Retour sur le 76th Society for Investigative Dermatology, April 26 – 29, 2017, Portland, Oregon, par Alessio Mylonas lauréat d'une bourse de voyage du CFCD
This year’s SID meeting, which took place in Portland (Oregon), was the society’s 76th and as with previous occasions, had an exciting programme with abstracts received from all across the globe. A staggering 1600 participants attended, a record-breaking number for the SID. Here is a summary of the most notable oral presentations at this year’s SID meeting.
Several associations joined in to form part of satellite meetings, and the American Acne & Rosacea Society opened the session on day 1 with an interesting line-up. James Sanford and Rich Gallo at UCSD presented work on how keratinocytes are activated by short-chain fatty acids from P.acnes, a commensal bacterium, to allow them to respond to TLR2/3 ligands. The implications of this work indicate that under homeostatic conditions there is tolerance to microbial stimuli in keratinocytes provided the barrier isn’t breached, thus an active mechanism that overcomes tolerance to commensals is required for inflammatory responses to bacteria at the surface of the skin. Of notable mention, George Agak and Kim at UCLA showed data that confirms observations from our laboratory about the antimicrobial efficacy of Th17 cells via IL-26. In the specific context of P.acnes, however, they find that supernatants from T-cell clones that are low/negative IL-26 producers are still able to inhibit growth, thus killing of P.acnes may be independent of IL-26. Two new compounds, SIG-1459 and 1460, developed by Signum Biosciences, Inc. are currently in phase trials for acne, and there is substantial increase in efficacy as compared to Benzonyl peroxide. The phytyl-cysteine based compounds are thought to alleviate TLR2/4-mediated inflammation in keratinocytes, and inhibit P.acnes proliferation directly as observed by decreased porphyrins in treated individuals using UV light visualization techniques. In a parallel satellite meeting, Rich Gallo from UCSD highlighted the underestimated surface area of skin, with even conservative estimates placing it at upwards of 30m2 of total area per individual. Thus, he argues that the microbiome/skin interface dictates strongly systemic inflammatory potential. Importantly, he showed compelling evidence, using laser-microdissection methods, that the microbiota is able to actively translocate through the epidermis into the deeper areas of the dermis. This seems to be mediated by particular bacterial toxins which induce skin proteases that mediate transient barrier disruption, resulting in microbial penetration into deeper compartments of the skin. These toxins raise the possibility for targeted approaches to treat loss of barrier integrity in a number of disease conditions.
Following the conclusion of satellite meetings, Angela Christiano president-elect of the SID, opened the meeting with the American Skin Association awards for outstanding research achievements to 6 established scientists. Following this, the Albert Kligman award was presented to Thomas Kupper for his innumerable contributions to the understanding of skin T-cell biology and maintenance, where he gave a memorable account of the journey undertaken to understand the characteristics of malignant T-cells in Cutaneous T-cell Lymphomas.
Day 2 of the meeting started in high gear, with engaging plenary sessions. Nair and Christiano from Columbia University described a previously unknown contribution of the microbial-flora in the development of alopecia areata, an autoimmune disease mediated by autoreactive T-cells. Antibiotic treated mice were protected from alopecia in a model of C3H engraftment, and the current proposal they put forth is that Lactobacilli in the gut are responsible for pathogenic
priming of the immune system, distally from the hair follicle. The honour of this year’s Eugene Farber lecture was given to Jonathan Barker from King’s College London, who presented a comprehensive summary of the genetics involved in psoriasis. He gave an outlook on the current herculean UK-wide consortium that aims at comparing samples from more than 12,000 patients pre- and post-treatment in wide -omics studies in order to identify efficacy and future outcomes of current biologic treatments. On a different topic, the acclaimed president of the Novartis Institute for BioMedical Research, James Bradner, was given the Naomi Kanof lectureship award for which he gracefully refused royalties due to conflict of interests. His talk was an awe-inspiring journey through drug development at Novartis and how the company’s future is evolving towards open-source strategies for drug discoveries, potentially opening the doors to accelerated drug development. Practically, they are bringing new technologies for hijacking the proteasome in order to degrade select protein targets such as oncogenes. Debra, a foundation dedicated to research on Epidermolysis Bullosa (EB) organised a special symposium to celebrate new advances in the field. EB is a debilitating inherited connective tissue disorder, for which many of the causative mutations are known, yet there is lack of an efficacious treatment. The meeting started with several case reports being presented, the majority of which were of children, and emphasised the current poor prognosis, with early childhood mortality and much suffering by the individuals affected. Importantly, new technologies are being used for genetic correction of said mutations using CRISPR/Cas9 approaches, with encouraging results. The meeting closed with a heart-wrenching testimony from executive director of debra Brett Kopelan who shared a glimpse into what it is like for his wife and affected 6 year-old daughter to live with such a debilitating disorder. I encourage people to visit the site (https://www.debra.org/itwonthurttowatch) to understand why their motto “the cost of doing nothing is too great” rings so desperately true. Graphic content, viewer discretion is advised. In one of the concurrent mini-symposia, locals Greiling and Kriegel suggest a mechanism by which there is molecular mimicry between the human Ro60 protein and the B.thetaiotaomicron Ro60 bacterial protein, and that this might be an important auto-antigen in Systemic Lupus Erythematosus, for both T- and B-cell activation.
