Basic Immunology and Its Clinical Application (Advances in Experimental Medicine and Biology, 1444)

Preface
Contents
Part I: From the Bench to the Bedside
	1: Novel Insights into the Autoimmunity from the Genetic Approach of the Human Disease
		1.1	 Introduction
		1.2	 The Identification of the AIRE Gene
		1.3	 AIRE Has Domains Characteristic of the Transcriptional Regulator
		1.4	 AIRE Has a Unique Role in Guarding Self-Tolerance
		1.5	 APECED Starts Early in Childhood and Is Heterogenic
		1.6	 AIRE Mutations: Expanding Universe
		1.7	 Autoantibodies to Intracellular Enzymes
		1.8	 Autoantibodies to Cytokines Add Another Puzzle to the Tolerance Paradigm
		1.9	 Do We Have a Full Understanding of How AIRE Regulates Immune Tolerance?
		References
	2: Learning the Autoimmune Pathogenesis Through the Study of Aire
		2.1	 Introduction
		2.2	 Animal Models of Aire Deficiency
		2.3	 Molecular Biology of Aire
		2.4	 Aire Controls the Differentiation Program of mTECs
		2.5	 The Tolerogenic Function of Aire
		2.6	 Single-Cell Approach for the Understanding of Aire
		2.7	 The Unique Role of Aire Achieved Only in mTECs
		2.8	 Adverse Effect of Aire in Tolerance Induction
		2.9	 Post-Aire mTECs
		2.10	 Aire Outside the Thymus
		2.11	 Beyond the Autoimmunity
		2.12	 Concluding Remarks
		References
	3: Extrathymic AIRE-Expressing Cells: A Historical Perspective
		3.1	 APECED, Aire and Immune Tolerance
		3.2	 Extrathymic Aire Expression
		3.3	 Stage 1. Classical Biochemistry Tools for Aire Expression (1997–2010)
		3.4	 Stage 2. The Hunt for Aire-Expressing Cells by Transgenics (2008–Present)
		3.5	 Stage 3. Rethinking eTACs: Implementation of scRNAseq (2021–Present)
		3.6	 Is There a Non-immune Role of Extrathymic Aire?
		3.7	 Role of Extrathymic AIRE: TRA Transcription Model Versus Maturation Model
		3.8	 Conclusions
		References
	4: Neoself Antigens Presented on MHC Class II Molecules in Autoimmune Diseases
		4.1	 Introduction
		4.2	 Presentation of Neoself Antigens by Aberrant Expression of MHC Class II Molecules
		4.3	 Neoself Antigens Presented on MHC Class II Molecules Are Targets of Autoantibodies
		4.4	 Presentation of Neoself Antigens by MHC Class II Molecule Is Associated with the Risk of Autoimmune Diseases
		4.5	 Mechanism of Autoantibody Production Through Neoself Antigen Presented on MHC Class II Molecules
		4.6	 Conclusions
		References
	5: Regulatory T Cells for Control of Autoimmunity
		5.1	 Treg Cells in Immunological Self-Tolerance and Their Anomalies as a Cause of Autoimmune Disease
		5.2	 Mechanisms of Treg-Mediated Immune Suppression
		5.3	 Functional Adaptation and Maintenance of Treg Cells
		5.4	 Development of Treg Cells
			5.4.1	 Treg Development in the Thymus
			5.4.2	 Treg Development in the Periphery
		5.5	 Therapeutic Application of Treg Cells for Autoimmune Diseases
			5.5.1	 In Vivo Expansion of nTreg Cells by Low-Dose IL-2 or IL-2 Muteins
			5.5.2	 Adoptive Cell Therapy (ACT) with Treg Cells
			5.5.3	 CAR (Chimeric Antigen Receptor)-Treg Cells for ACT
		5.6	 Concluding Remark
		References
	6: Autoinflammatory Diseases Due to Defects in Degradation or Transport of Intracellular Proteins
		6.1	 Introduction
		6.2	 Autoinflammatory Disease
		6.3	 Proteasome-Associated Autoinflammatory Syndrome
