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2019 CSID Abstract 2019CSID Plenary Lecture 2019 CSID Abstract 2019CSID Plenary lecture Epigenetics in autoimmue skin diseases Ming Zhao Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha Systemic Lupus Erythematosus (SLE) is an autoimmune disease in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage. T lymphocyte activation and differentiation and over-production of autoantibody and Immune complex deposits are the major immunological characters of SLE. CD4+ T effect cells play an important role in the autoimmune response. Previous studies have found that the increased Th17 cells and follicular T cells and the defect of Treg cells are involved in peripheral blood of SLE patients. According to our previous studies, these aberrantly epigenetic modifications such as DNA hypomethylation and histone hyper-acetylation contribute to the increased autoreactivity of CD4+ T cells via up- regulating some immune related genes including CD11a, Perforin, CD70 and CD40L. In recent years, some DNA methylation array and sequencing have identified DNA hypomethylation in genome-wide in lupus CD4+ T cells. However, why the epigenetic modifications were changed in lupus compared to normal. How the aberrant epigenetic modifications contribute to the over- activation of CD4+ T cells in SLE? We try to clarify the question. Our results demonstrate that RFX1 expression defect leads to IL-17A overexpression and Th17 cell differentiation via inducing the increased histone acethylation and the decreased H3K9 tri-metylation and DNA hypomethylation in promoter region of IL17A gene in CD4+ T cells of SLE patients. RFX1 deficiency promotes the pathologic changes of autoimmune diseases. This work was published in Nature communication last year. In addition, we detected the DNA methylation level of IFI44L in two cohorts from China and one cohort from European. The methylation levels of two CG Paris were detected in SLE, healthy controls and disease control including rheumatoid arthritis and primary sjogren syndrome. Through the validation in the large cohorts, we identified that the sensitivity is about 94% and the specificity is about 98% when we distinguish SLE from healthy controls using IFI44L methylation levels. Based on the novel findings, we construct a DNA methylation diagnostic kit for SLE. 1 2019CSID Plenary lecture Leprosy: an ideal model for infection, genetics and immunology Hong Liu, Zihao Mi, Zhenzhen Wang, Chuan Wang, Lele Sun, Furen Zhang Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China Leprosy, a chronic intracellular infectious skin disease, has affected humans for more than 1000 years and is a stigmatized disease even now. Due to the immune-related spectrum of clinical manifestation, leprosy is regarded as an ideal model for studying the interaction between host immune response and infection; in fact, the landscape of leprosy immune responses has been extensively investigated. Meanwhile, leprosy is to some extent a genetic disease because the genetic factors of hosts have long been considered major contributors to this disease. Many immune-related genes have been associated with leprosy. A total of 30 susceptibility genes of leprosy has been identified in Chinese population, which highlighted the crucial roles of NOD2 mediated innate immune response and Th-17-IL23-IL23R mediated adaptive immune response in the pathogenesis of leprosy. In this context, we have summarized advances in both the immunology and genetics of leprosy and present a combined analysis of immunological and genetic studies, which explain how gene variants alter the immune response against the leprosy pathogen and elucidate the molecular pathogenesis of leprosy. 2 2019CSID Plenary lecture DC-HIL is a novel immune checkpoint and a promising target for treating melanoma and other cancers P. Cruz, K. Ariizumi Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Introduction Despite the success of immune checkpoint blockers (like anti-PD1/PDL1 mAb) in improving survival of patients with melanoma and other cancers, most cases fail to benefit from this current best-treatment option. Objective To develop better immunotherapy for melanoma and other cancers. Materials & Methods DNA subtraction analyses; Knock out mice; In vitro cell assays; mAb production. Results We discovered DC-HIL (also known as Gpnmb), which exists in 2 forms: a cell-bound receptor, and a soluble factor secreted into circulation. We have shown DC-HIL to inhibit T-cell activation by binding to its ligand syndecan-4 on effector T cells. In healthy individuals, we showed DC-HIL expressed