Day 3 started early on Friday, with a well-thought out presentation by Johann Gudjonsson from Ann-Arbour, indicating the systemic nature of inflammation in psoriasis, and delineating the evidence for auto-immunity versus auto-inflammation. His take-home message is that different types of psoriasis represent a spectrum of auto-inflammation and auto-immunity, and that clarifying the still blurred distinctions between psoriasis subtypes will dictate efficacious personalised treatments. Kim and Prince from Stanford report an increased efficacy of Brentuximab, an anti-CD30, in CTCL as compared to standard Methotrexate treatment in a randomized, multi-centered, phase III trial. Nobel-prize winner Bruce Beutler from UT Southwestern was awarded the Julius Stone Lectureship award in immunology, for outstanding work in creation of extensive forward genetics screening platforms. In one such example, Bruce Beutler demonstrated how mutagens led to the selection of tny mice which are small, diabetic and highly insulin resistant. This work led to the identification of KBTBD2 which turns out is an E3 ligase that functions by targeting a PI3K regulatory subunit. He argued that, in the near future, such platforms will be used to target disease progression. In the afternoon, I gave my presentation on the role of plasmacytoid dendritic cells, and how we believe that their production of type-I interferon participates in driving active flare-ups of disease. This was undertaken during a concurrent symposium on innate immunity, microbiology and inflammation, and led to key questions from the audience and fruitful discussions that are likely to define the future directions of our work. Of notable interest, Swindell and Ward from Athens, Ohio presented their published paper that aimed at comparing the gene expression profiles of imiquimod treatment in different strains of mice. The major conclusion of the study is that not all mouse backgrounds are similar to human psoriasis. Questions followed regarding the study, including whether the authors had considered comparing the results to the gene profiles in human imiquimod application. Unfortunately, this had not been taken into account but the presenter agreed that this would be an interesting undertaking. Merrill and Belkaid from Bethesda presented their new findings on how they believe that a subset of γδ T-cells are able to expand in a gut microbiome-dependent manner and that they dictate the intensity of skin inflammation. Evidence was lacking, however, on the specificity of the gut compartment colonisation, and further work is needed to rule out a direct effect by microbial superantigens on the skin compartment.
With this, I would like to thank the CFCD for their travel support. We intend to publish our work shortly, and being able to attend this meeting has allowed us to announce our findings in preparation of this next hurdle.
This year’s SID meeting, which took place in Portland (Oregon), was the society’s 76th and as with previous occasions, had an exciting programme with abstracts received from all across the globe. A staggering 1600 participants attended, a record-breaking number for the SID. Here is a summary of the most notable oral presentations at this year’s SID meeting.
Several associations joined in to form part of satellite meetings, and the American Acne & Rosacea Society opened the session on day 1 with an interesting line-up. James Sanford and Rich Gallo at UCSD presented work on how keratinocytes are activated by short-chain fatty acids from P.acnes, a commensal bacterium, to allow them to respond to TLR2/3 ligands. The implications of this work indicate that under homeostatic conditions there is tolerance to microbial stimuli in keratinocytes provided the barrier isn’t breached, thus an active mechanism that overcomes tolerance to commensals is required for inflammatory responses to bacteria at the surface of the skin. Of notable mention, George Agak and Kim at UCLA showed data that confirms observations from our laboratory about the antimicrobial efficacy of Th17 cells via IL-26. In the specific context of P.acnes, however, they find that supernatants from T-cell clones that are low/negative IL-26 producers are still able to inhibit growth, thus killing of P.acnes may be independent of IL-26. Two new compounds, SIG-1459 and 1460, developed by Signum Biosciences, Inc. are currently in phase trials for acne, and there is substantial increase in efficacy as compared to Benzonyl peroxide. The phytyl-cysteine based compounds are thought to alleviate TLR2/4-mediated inflammation in keratinocytes, and inhibit P.acnes proliferation directly as observed by decreased porphyrins in treated individuals using UV light visualization techniques. In a parallel satellite meeting, Rich Gallo from UCSD highlighted the underestimated surface area of skin, with even conservative estimates placing it at upwards of 30m2 of total area per individual. Thus, he argues that the microbiome/skin interface dictates strongly systemic inflammatory potential. Importantly, he showed compelling evidence, using laser-microdissection methods, that the microbiota is able to actively translocate through the epidermis into the deeper areas of the dermis. This seems to be mediated by particular bacterial toxins which induce skin proteases that mediate transient barrier disruption, resulting in microbial penetration into deeper compartments of the skin. These toxins raise the possibility for targeted approaches to treat loss of barrier integrity in a number of disease conditions.
