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Published in final edited form as: J Invest Dermatol. 2020 Jun 27;140(11):2105–2110. doi: 10.1016/j.jid.2020.06.010

68th Montagna Symposium on the Biology of Skin “Decoding Complex Skin Diseases: Integrating Genetics, Genomics, and Disease Biology”

Johann E Gudjonsson 1, James T Elder 1,2
PMCID: PMC7606754  NIHMSID: NIHMS1631775  PMID: 32603751

Abstract

The 68th Montagna Symposium on the Biology of the Skin was held from October 10–14, 2019, at Salishan Lodge in Gleneden Beach, Oregon. The theme of the meeting was “Decoding Complex Skin Diseases: Integrating Genetics, Genomics, and Disease Biology”. The meeting emphasized integration of multiple themes and disciplines to better understand some of the most common skin diseases, ranging from psoriasis to alopecia areata to vitiligo to lupus erythematosus to atopic dermatitis and food allergy. Promising therapeutic strategies are emerging for all of these diseases, providing clues for ways to connect the bench to the bedside. A common thread was the success of genome-wide association studies (GWAS), which have highlighted the importance of regulatory signals vs. coding variation. These diseases also share an environmental component linked to immune system function. Hence, beyond GWAS studies, this meeting focused on gene regulatory mechanisms, the “single-cell revolution”, in vivo systems for dissection of disease pathogenesis, and the relationship between genetics and environment in the context of host defense. We concluded with a “Translational Roundtable” designed to explore how these interrelated fields can best be directed towards long term disease control, and ultimately, cure.

The Montagna Symposium on the Biology of Skin, formerly the Annual Symposium on the Biology of Skin, was initiated at Brown University in 1950 by Dr. William Montagna. The Symposium grew from the need to communicate investigative work in cutaneous biology and to provide a link between basic scientists studying the skin in humans and animals and clinically trained scientists in investigative dermatology. Since then, over 5,000 scientists, physicians, and students from around the world have attended the Symposium, which annually addresses a major topic in cutaneous biology. The topic of this year’s 68th Symposium was “Decoding Complex Skin Diseases: Integrating Genetics, Genomics, and Disease Biology”. Three speakers from the 42th Montagna Symposium on the Genetics of Complex Skin Diseases accepted our invitation to speak at the 68th meeting: Angela Christiano (Columbia University), John Harley (University of Cincinnati), and Richard Spritz (University of Colorado). Our thanks go out to our session directors, Drs. Dennis Roop, Bogi Andersen (UC Irvine), and Anne Bowcock (Icahn School of Medicine), all of whom have been noted participants at previous Montagna Symposia.

What Have GWAS Taught Us About Common Skin Diseases?

As of this writing, genome-wide association studies (GWAS) have generated over 4,346 publications involving at least 166,103 associations between genetic variants and many human traits and diseases (Buniello et al., 2019). The concept underlying this 68th Montagna Symposium was to “nucleate” the meeting with key skin-relevant GWAS studies, then to bring to bear the many other facets of what we have learned to elucidate the nature of complex genetic skin diseases in the “post-GWAS era” (Swindell et al., 2014), including genomics, immunology, environment, and tools for relating these findings to disease biology, including validation of pathogenic mechanisms and therapeutic translation (Figure 1).

Figure 1.

Figure 1.

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Main themes of the meeting and integration with disease biology

After investing the better part of a decade in “fine mapping” of GWAS studies, one of the most consistent features of complex trait GWAS has been the observation that the majority of genetic signals underlying complex traits are regulatory in nature (Boyle et al., 2017). Keynote speaker Dr. Paul Khavari (Stanford University) provided a comprehensive look at the landscape of genetic regulation of gene expression in keratinocytes as well as immune cells, utilizing a combination of CRISPR perturbations and single-cell chromatin accessibility profiling using the assay for transposase-accessible chromatin and sequencing (ATAC-seq). The keratinocyte studies defined a trajectory of epidermal differentiation regulated by five key transcription factors interacting either positively or negatively: CEBPA, EHF, ZNF750, KLF4, and JUNB (Rubin et al., 2019). Notably, ZNF750 and KLF4 have been implicated as psoriasis genetic loci in either GWAS (KLF4) (Tsoi et al., 2012) or pedigree studies (ZNF750) (Yang et al., 2008). Dr. Khavari’s results also emphasized the role of chromatin looping in determining the nature of transcription factor interactions (Rubin et al., 2019).

