Cutaneous lupus erythematosus (CLE) represents a complex autoimmune disease with a broad phenotypic spectrum ranging from acute to chronic destructive cutaneous lesions. Patients with CLE exhibit high photosensitivity and ultraviolet (UV) irradiation can lead to systemic flares in systemic lupus erythematosus. However, the exact mechanisms how UV irradiation enhances cutaneous inflammation in lupus are not fully understood. Recently, new molecular mechanisms of UV-driven immune responses in CLE were identified, offering potential therapeutic approaches. Especially the induction of type I interferons, central cytokines in lupus pathogenesis which are released by various skin cells, have become the focus of current research. In this review, we describe current pathogenic concepts of photosensitivity in lupus erythematosus, including UV-driven activation of intracellular nucleic acid sensors, cellular cytokine production and immune cell activation. Furthermore, we discuss activated pathways contributing to enhanced apoptosis as well as intracellular translocation of autoantigens thereby promoting CLE upon UV light exposure.

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23783号 / 医博第4829号 / 新制||医||1057(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中山 健夫, 教授 上野 英樹, 教授 金子 新 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p>Measurement of human tactile spatial acuity – the ability to perceive the</p> <p>fine spatial structure of surfaces contacting our fingertips – provides a valuable</p> <p>tool for probing both the peripheral and central nervous system. However,</p> <p>measures of tactile spatial acuity have long been plagued by a prodigious amount</p> <p>of variability present between individuals in their sense of touch. Previously</p> <p>proposed sources of variability include sex, and age; here we propose a novel</p> <p>source of variability – fingertip size. Building upon anatomical research, we</p> <p>hypothesize that mechanoreceptors are more sparsely distributed in larger fingers.</p> <p>In this thesis, I provide empirical and theoretical support for the hypothesis</p> <p>that fingertip growth from childhood into adulthood sets up an apparent sex</p> <p>difference in human tactile spatial acuity during young adulthood (Chapter 2), and</p> <p>also predicts changes in acuity more strongly than does age over development</p> <p>(Chapter 3). To further understand how fingertip size could limit an individual's</p> <p>tactile spatial acuity, we develop an ideal observer model using</p> <p>neurophysiological data collected by other labs (Chapter 4).</p> <p>In summary, this research provides support for a novel source of variability</p> <p>in the sense of touch: one that parsimoniously explains an apparent sex difference,</p> <p>and helps clarify the source of changes in tactile spatial acuity occurring with age</p> <p>during childhood.</p> / Doctor of Philosophy (PhD)

Chronic itch has a significant impact on quality of life for millions of patients worldwide, on a level comparable to that of chronic pain. Yet, although there are a host of effective drugs available for pain, there are no therapies that specifically target chronic itch. Current experimental approaches to investigate the pathogenesis of chronic pruritus and to test novel therapeutic agents are largely limited to rodent models. However, rodent models display significant dermatological, neurophysiological, and immunological differences from humans with chronic itch. The disadvantages of the current rodent paradigms call for the design of a valid primate model of chronic itch. For four years, we have monitored scratching behavior in a primate colony (n=35) of Cynomolgus macaques (Macaca fascicularis) suffering from idiopathic chronic itch. By comparing molecular and genetic analyses of the primates’ skin to their quantified scratching behavior, we attempted to characterize the underlying mechanisms of chronic itch in this model. Furthermore, the expression of itch-related proteins was examined in both the primate model and in humans with pruritic diseases. The first aim of the study was to characterize the underlying molecular and genetic basis of chronic itch in the primate model. We were able to distinguish specific peripheral targets related to pruritus by correlating the genetic and protein expression results to the primates’ scratching severity. In Aim 1a, RNA-sequencing was performed on skin biopsies from the primates to identify differentially expressed genes in pruritic, lichenified versus non-pruritic, non-lichenified skin. These results were then correlated to the quantified primate scratching behavior. This led to the identification of over 400 genes that were differentially expressed in the skin based on scratching intensity. Many of these differentially expressed transcripts were associated with sensory nerve fibers, keratinocytes, mast cells, or lymphocytes. Selected genes that were overexpressed and correlated to itch intensity were then targeted for immunohistochemical and proteomic analysis in Aim 1b. Immunohistochemical examination of the primate skin biopsies revealed that histamine levels were not elevated in primates that exhibited increased scratching behavior. However, mast cells containing tryptase were significantly increased in the skin of primates with severe scratching as compared to primates with mild scratching. The increased levels of gastrin-releasing peptide and substance P in lichenified skin were also found to be correlated to the primates’ scratching behavior. Of note, transient receptor potential channels V1, V3, and A1 were increased in the epidermis of primate skin, but the numbers of TRPV1+ and TRPA1+ nerve fibers were not significantly different between lichenified and non-lichenified skin. Transcriptome analysis of the opioid receptors and their ligands showed that primates with severe scratching behavior had a significant imbalance between the µ- and κ-opioid receptors and ligands. The µ-opioids had upregulated gene expression, while the κ-opioids were downregulated. In Aim 2, to further characterize this primate model of chronic itch, we compared immunohistochemical results from the primate studies to human findings. Lesional and non-lesional skin biopsies from patients with atopic dermatitis, psoriasis, and cutaneous T-cell lymphoma underwent immunohistochemical analysis in order to reveal the similarities and differences between the primate model and different types of chronic itch in humans. As in the primate model, substance P was found to be increased in the skin of lesional atopic and psoriasis skin. Additionally, similar to primate skin, human atopic and psoriatic skin had high levels of tryptase and its receptor in the epidermis. While IL-31 was only slightly elevated in primates, patients with cutaneous T-cell lymphoma or atopic dermatitis showed a significant correlation between itch severity and IL-31 levels. In conclusion, our primate model displayed expression patterns of many endogenous pruritogens and receptors that were similar to those of humans with atopic dermatitis or psoriasis. While the primate model did not completely mimic these specific pruritic diseases, the overlap of pruritic components suggests a commonality of signaling pathways across several different chronic itch states. The similarity of this primate model to human disease offers the combined advantages of experimental modeling and long-term behavioral follow-up. / Biomedical Sciences

