Novel Insights into the Autoimmunity from the Genetic Approach of the Human Disease
Adv Exp Med Biol. 2024;1444:3-18. doi: 10.1007/978-981-99-9781-7_1.ABSTRACTAutoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic inborn error of autoimmunity that is caused by damaging germline variants in the AIRE gene and clinically manifests with multiple autoimmune diseases in patients. Studies on the function of the AIRE gene, discovered in 1997, have contributed to fundamental aspects of human immunology as they have been important in understanding the basic mechanism of immune balance between self and non-self. This chapter looks back to the discovery of the AIRE gene, reviews its ma...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: P ärt Peterson Source Type: research

Learning the Autoimmune Pathogenesis Through the Study of Aire
Adv Exp Med Biol. 2024;1444:19-32. doi: 10.1007/978-981-99-9781-7_2.ABSTRACTOne of the difficulties in studying the pathogenesis of autoimmune diseases is that the disease is multifactorial involving sex, age, MHC, environment, and some genetic factors. Because deficiency of Aire, a transcriptional regulator, is an autoimmune disease caused by a single gene abnormality, Aire is an ideal research target for approaching the enigma of autoimmunity, e.g., the mechanisms underlying Aire deficiency can be studied using genetically modified animals. Nevertheless, the exact mechanisms of the breakdown of self-tolerance due to Aire...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Mitsuru Matsumoto Minoru Matsumoto Source Type: research

Extrathymic AIRE-Expressing Cells: A Historical Perspective
Adv Exp Med Biol. 2024;1444:33-49. doi: 10.1007/978-981-99-9781-7_3.ABSTRACTSince its discovery, Aire has been the topic of numerous studies in its role as a transcriptional regulator in the thymus where it promotes the "promiscuous" expression of a large repertoire of tissue-restricted antigens (TRAs) that are normally expressed only in the immune periphery. This process occurs in specialized medullary thymic epithelial cells (mTECs) and mediates the elimination of self-reactive T cells or promotes their conversion to the Foxp3+ regulatory T cell lineage, both of which are required for the prevention of autoimmunity. In r...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Dominik Filipp Jasper Manning Jana Petrusov á Source Type: research

Neoself Antigens Presented on MHC Class II Molecules in Autoimmune Diseases
Adv Exp Med Biol. 2024;1444:51-65. doi: 10.1007/978-981-99-9781-7_4.ABSTRACTMajor histocompatibility complex (MHC) class II molecules play a crucial role in immunity by presenting peptide antigens to helper T cells. Immune cells are generally tolerant to self-antigens. However, when self-tolerance is broken, immune cells attack normal tissues or cells, leading to the development of autoimmune diseases. Genome-wide association studies have shown that MHC class II is the gene most strongly associated with the risk of most autoimmune diseases. When misfolded self-antigens, called neoself antigens, are associated with MHC clas...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Hui Jin Hisashi Arase Source Type: research

Regulatory T Cells for Control of Autoimmunity
Adv Exp Med Biol. 2024;1444:67-82. doi: 10.1007/978-981-99-9781-7_5.ABSTRACTRegulatory T (Treg) cells, which specifically express the master transcription factor FoxP3, are indispensable for the maintenance of immunological self-tolerance and homeostasis. Their functional or numerical anomalies can be causative of autoimmune and other inflammatory diseases. Recent advances in the research of the cellular and molecular basis of how Treg cells develop, exert suppression, and maintain their function have enabled devising various ways for controlling physiological and pathological immune responses by targeting Treg cells. It i...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Ryoji Kawakami Shimon Sakaguchi Source Type: research

