune protection. Dr. Liu’s work suggests that scarification is a safe and highly effective vaccination route capable of inducing potent immune protection.
James Campbell (Harvard University, Boston) described his work on T-cell homing to skin in mice. He pointed out that a T cell’s homing receptor expression should be considered separately from its functional characteristics. The chemokine profile of a T cell indicates its homing characteristics but does not define its functional differentiation (e.g. Th17). Immunization via the skin gave rise to T cells with skin homing phenotypes and immunization through the gut generated gut homing T cells. CCR4 is a chemokine receptor expressed by T cells in human and mouse skin but it is also expressed by non-cutaneous T cells. This raises the question of whether CCR4 functions as a skin homing receptor. Using CCR4 deficient mice, Dr. Campbell demonstrated that CCR4 does play a critical role in supporting T cell entry into the skin.
The meeting was concluded with a fascinating presentation by Robert Sackstein (Harvard University, Boston) on mesenchymal stem cells (MSC). In contrast to embryonic stem cells, MSC can be obtained from adult bone marrow and do not form teratomas. MSC have many natural functions including the formation of vascular pericytes. MSC can also enhance tissue repair and are markedly immunosuppressive. MSC secrete nitric oxide, produce IDO and PGE2 and suppress MLR reactions. MSC from unrelated donors can halt the progression of severe graft versus host disease in patients. By inducing the formation of the carbohydrate HCELL on cell surfaces, Dr. Sackstein targeted IV infused MSC to the bone marrow with the goal of enhancing bone production, a possible treatment for osteoporosis.
Dr. Fuhlbrigge concluded the course with thanks to the organizers, speakers, and attendees.
*Immunology and Skin Disease 2009: Frontiers in Cutaneous Immunology was held at the Fairmont Copley Plaza Hotel in Boston, Massachusetts, USA, 19 21 March 2009.