Led by Dr. Anne Bowcock, the next session featured invited presentations by Drs. Elder, Harley, Spritz, and Dr. Sara Brown (University of Dundee) along with young investigator presentations selected from the abstracts by Viktoryia Laurynenka (University of Cincinnati) and Bing-Jian Feng (University of Utah). Noting that approximately 80 to 90% of GWAS signals are regulatory, Dr. Elder pointed out how chromatin looping can complicate the mapping of GWAS hits to relevant target genes in the context of promoter-enhancer interactions. To address this, he presented ongoing studies of T-cell subsets from 150 individuals, analyzed for chromatin accessibility by ATAC-seq, coupled with transcriptome analysis by RNA-seq and GWAS genotyping to generate chromatin quantitative trait loci (chrQTLs) and expression quantitative trait loci (eQTLs). He reported that 10 of 11 evaluable GWAS hits displaying genotype-dependent chromatin accessibility in activated CD8+ T-cells are also eQTLs in blood cells, as defined by the eQTLGen database (Vosa et al., 2018). Turning from regulatory to coding variants, he showed how the Act1 D10N variant in the TRAF3IP2 gene can enhance human Th17 cell polarization in vitro, in a manner that is enhanced by neutrophil extracellular traps (NETs) Lambert et al., 2019).

Dr. Harley’s presentation summarized his longstanding interest in the genetics of systemic lupus erythematosus (SLE) (Harley et al., 2009) and its potential relationship to Epstein-Barr virus (EBV) (Arbuckle et al., 2003). He demonstrated highly significant overlap of genetic signals for SLE and five other autoimmune diseases with binding sites for both virally-encoded (EBNA-2) and host-encoded transcription factors (TF) involved in EBV latency (Harley et al., 2018). More recent expansion of the Harley lab ChIP-seq database to other EBV-encoded transcription factors involved in the latency III program involved in maintaining proliferation of EBV-transformed B-cells (Allday et al., 2015), including EBNA3B, EBNA3C, and EBNALP. These studies point towards a “balancing act” for the immune system between the need to control EBV (which is nearly ubiquitous in adults) and the development of autoimmunity.

Dr. Spritz reviewed the current status of vitiligo GWAS, which have currently identified 52 vitiligo susceptibility loci in individuals of European ancestry. He made the case for vitiligo being a “simple” type of complex genetic disorder, because vitiligo heritability is high (estimated at 46–72%), with very little “missing heritability”, with about one-third of heritability represented by common variants and two-thirds by rare variants. As is the case in psoriasis (Henseler and Christophers, 1985), vitiligo is a strongly HLA-associated disease with a bimodal distribution of age at onset (Jin et al., 2019). Dr. Spritz and colleagues identified a major locus specific to the early-onset case subgroup mapping to an indel in an MHC class II enhancer. They identified a haplotype containing this indel that confers high risk for vitiligo (odds ratio of 8.1) as well as early onset, is more important than traditional HLA Class II alleles, and increases expression of HLA-DQB1 mRNA and HLA-DQ protein on professional antigen-presenting cells. Dr. Spritz also noted that vitiligo age-of-onset has become more delayed in recent years, especially over 1973–2004, suggesting the importance of interactions between genetics and environment. (Jin et al., 2020).

Dr. Brown reviewed GWAS and meta-analyses that have revealed 31 loci associated with atopic dermatitis (AD), and noted that these loci jointly account for less than 20% of AD heritability, meaning that further work is needed to fully understand individual risk. While some AD risk loci have confirmed pre-existing knowledge, including the role of skin barrier and type 2 inflammation in AD pathogenesis, others have yielded new insights including evidence of autoimmunity and a role for Langerhans cells. While most significant AD GWAS peak, mapping to the Epidermal Differentiation Complex (EDC) on chromosome 1q21.3, contains the well-known filaggrin (FLG) gene, loss-of-function mutations and copy number variation within FLG do not fully explain this strong effect. Thus, the EDC is likely to contain additional risk variants that remain to be defined. As is the case in psoriasis, lupus, vitiligo and other complex disorders, the majority of other AD risk loci are in intergenic regions, which will require detailed molecular studies, carried out in cells and tissues of relevance to AD. She reported that one such region lies between the EMSY and LRRC32 genes, both of which are strong candidate genes for AD risk.