		6.4	 Phenotype of Proteasome Subunit-Deficient Mice
		6.5	 Proteasome-Associated Autoinflammatory Syndrome with Immunodeficiency
		6.6	 COPA Syndrome
		6.7	 COPA Syndrome Model Mice
		6.8	 SAVI Model Mice
		6.9	 Summary
		References
	7: Endosomal Toll-Like Receptors as Therapeutic Targets for Autoimmune Diseases
		7.1	 Introduction
		7.2	 NA Metabolism in the Endosomal Compartments
		7.3	 Endosomal TLR Ligands Are Produced Through NA Metabolism
		7.4	 Lysosomal DNA Stress Induces Constitutive TLR Activation
		7.5	 Diseases Caused by Lysosomal RNA Stress
		7.6	 Diseases Caused by Lysosomal Nucleoside Stress
		7.7	 TLR7 Stress Responses and TLR7 Inflammatory Responses
		7.8	 Mitochondrial Damage Causes Lysosomal NA Stress
		7.9	 SLE and TLR7/8
		7.10	 SLE Susceptibility Genes That Activate Endosomal TLRs
		7.11	 Conclusion
		References
Part II: Manipulating the Immune System
	8: Control of the Development, Distribution, and Function of Innate-Like Lymphocytes and Innate Lymphoid Cells by the Tissue Microenvironment
		8.1	 NKT Cells
			8.1.1	 Developmental Stages of NKT Cells
			8.1.2	 Differentiation of NKT Subsets in the Periphery
			8.1.3	 The Heterogeneity and Tissue Residency of Peripheral NKT Cells
			8.1.4	 The Heterogeneity of iNKT1 Cells
		8.2	 ILC1s
			8.2.1	 ILC1s and NK Cells: Distinct Subsets in ILCs
			8.2.2	 ILC1 Heterogeneity Between and Within Tissues
			8.2.3	 Environmental Cues Controlling ILC1 Function and Heterogeneity in Tissues
				8.2.3.1	 IL-15
				8.2.3.2	 Transforming Growth Factor-β (TGF-β)
				8.2.3.3	 IL-12
				8.2.3.4	 Retinoic Acid (RA)
				8.2.3.5	 Other Endogenous and Exogenous Factors in Diseases
			8.2.4	 Future Perspectives on ILC1s
		8.3	 NK Cells
			8.3.1	 Bone Marrow Microenvironment for NK Cell Development
			8.3.2	 Environmental Factors Controlling NK Cell Retention in the Bone Marrow
		8.4	 ILC2s
			8.4.1	 Distribution of Lung ILC2s Under Normal Conditions and in Inflammation
			8.4.2	 Mobilization of ILC2s from Other Tissues to the Lung During Inflammation
		8.5	 Conclusion
		References
	9: Necroptosis and Its Involvement in Various Diseases
		9.1	 Signaling Pathways to Necroptosis
		9.2	 Plasma Membrane Rupture (PMR) Is a Regulated Process
			9.2.1	 Effector Molecules Involved in the Release of PMR
			9.2.2	 Regulation of the Release of DAMPs
			9.2.3	 Imaging of Live Cells Undergoing Necroptosis In Vitro and In Vivo
			9.2.4	 Live Cell Imaging for Secretion Activity (LCI-S)
		9.3	 RIPK1 Plays Dual Roles That Promote Both Cell Death and Cell Survival
		9.4	 Involvement of Necroptosis in Various Diseases
			9.4.1	 Inflammatory Bowel Diseases
			9.4.2	 Dermatitis
			9.4.3	 Hepatitis
			9.4.4	 Neurological Diseases
			9.4.5	 Cisplatin-Induced Kidney Injury
			9.4.6	 Cancers
			9.4.7	 Viral Infection
		9.5	 Hereditary Diseases Associated with Necroptosis
			9.5.1	 Loss-of-Function and Toxic Gain-of-Function Mutations of RIPK1
			9.5.2	 Toxic Gain-of-Function Mutations in MLKL
			9.5.3	 Mutations in ADAR1
		9.6	 Development of Drugs to Target Necroptosis
		References
	10: RNA Metabolism Governs Immune Function and Response
		10.1	 Introduction
		10.2	 mRNAs Are Degraded by Multiple mRNA Decay Pathways