Throughout gestation, the blood vessel network of the placenta is formed sequentially by processes known as vasculogenesis and angiogenesis, which together meet the needs of the growing fetus. Normal placental angiogenesis is critical to support adequate fetal growth and assure the health of the offspring. Proper angiogenesis requires precise regulation of expression of agents that modulate this process; otherwise, pathologies of pregnancy such as preeclampsia may occur. The placenta is composed of different layers of tissue, including the lamellar (LZ), junctional, and glandular zones, each with a vascular morphology attuned to its function. We hypothesized that higher expression of pro-angiogenic factors is associated with increased morphological metrics in the LZ, the major vascularized zone. Thus, we aimed to characterize the major changes in morphology and vascular development in the placenta throughout pregnancy in cats, alongside a compressive analysis of the expression of major angiogenic factors and their receptors in the placenta, with an emphasis on the identification and interaction of different isoforms of the VEGF family. Microscopic analysis of tissue specimens from different stages of pregnancy revealed increased thickness of the LZ, especially during early to mid-gestation, at which time the tissue is composed of abundant materno-fetal interdigitations that appears rich in capillaries. VEGF proteins were detected in placental tissue in both fetal and maternal cells of the placenta, suggesting stimulatory interactions between different cell types to promote growth and angiogenesis. Gene expression analysis of placenta revealed upregulation of the pro-angiogenic factor VEGF-A in mid-pregnancy, followed by a steady decline toward term, consistent with morphologic changes in the LZ. In contrast, another pro-angiogenic factor, PlGF, showed a marked increase toward term; Flt-1, which acts as a receptor or reservoir for PLGF and VEGF A, was also upregulated at late pregnancy. Increased ratios of PLGF:VEGF-A may contribute to LZ proliferation in the last trimester. These findings are consistent with the creation of a proangiogenic placental state during gestation. Overall, we expect that this research will help elucidate mechanisms of placental vascularization, which can be applied to the design of improved strategies to treat vascular complications of pregnancy. Lastly, we applied the tools developed for placental studies to investigate pathologic angiogenesis in cutaneous squamous cell carcinoma (CSCC), a common skin cancer with major economic and medical impacts in humans and veterinary species. The creation of a new blood supply is essential for growth and metastasis of many tumor types. The goal of this study was to measure expression of variants of proteins that stimulate angiogenesis or transmit an angiogenic stimulus in feline CSCC. The results were mixed, with differences detected in expression of some regulatory agents and, for others, unexpectedly lower expression in CSSC compared to controls. Interestingly, the expression of VEGF-A relative to the protein that transmits its signal (KDR) was elevated in CSCC, suggestive of an altered signaling relationship. This finding supports our hypothesis and is consistent with human SCC studies. Our results encourage further studies on angiogenic factor variants in feline CSCC. / PHD