Understanding GWAS Signals – Chromatin Structure & Gene Regulation

Focusing further on the roles of chromatin structure and gene regulation as tools for understanding GWAS signals, a session directed by Dr. Bogi Andersen included invited talks by Drs. Evan Boyle (UCSD), Tõnu Esko (University of Tartu, Estonia), Roger Pique-Regi (Wayne State University), and Manuel Garber (University of Massachusetts Medical School), and included Young Investigator oral presentations selected from the abstracts by Sheng-Pei Wang, Ph.D. (National Cheng Kung University, Taiwan) and Sarah T. Arron, M.D., Ph.D. (University of California, San Francisco). Dr. Boyle’s talk expanded on a thought-provoking recent publication (Boyle et al., 2017), taking a global approach to understanding the links between genetic variation and disease. He proposed that gene regulatory networks interconnect in such a way that many different genes expressed in disease-relevant cells are liable to affect the functions of core disease-related genes and hence, that the so-called “missing heritability” problem may be explained at least in part by effects of genetic variation on genes outside core pathways.

Dr. Esko described his team’s efforts to determine how the genes and pathways through which disease-associated genetic variants identified by GWAS exert their effects on the phenotype. To this end, they combined genetic and transcriptomic data from over 30,000 blood samples within the eQTLGen Consortium (Vosa et al., 2018) to perform cis-eQTL mapping (i.e., the genetic variant influencing gene expression is near the target gene) and trans-eQTL mapping (i.e., genetic variant is far from the target gene) on >10,000 genetic risk factors identified by GWAS. They also calculated polygenic risk scores for over 1,300 complex traits and correlated those with gene expression levels. They found that 90% of all protein-coding genes show a significant cis-eQTL effect, and that over 30% of all established genetic risk factors for disease manifested trans-eQTLs effects, impacting expression of 4,700 unique genes, with examples of individual “hub” SNPs having downstream effects on over 200 genes. They found both cis and trans effects on gene expression for 2,600 risk SNPs, finding these interactions between their encoded proteins more often than would be expected by chance. In several cases, the trans-eQTL effect was mediated by the corresponding cis-eQTL gene. Overall, these findings emphasized the value of a highly-powered sample to uncover the relationships between GWAS signals and genetic effects on gene expression.

Continuing the theme that genetic variants relevant for complex traits are more commonly found in non-coding regions, Dr. Pique-Regi described his group’s efforts to understand the “the gene regulatory grammar” encoded in the human genome. He emphasized that the heterogeneity of cell types found in most tissues and the additional complexity due to various environmental conditions both represent important knowledge gaps in decoding these grammar rules. He also summarized computational methods [such as CENTIPEDE (Pique-Regi et al., 2011)] for identifying gene regulatory elements from chromatin accessibility data, as well as tools for predicting the effect of disease-associated genetic variants on gene regulation (Wen et al., 2017), and for studying the regulatory elements directing gene expression response to different environmental conditions using ATAC-seq and massively parallel reporter gene assays (MPRA).

Dr. Garber addressed the interesting question of why some enhancers are not functionally well-conserved across species (Villar et al., 2015), but others are. Continuing his lab’s interest in chromatin structure and gene regulation in dendritic cells (DC), they focused on genes responsive to lipopolysaccharide (LPS) in DC derived from mouse bone marrow and cytokine-induced human monocytes, followed by ATAC-seq, RNA-seq, and chromatin immunoprecipitation (ChIP) for H3K27Ac (Donnard et al., 2018). This work revealed that AP-1 family members tend to connect promoters and enhancers. They also found that gene expression programs are more divergent between man and mouse for mildly induced genes, but are more highly- conserved for strongly induced genes and early-response genes. Consistent with selective pressure for pathogen resistance, they found that the density of these conserved motifs strongly predicted the responsiveness of a gene to pathogen exposure, again emphasizing the interaction of genetics and environment.