		10.3	 Inflammation-Related mRNAs Harbor Multiple Motifs to Be Recognized by RBPs
		10.4	 RBPs Govern mRNA Metabolism to Control Immune Cell Development and Functions
			10.4.1	 ARE-Binding Proteins Regulate Immune Cell Development and Functions
			10.4.2	 Roquin Destabilizes Immune-Related mRNAs to Control the Adaptive Immune Response
			10.4.3	 Regnase-1-Mediated Regulation of mRNAs Containing Stem-Loop Elements
			10.4.4	 Regnase-1-Related Endonucleases Regulate Immune Reactions
			10.4.5	 Arid5a Promotes the Expression of Immune-Related Genes via Post-transcriptional Mechanisms
		10.5	 RNA Modification Is a Novel Mechanism for Controlling RNA Metabolism in the Immune System
			10.5.1	 RNA m6A Methylation: Writers, Readers, and Erasers
			10.5.2	 The Roles of m6A in Innate Immune Response and Signaling
			10.5.3	 The Roles of m6A in Adaptive Immune Response
		10.6	 Future Perspectives
		References
Part III: Coopting with Microorganisms
	11: Development of Orally Ingestible IgA Antibody Drugs to Maintain Symbiosis Between Humans and Microorganisms
		11.1	 Introduction
		11.2	 Production of Intestinal IgA Antibodies
		11.3	 Functions of Intestinal IgA
		11.4	 The Significance of Somatic Hypermutation (SHM) in Immunoglobulin Genes in the Homeostasis of Intestinal Immunity
		11.5	 Disruption of Gut Homeostasis in Mice with Impaired SHM
		11.6	 Poly-reactive IgA Is Important in Protection Against Cholera Toxin
		11.7	 The Quality as well as the Quantity of IgA Antibodies Is Important for the Control of Intestinal Bacterial Flora in Human
		11.8	 Intestinal Monoclonal IgA Is Poly-reactive
		11.9	 Analysis of Gut-Derived Monoclonal IgA Antibodies Reacting with Normal Intestinal Flora
		11.10	 Poly-reactive W27 Antibody Recognizes a Bacterial Metabolic Enzyme
		11.11	 Growth Inhibition of Bound Bacteria by the W27 IgA Antibody
		11.12	 Improvement of Dysbiosis and Pathology in Mice by Oral Administration of W27 Antibody
		11.13	 Conclusion
		References
	12: TCR Signals Controlling Adaptive Immunity against Toxoplasma and Cancer
		12.1	 Introduction
		12.2	 TCR Signaling Common to T Cells
			12.2.1	 TCR Signaling Cascade
				12.2.1.1	 DAG Activates PKCθ, Leading to NF-κB Activation
				12.2.1.2	 DAG and Ca2+ Activate RasGRP and MAPK Cascade to Form AP-1
				12.2.1.3	 Ca2+ Indirectly Activates NFAT
			12.2.2	 Co-stimulatory Receptor Signaling
			12.2.3	 Inhibitory Receptor Signaling
				12.2.3.1	 PD-1
				12.2.3.2	 CTLA4
				12.2.3.3	 LAG3
		12.3	 TCR Signaling Specific to CD8+ T Cells
			12.3.1	 Presumption of Distinct TCR Signal in CD8+ T Cells
			12.3.2	 PLCβ4, a Key Mediator of CD8+ T Cell-Specific TCR Signaling
			12.3.3	 TCR Signaling Pathway Involving PLCβ4
			12.3.4	 PLCβ4-Mediated CD8+ T Cell Activation in Toxoplasmosis and Cancer
				12.3.4.1	 Toxoplasmosis
				12.3.4.2	 Cancer
		12.4	 TCR Signaling in Toxoplasmosis and Tumor Immunity
			12.4.1	 TCR Signaling in Toxoplasmosis
			12.4.2	 TCR-Based Therapeutic Applications for Cancer
		12.5	 Concluding Remarks
		References
Part IV: Novel Methodologies for the New Era of Immunology
	13: Molecular Imaging of PD-1 Unveils Unknown Characteristics of PD-1 Itself by Visualizing “PD-1 Microclusters”
		13.1	 Background of PD-1 and Its Ligands, PD-L1 and PD-L2