Following the conclusion of satellite meetings, Angela Christiano president-elect of the SID, opened the meeting with the American Skin Association awards for outstanding research achievements to 6 established scientists. Following this, the Albert Kligman award was presented to Thomas Kupper for his innumerable contributions to the understanding of skin T-cell biology and maintenance, where he gave a memorable account of the journey undertaken to understand the characteristics of malignant T-cells in Cutaneous T-cell Lymphomas.
Day 2 of the meeting started in high gear, with engaging plenary sessions. Nair and Christiano from Columbia University described a previously unknown contribution of the microbial-flora in the development of alopecia areata, an autoimmune disease mediated by autoreactive T-cells. Antibiotic treated mice were protected from alopecia in a model of C3H engraftment, and the current proposal they put forth is that Lactobacilli in the gut are responsible for pathogenic
priming of the immune system, distally from the hair follicle. The honour of this year’s Eugene Farber lecture was given to Jonathan Barker from King’s College London, who presented a comprehensive summary of the genetics involved in psoriasis. He gave an outlook on the current herculean UK-wide consortium that aims at comparing samples from more than 12,000 patients pre- and post-treatment in wide -omics studies in order to identify efficacy and future outcomes of current biologic treatments. On a different topic, the acclaimed president of the Novartis Institute for BioMedical Research, James Bradner, was given the Naomi Kanof lectureship award for which he gracefully refused royalties due to conflict of interests. His talk was an awe-inspiring journey through drug development at Novartis and how the company’s future is evolving towards open-source strategies for drug discoveries, potentially opening the doors to accelerated drug development. Practically, they are bringing new technologies for hijacking the proteasome in order to degrade select protein targets such as oncogenes. Debra, a foundation dedicated to research on Epidermolysis Bullosa (EB) organised a special symposium to celebrate new advances in the field. EB is a debilitating inherited connective tissue disorder, for which many of the causative mutations are known, yet there is lack of an efficacious treatment. The meeting started with several case reports being presented, the majority of which were of children, and emphasised the current poor prognosis, with early childhood mortality and much suffering by the individuals affected. Importantly, new technologies are being used for genetic correction of said mutations using CRISPR/Cas9 approaches, with encouraging results. The meeting closed with a heart-wrenching testimony from executive director of debra Brett Kopelan who shared a glimpse into what it is like for his wife and affected 6 year-old daughter to live with such a debilitating disorder. I encourage people to visit the site (https://www.debra.org/itwonthurttowatch) to understand why their motto “the cost of doing nothing is too great” rings so desperately true. Graphic content, viewer discretion is advised. In one of the concurrent mini-symposia, locals Greiling and Kriegel suggest a mechanism by which there is molecular mimicry between the human Ro60 protein and the B.thetaiotaomicron Ro60 bacterial protein, and that this might be an important auto-antigen in Systemic Lupus Erythematosus, for both T- and B-cell activation.
Day 3 started early on Friday, with a well-thought out presentation by Johann Gudjonsson from Ann-Arbour, indicating the systemic nature of inflammation in psoriasis, and delineating the evidence for auto-immunity versus auto-inflammation. His take-home message is that different types of psoriasis represent a spectrum of auto-inflammation and auto-immunity, and that clarifying the still blurred distinctions between psoriasis subtypes will dictate efficacious personalised treatments. Kim and Prince from Stanford report an increased efficacy of Brentuximab, an anti-CD30, in CTCL as compared to standard Methotrexate treatment in a randomized, multi-centered, phase III trial. Nobel-prize winner Bruce Beutler from UT Southwestern was awarded the Julius Stone Lectureship award in immunology, for outstanding work in creation of extensive forward genetics screening platforms. In one such example, Bruce Beutler demonstrated how mutagens led to the selection of tny mice which are small, diabetic and highly insulin resistant. This work led to the identification of KBTBD2 which turns out is an E3 ligase that functions by targeting a PI3K regulatory subunit. He argued that, in the near future, such platforms will be used to target disease progression. In the afternoon, I gave my presentation on the role of plasmacytoid dendritic cells, and how we believe that their production of type-I interferon participates in driving active flare-ups of disease. This was undertaken during a concurrent symposium on innate immunity, microbiology and inflammation, and led to key questions from the audience and fruitful discussions that are likely to define the future directions of our work. Of notable interest, Swindell and Ward from Athens, Ohio presented their published paper that aimed at comparing the gene expression profiles of imiquimod treatment in different strains of mice. The major conclusion of the study is that not all mouse backgrounds are similar to human psoriasis. Questions followed regarding the study, including whether the authors had considered comparing the results to the gene profiles in human imiquimod application. Unfortunately, this had not been taken into account but the presenter agreed that this would be an interesting undertaking. Merrill and Belkaid from Bethesda presented their new findings on how they believe that a subset of γδ T-cells are able to expand in a gut microbiome-dependent manner and that they dictate the intensity of skin inflammation. Evidence was lacking, however, on the specificity of the gut compartment colonisation, and further work is needed to rule out a direct effect by microbial superantigens on the skin compartment.
With this, I would like to thank the CFCD for their travel support. We intend to publish our work shortly, and being able to attend this meeting has allowed us to announce our findings in preparation of this next hurdle.