Transcriptomics: The Single-Cell Revolution

Moving on from the role of genetic regulation of gene expression and chromatin structure in order to understand GWAS signals, the next session focused on single-cell transcriptomic profiling to gain deeper insights into biological mechanisms in various disease states. Directed by Dr. Gudjonsson, this session included invited talks by Drs. Niroshana Anandasabapathy (Weill Cornell Medicine), Muzlifah Haniffa (Newcastle University), Michael D. Rosenblum (University of California, San Francisco), and Rui Yi (University of Colorado, Boulder) as well as presentations selected from the abstracts by Fabian V. Filipp (Helmholtz Zentrum München) and Mrinal K. Sarkar (University of Michigan).

Dr. Anandasabapathy addressed how dendritic cells in peripheral tissues, such as the skin, influence T cell behavior and memory formation through PDL1/2 signaling. She addressed the consequences this activation has for immune memory, with a focus on response to melanoma. These findings were related to behavior of immune populations in tumors and the consequences this has for melanoma-specific outcomes.

Dr. Haniffa demonstrated the power and utility of single cell RNA-sequencing to understand the functional organization of the developing human immune system. She identified, using single-cell transcriptomic profiling of approximately 140,000 liver and 74,000 skin, kidney, and yolk sac cells, the repertoire of human blood and immune cells during development (Popescu et al., 2019). Using this unique source of fetal tissue, her group was able to demonstrate physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac, thus providing a blueprint for the study of pediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of hematopoietic stem cells (Popescu et al., 2019).

Dr. Rosenblum showed novel findings in-regards-to the role of regulatory T cells in skin and how they may actively suppress profibrotic immune responses in skin. His work demonstrated that skin T regs preferentially express high levels of GATA3, a master Th2 transcription factor. Notably, T reg depletion resulted in preferential increase in Th2 cytokine production in skin, and this was accompanied by spontaneous fibroblast activation, profibrotic gene expression and dermal fibrosis (Kalekar et al., 2019). This work suggests that Tregs play an important role in regulating fibroblast activation in skin and play an active role in fibrotic skin diseases.

Dr. Yi addressed single cell transcriptomics and open chromatin analysis of developing skin. He discussed how few embryonic progenitors give rise to self-sustaining cell lineages that maintain tissue integrity throughout the lifespan of the organisms, how mammalian skin can be used as a model system, and how sophisticated genetic manipulation can be used to characterize this system at the single-cell level using both single-cell RNA-sequencing and single-cell ATAC-sequencing, providing unprecedented insights into understanding transcriptional mechanisms that govern epidermal development and maintenance of hair follicle stem cells (Fan et al., 2018).

The second keynote speaker of the Symposium was Dr. Richard Flavell (Yale University School of Medicine). As was noted during his introduction, during his highly-decorated career he has been a driving force in many of the key research developments upon which this meeting was based, including the discovery of gene regulation in trans via “kissing chromosomes” as well as the molecular basis of T-cell differentiation and the role of several receptor families in the innate immune response, including Toll-like receptors and intracellular nucleotide-binding oligomerization domain (NOD)-like receptors. He was also among the first to demonstrate the role of inflammasomes and microbial homeostasis in the pathogenesis of several chronic diseases, including inflammatory bowel disease and the metabolic syndrome. He presented new work focused on the role of neuronal innervation in the control of IL-18 expression and secretion in the gut. This “neuroinflammatory synapse” was unexpected but fascinating and seems very much in keeping with the major role of the nervous system in regulating gut physiology.

Immunopathogenesis of Complex Skin Diseases

The next session continued on the same theme but dove into how these technologies could be used to gain better insights into the immunopathogenesis of complex skin diseases. This session was directed by Dr. Dennis Roop and included talks by Dr. Nicole Ward (Case Western Reserve University), Johann E. Gudjonsson (University of Michigan), Angela Christiano (Columbia University), and J. Michelle Kahlenberg (University of Michigan). This session included Young Investigator oral presentations by Jessica Ludwig BS (Case Western University) and Dr. Matthew D. Veseley MD, PhD (Yale University).

In her talk, Dr. Ward presented data showing how to use –omics approaches to generate innovative mouse models of psoriasis and how these models can be used to gain new insights into disease pathogenesis that can be brought back to the patient to better understand their disease pathogenesis (Hawkes et al., 2018). She also presented data describing the utility of using mouse models to explore at the cellular and molecular levels epidemiological findings, such as thrombosis, atherosclerosis, and psoriatic arthritis, which are associated with psoriasis (Wang et al., 2012, Wang et al., 2016), as well as addressing anecdotal reports from psoriasis patients such as the lack of improvement or worsening with anti-IL-6 agents in psoriasis (Fritz et al., 2017). This demonstrated the usefulness of using appropriate mouse models to study and understand psoriatic disease pathogenesis.