Autoinflammatory Diseases Due to Defects in Degradation or  Transport of Intracellular Proteins
Adv Exp Med Biol. 2024;1444:83-95. doi: 10.1007/978-981-99-9781-7_6.ABSTRACTThe number of human inborn errors of immunity has now gone beyond 430. The responsible gene variants themselves are apparently the cause for the disorders, but the underlying molecular or cellular mechanisms for the pathogenesis are often unclear. In order to clarify the pathogenesis, the mutant mice carrying the gene variants are apparently useful and important. Extensive analysis of those mice should contribute to the clarification of novel immunoregulatory mechanisms or development of novel therapeutic maneuvers critical not only for the rare mo...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Izumi Sasaki Takashi Kato Nobuo Kanazawa Tsuneyasu Kaisho Source Type: research

Endosomal Toll-Like Receptors as Therapeutic Targets for Autoimmune Diseases
Adv Exp Med Biol. 2024;1444:97-108. doi: 10.1007/978-981-99-9781-7_7.ABSTRACTNucleic acid (NA)-sensing Toll-like receptors (TLRs) reside in the endosomal compartment of innate immune cells, such as macrophages and dendritic cells. NAs transported to the endosomal compartment are degraded by DNases and RNases. Degradation products, including single-stranded DNA, oligoRNA, and nucleosides, are recognized by TLR7, TLR8, and TLR9 to drive the defense responses against pathogens. NA degradation influences endosomal TLR responses by generating and degrading TLR ligands. TLR ligand accumulation because of impaired NA degradation ...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Kensuke Miyake Takuma Shibata Ryutaro Fukui Yusuke Murakami Ryota Sato Ryosuke Hiranuma Source Type: research

Control of the Development, Distribution, and Function of Innate-Like Lymphocytes and Innate Lymphoid Cells by  the Tissue Microenvironment
Adv Exp Med Biol. 2024;1444:111-127. doi: 10.1007/978-981-99-9781-7_8.ABSTRACTRecently, considerable attention has been directed toward innate-like T cells (ITCs) and innate lymphoid cells (ILCs) owing to their indispensable contributions to immune responses, tissue homeostasis, and inflammation. Innate-like T cells include NKT cells, MAIT cells, and γδ T cells, whereas ILCs include NK cells, type 1 ILCs (ILC1s), type 2 ILCs (ILC2s), and type 3 ILCs (ILC3s). Many of these ITCs and ILCs are distributed to specific tissues and remain tissue-resident, while others, such as NK cells and some γδ T cells, circulate through t...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Koichi Ikuta Takuma Asahi Guangwei Cui Shinya Abe Daichi Takami Source Type: research

Necroptosis and Its Involvement in Various Diseases
Adv Exp Med Biol. 2024;1444:129-143. doi: 10.1007/978-981-99-9781-7_9.ABSTRACTNecroptosis is a regulated form of cell death involved in the development of various pathological conditions. In contrast to apoptosis, plasma membrane rupture (PMR) occurs in cells in the relatively early stage of necroptosis; therefore, necroptosis induces a strong inflammatory response. Stimuli, including tumor necrosis factor (TNF), interferon (IFN)α/β, lipopolysaccharide, polyI:C, and viral infection, induce the formation of necrosomes that lead to membrane rupture and the release of intracellular contents, termed danger-associated molecul...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Hiroyasu Nakano Source Type: research

RNA Metabolism Governs Immune Function and Response
Adv Exp Med Biol. 2024;1444:145-161. doi: 10.1007/978-981-99-9781-7_10.ABSTRACTInflammation is a complex process that protects our body from various insults such as infection, injury, and stress. Proper inflammation is beneficial to eliminate the insults and maintain organ homeostasis, however, it can become detrimental if uncontrolled. To tightly regulate inflammation, post-transcriptional mechanisms governing RNA metabolism play a crucial role in monitoring the expression of immune-related genes, such as tumor necrosis factor (TNF) and interleukin-6 (IL-6). These mechanisms involve the coordinated action of various RNA-b...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Masanori Yoshinaga Osamu Takeuchi Source Type: research