by some immune cells at very low levels. By contrast, in patients with melanoma and other cancers (including breast, colorectal, kidney, lung, prostate), DC-HIL is expressed highly by myeloid-derived suppressor cells (MDSC) that expand exponentially with progression of the malignancy. Soluble DC-HIL (sDC-HIL) is also detectable in the blood of many of these patients at levels increasing with metastasis. MDSC are the most powerful suppressors of T-cell activation, and we showed the DC-HIL receptor on MDSC to mediate this adverse function. We have generated an anti-DC-HIL mAb that in animal models can reduce melanoma growth and metastasis dramatically, as well as block the T-cell suppressor function of MDSC from patients with metastatic melanoma and other cancers. Conclusions We identified a novel immune checkpoint molecule with great promise as a therapeutic target for melanoma and other cancers. 3 2019CSID Plenary lecture Lessons from mouse models of psoriasis Hwang ST1 1Department of Dermatology, University of California, Davis, Sacramento, CA, 95817, USA. Murine models of human disease have helped further our understanding of the pathophysiology of dermatologic conditions ranging from skin cancer to psoriasis. In my laboratory, we have work with sseveral mouse models of psoriasis. To model psoriasis in mice, we have used injection of IL-23 directly into ear skin, application of topical imiquimod on skin, and, now, systemic hydrodynamic delivery of IL-23 via IL-23 minicircle DNA to induce both skin and joint changes that mimic the psoriasiform dermatitis and joint injury. The skin of IL-23 MC injected mice develop severe psoriasis-like epidermal hyperplasia and dermal inflammation as early as 5-7 days after initiation. The resulting dermatitis lasts >30 days. Years ago, we showed that CCR6 was a chemokine receptor that was abundant on Th17 cells in both mice and humans. CCR6 has been shown by us and others to be critical for the development of psoriasiform dermatitis in mice. Furthermore, in mice, CCR6 is strongly expressed by gamma-delta T cells, rendering them responsive to the chemotactic effects of its sole chemokine ligand, CCL20, that is produced by endothelial as well as keratinocytes. Remarkably, an engineered dimeric variant of the CCL20 ligand which binds to CCR6, but doesn't render chemotactic signaling, can effectively prevent both psoriasiform skin and joint signs of injury in the systemic IL-23 minicircle model at the clinical, histologic, and molecular levels. In summary, murine models of skin disease can help us identify key cells, receptors, and pathways that may also be critical in human skin diseases such as psoriasis. These models advance new therapeutic agents and concepts that may one day benefit patients. 4 2019CSID Plenary lecture Molecular Insights into the Pathogenesis of Hand, Foot and Mouth Disease: Immunity Evasion and Beyond Xiaobo Lei1, Zhendong Zhao1, Bin He2, Jianwei Wang1 1. NHC Key Laboratory of System Biology of Pathogens and Christophe Merieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; 2. Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, Illinois, USA Hand, foot, and mouth disease (HFMD), a syndrome characterized by fever with vesicular eruptions mainly on the skin of the human hands, feet, and oral cavity, has been a great public health challenge in Asia-pacific area over the past decades. HFMD primarily affects infants and children less than five years old. Although most infection is mild and self-limited, severe or even fatal neurological complications may occur in some cases. HFMD can be caused by a number of enterovirus (EV) serotypes, belonging to the Enterovirus genus of the family of Picornavirridae. The most important serotype responsible for severe cases is EV71. However, there are no licensed antivirals as the pathogenesis of HFMD remains poorly understood. The innate immunity is the first line of defense against viral infection. Our studies suggested that EVs have evolved sophisticated strategies to evade such host antiviral responses. The virus genome encoded proteases, 3C and 2A, play pivotal roles on evasion the innate immunity by cleaving or blocking multiple key factors in the innate immunity signaling pathway, which may contribute to the pathogenesis of HFMD. In addition, pyroptosis, an inflammatory form of programmed cell death also emerges as a host defense against invasive pathogenic microbiology infection. We found that EV71 infection induces pyroptosis by triggering cleavage of GSDME, an essential switch for caspase-3-mediated apoptosis
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