		13.2	 PD-1 Signaling
		13.3	 Immune Checkpoint Inhibitors Interfering PD-1-PD-L1 Binding
		13.4	 Imaging of PD-1 Microclusters
		References
	14: Development of Immune Cell Therapy Using T Cells Generated from Pluripotent Stem Cells
		14.1	 Introduction
		14.2	 Cloning and Expansion of T Cells Using Reprogramming Techniques
		14.3	 Strategies for Allogenic Transplantation: TCR Gene Transfer Method and Versatile iPSC Lines
		14.4	 Background of the Strategy to Target WT1 Antigen
		14.5	 Regeneration of Killer T Cells Expressing WT1 Antigen-Specific TCR and Establishment of a Therapeutic Model
		14.6	 Toward Clinical Trials
		14.7	 Application to Viral Infections
		14.8	 Current Strategies Using Other Cell Types
			14.8.1	 NKT Cells
			14.8.2	 MAIT Cells
			14.8.3	 γδ T Cells
			14.8.4	 CAR-T Cells and CAR-NK Cells
			14.8.5	 Myeloid Cells to Be Used as Antigen-Presenting Cells
		14.9	 Perspective
		References
	15: Dissecting the Immune System through Gene Regulation
		15.1	 Introduction
		15.2	 Regulation of Gene Expression
		15.3	 Methods for Dissecting Gene Regulation and Expression
		15.4	 Genetics and Genomics: The Beginnings
		15.5	 Genetics and Genomics: Remarkable Advancements
		15.6	 Genetics and Genomics: Advances in GWAS
		15.7	 Genetics and Genomics: NGS and SNV
		15.8	 Genetics and Genomics: Understanding Immune Disorders
		15.9	 Genetics and Genomics: Recognizing Limitations
		15.10	 Transcriptomics: Historical Perspective
		15.11	 Transcriptomics: The Evolution of Microarrays
		15.12	 Transcriptomics: Insights from Differentially Expressed Genes
		15.13	 Transcriptomics: Applications in Immune Disorders
		15.14	 Transcriptomics: Advent and Advantages of RNA-Seq
		15.15	 Transcriptomics: Advancing Beyond DEGs
		15.16	 Transcriptomics: eQTL
		15.17	 Epigenomics: An Overview
		15.18	 Epigenomics: Mechanisms of Epigenetic Regulation
		15.19	 Epigenomics: Chromatin Accessibility
		15.20	 Epigenomics: Impact on Immunological Disorders
		15.21	 Single-Cell Analysis: Traditional Methods
		15.22	 Single-Cell Analysis: Advancements in Single-Cell Omics
		15.23	 Single-Cell Analysis: Refining the Definition of Cell Populations
		15.24	 Immune Cells as a Model for Studying Gene Regulation
		15.25	 Future Perspectives
		References
	16: HLA Genetics for the Human Diseases
		16.1	 Introduction
		16.2	 Characteristics of the HLA Genomic Region
			16.2.1	 Gene Numbers in the HLA Region
			16.2.2	 Transposable Elements
			16.2.3	 Structural Diversity of Major HLA Haplotypes
		16.3	 Characteristics of HLA Polymorphisms
			16.3.1	 Developmental History of HLA DNA Typing Methods
			16.3.2	 HLA Allele Numbers
			16.3.3	 Worldwide Population Variation of HLA Allele and Haplotype Frequencies
			16.3.4	 Importance of the NGS-HLA Typing for Improving Transplant Outcome
		16.4	 Association of the HLA Alleles with Diseases
			16.4.1	 Overview of HLA-Associated Diseases
			16.4.2	 HLA Association Study by Subdivision for Disease Types in Idiopathic Inflammatory Myopathy
		16.5	 Association of the HLA Allele Expression with Diseases
			16.5.1	 Effect of Regulation of the HLA Expression
			16.5.2	 HLA Allele-Level Expression and Disease Susceptibility
		16.6	 HLA Loss in Cancer
		16.7	 Conclusion
		References