Development of Orally Ingestible IgA Antibody Drugs to Maintain Symbiosis Between Humans and Microorganisms
Adv Exp Med Biol. 2024;1444:165-176. doi: 10.1007/978-981-99-9781-7_11.ABSTRACTIn recent years, dysbiosis, abnormalities in the gut microbiota, has been reported to be associated with the development of many diseases, and improving the gut microbiota is important for health maintenance. It has been shown that the host recognizes and regulates intestinal bacteria by means of IgA antibodies secreted into the gut, but the precise nature of the commensal gut bacteria recognized by each IgA antibody is unclear. We have cloned monoclonal IgA antibodies from mouse intestinal IgA-producing cells and are searching for bacterial mol...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Reiko Shinkura Source Type: research

TCR Signals Controlling Adaptive  Immunity against Toxoplasma and Cancer
Adv Exp Med Biol. 2024;1444:177-193. doi: 10.1007/978-981-99-9781-7_12.ABSTRACTT cells play a crucial role in adaptive immunity by recognizing and eliminating foreign pathogens and abnormal cells such as cancer cells. T cell receptor (TCR), which is expressed on the surface of T cells, recognizes and binds to specific antigens presented by major histocompatibility complex (MHC) molecules on antigen-presenting cells (APCs). This activation process leads to the proliferation and differentiation of T cells, allowing them to carry out their specific immune response functions. This chapter outlines the TCR signaling pathways th...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Masaaki Okamoto Masahiro Yamamoto Source Type: research

Molecular Imaging of PD-1 Unveils Unknown Characteristics of PD-1 Itself by Visualizing "PD-1 Microclusters"
Adv Exp Med Biol. 2024;1444:197-205. doi: 10.1007/978-981-99-9781-7_13.ABSTRACTProgrammed cell death-1 (PD-1) is one of the most famous coinhibitory receptors that are expressed on effector T cells to regulate their function. The PD-1 ligands, PD-L1 and PD-L2, are expressed by various cells throughout the body at steady state and their expression was further regulated within different pathological conditions such as tumor-bearing and chronic inflammatory diseases. In recent years, immune checkpoint inhibitor (ICI) therapies with anti-PD-1 or anti-PD-L1 has become a standard treatment for various malignancies and has shown ...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Wataru Nishi Ei Wakamatsu Hiroaki Machiyama Ryohei Matsushima Yosuke Yoshida Tetsushi Nishikawa Hiroko Toyota Masae Furuhata Hitoshi Nishijima Arata Takeuchi Makoto Suzuki Tadashi Yokosuka Source Type: research

Development of Immune Cell Therapy Using T Cells Generated from Pluripotent Stem Cells
Adv Exp Med Biol. 2024;1444:207-217. doi: 10.1007/978-981-99-9781-7_14.ABSTRACTIn the field of cancer immunotherapy, the effectiveness of a method in which patient-derived T cells are genetically modified ex vivo and administered to patients has been demonstrated. However, problems remain with this method, such as (1) time-consuming, (2) costly, and (3) difficult to guarantee the quality. To overcome these barriers, strategies to regenerate T cells using iPSC technology are being pursued by several groups in the last decade. The authors have been developing a method by which specific TCR genes are introduced into iPSCs and...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Hiroshi Kawamoto Kyoko Masuda Seiji Nagano Source Type: research

Dissecting the Immune System  through Gene Regulation
Adv Exp Med Biol. 2024;1444:219-235. doi: 10.1007/978-981-99-9781-7_15.ABSTRACTThe immune system plays a dual role in human health, functioning both as a protector against pathogens and, at times, as a contributor to disease. This feature emphasizes the importance to uncover the underlying causes of its malfunctions, necessitating an in-depth analysis in both pathological and physiological conditions to better understand the immune system and immune disorders. Recent advances in scientific technology have enabled extensive investigations into gene regulation, a crucial mechanism governing cellular functionality. Studying g...
Source: Advances in Experimental Medicine and Biology - March 12, 2024 Category: Research Authors: Hideyuki Yoshida Source Type: research