Switching over to a skin disease often characterized as “allergic” rather than “autoimmune” in origin, Dr. Gudjonsson demonstrated the use of transcriptomic approaches to study the comparative pathogenesis of psoriasis and atopic dermatitis. This work shows that over 80% of genes dysregulated in atopic dermatitis skin overlaps with dysregulated genes in psoriasis. However, despite this overlap, atopic dermatitis was more heterogeneous in terms of transcriptomic variability and showed dominance of IL-13 pathways, whereas in contrast psoriasis was dominated by IL-17 responses (Tsoi et al., 2019).

In her talk on genetics and immunology of alopecia areata, Dr. Christiano described findings from her laboratory on the identification of the genetic basis of alopecia areata as a complex genetic disease (Petukhova et al., 2010), including the role of effector CD8+ cells and the role of IL-15 in maintaining their effector function. She described how this led to successful clinical trials using inhibitors of JAK signaling to inhibit IL-15 signaling (Xing et al., 2014). She also described exciting recent work using single cell T cell receptor (TCR) sequencing to help identify the autoantigen(s) in alopecia areata, and recent work focusing on the role of environmental triggers, particularly gut microbiota. Her work demonstrates how GWAS studies can be used to uncover new disease mechanisms in complex autoimmune disorders, and how this can inform clinical investigation of repurposed drugs.

Dr. Kahlenberg discussed her group’s work outlining the pathogenesis of cutaneous lupus erythematosus (CLE). CLE is found in up to 70% of patients with systemic lupus erythematosus and can also occur as a skin-only condition (Stannard and Kahlenberg, 2016). In her talk Dr. Kahlenberg outlined recent developments in our understanding of CLE including inflammatory mediators, differences in lesional subtypes, predisposition to inflammation in normal-appearing SLE skin, and mechanisms of flare by ultraviolet light (Sarkar et al., 2018, Wolf et al., 2018). These findings have been the driver behind new trials of medications for CLE treatment.

Nature & Nurture: Microbiome in Complex Skin Diseases

The symposium ended on a high note with a shift in the focus to Nature and Nurture – the role of microbiome in complex skin disease. This session was led by Dr. Elder and included talks by Drs. Cathryn Nagler (University of Chicago), Jose U. Scher (New York University), Lloyd S. Miller (John Hopkins University), and Shruti Naik (New York University). Two Young Investigator Presentations were given by Dr. Tatsuya Ogawa (University of Tsukbua, Japan) and Dr. Tamara Terzian (University of Colorado).

Noting that the prevalence of life-threating food allergies is increasing rapidly in Westernized societies, Dr. Nagler suggested that emerging lifestyle practices including antibiotic use, Caesarean births, and formula feeding, and other dietary changes are altering intestinal bacterial communities, particularly early in life. Her team tested this idea by colonizing germ-free mice with feces from healthy or cow’s milk allergic infants. They found that colonization with bacteria from healthy, but not cow’s milk allergic, infants were protected against anaphylactic responses to a cow’s milk allergen, accompanied by differences in gut bacterial composition. Using transcriptomic analysis, they identified a signature from one of the altered bacterial species (a Clostridium) that was also associated with distinctive human transcriptome signals in the ileal epithelium relating to its barrier function (Feehley et al., 2019). Based on this research, Dr. Nagler and colleagues are working to construct a therapy to strengthen the gut barrier and prevent food allergens from passing out of the gut and into the bloodstream, where they can trigger allergic responses.

Dr. Scher addressed the role of microbiome in psoriasis and psoriatic arthritis. He described how there is increasing evidence for a role of the microbiome in contributing to and affecting the severity of psoriasis disease, and how alterations in the composition of the microbiome can result in dysbiosis which impacts the immune system leading to autoimmunity, persistent inflammation and tissue damage. A part of his talk addressed pharmacomicrobiomics, which is a novel area of research that investigates the effect of variations within the human microbiome on drugs (Abdollahi-Roodsaz et al., 2016).

Dr. Miller presented work on the interaction between filaggrin mutations, such as those associated with atopic dermatitis, injury, and the skin microbiome. He showed, using a mouse model of skin injury in filaggrin-deficient mice, development of a chronic atopic dermatitis-like skin inflammation associated with IL-1α intracellular release from keratinocytes, which could be blocked by inhibition of IL-1α but not IL-1β. Interestingly, topical antibiotics or cohousing of the filaggrin-deficient mice to alter or intermix the skin microbiota, resolved the skin inflammation and restored IL-1α localization (Archer et al., 2019). This work has implications for AD pathogenesis and potential therapeutic targeting.

The final speaker of the symposium was Dr. Shruti Naik who discussed choreographing of immune responses at the cutaneous interface. Dr. Naik showed how commensal bacteria affect skin immunity and the critical cellular mediators involved. Furthermore, her work demonstrated that tissue-resident cells are poised to sense and respond to alterations in microbial communities, likely representing an evolutionary means by which the skin immune system uses fluctuating commensal signals to calibrate barrier immunity and protection against invading pathogens (Naik et al., 2015). Her work reveals the highly dynamic interactions that occur in the skin between the host and the microbiota and how these can be rapidly and specifically remodeled by encounters with defined commensals.

Translational Roundtable

The final event of the meeting was the “Translational Roundtable”, where well established members from academia, National Institutes of Health, and industry gathered together for a highly stimulating and interactive discussion with the audience about the future of skin research. This included very lively discussion about the role of industry and academia in driving and prioritizing research areas, and how these are shaping the future of cutaneous research, and the role of the NIH to help guide the field and support it. It was generally agreed that the key to effective translation is to continue to advance our understanding of disease biology.

Summary and Perspectives

Over four days, this Symposium brought together 91 scientists, clinicians, and trainees (Figure 2) in a highly interactive and stimulating environment, with participants taking with them new connections and knowledge as they returned to their homes. The meeting emphasized how much research in common yet genetically complex skin diseases has moved towards integration of genetics, genomics and disease biology, and outlined the opportunities and challenges ahead. As beautifully summarized by our Keynote Speakers, the meeting was highlighted by advances in the role of chromatin structure in gene regulation, the single-cell revolution and the interaction of genetics and environment in maintaining the balance between response to pathogens and autoimmunity. These concepts provide important perspectives for the road ahead: while we should not expect that “changing our genes” will cure these diseases, we expect that the insights provided by “traditional” GWAS will serve as a “Rosetta Stone” for leveraging the potential of epigenetics to regulate gene expression, for continued development of targeted immunotherapies, and for therapeutically exploiting the complex relationship between host defense and autoimmunity.

Figure 2.

Figure 2.

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Attendees of the 68th Montagna Symposium on the Biology of Skin

ACKNOWLEDGEMENTS

The Montagna Symposium on the Biology of Skin, directed by Molly F. Kulesz-Martin, Ph.D., is an annual non-for-profit scientific meeting, inaugurated in 1950 by William Montagna, Ph.D., that gathers leading cutaneous biologists and dermatologists to discuss new findings, techniques, and goals in skin biology.

We gratefully acknowledge Dr. Jodi L. Johnson for editorial assistance, and the Society for Investigative Dermatology and the Japanese Society for Investigative Dermatology for travel awards. This meeting was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Environmental Health Sciences, and the National Institute on Aging (R13 AR009431–54). The Biology of Skin Foundation is a 501(c)(3) public charity incorporated to build enduring support of the Montagna Symposium on the Biology of Skin and its educational mission. Founders Nancy P. Durr in memory of Norman Orentreich (1923–2019), The Procter & Gamble Company and other contributors are acknowledged at www.biologyofskinfoundation.org, Other 2019 supporters of the meeting included Almirall, Galderma Laboratories, L.P., Sun Pharmaceutical Industries Ltd., National Psoriasis Foundation, National Alopecia Areata Foundation, OHSU Department of Dermatology, OHSU Knight Cancer Institute, David M.C. Ju Foundation, and Drs. Jim and Diane Baker.

Footnotes

Conflict of Interest

The authors declare no conflict of interest.

Data Availability Statement

No datasets were generated or analyzed in the process of preparing this meeting review.

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