Damage-Associated Molecular Patterns in Human Diseases: Volume 3: Antigen-Related Disorders

Foreword I
Foreword II
Preface
Acknowledgments
Contents
Abbreviations
Part I: Prologue
1: Perspectives of the Danger/Injury Model of Immunology as Applied to Antigen-Related Human Disorders
1.1 Introduction
1.1.1 The Danger/Injury Model of Immunology
1.1.2 DAMPs in Their Role as Friend and Foe
1.1.3 The Four Described Antigen-Related Disorders in Light of the Action of DAMPs
1.2 Classification of DAMPs: An Update
1.2.1 Introductory Remarks
1.2.2 Endogenous Constitutively Expressed DAMPs (Cat. I DAMPs)
1.2.2.1 Constitutively Expressed Native DAMPs, Passively Released from Necrotic Cells (IA DAMPs)
1.2.2.2 Constitutive DAMPs, Exposed at the Cell Surface of Stressed or Dying Cells (Cat. IB DAMPs)
1.2.3 Endogenous Constitutively Expressed Injury-Modified Molecules (Cat. II DAMPs)
1.2.3.1 Cell-Intrinsic Modified Molecules (IIC DAMPs)
Accumulation, Dislocation, and Translocation of Nucleic Acids
Intracellular Endogenous Host Nucleic Acids and Exogenous Bacterial/Viral Nucleic Acids: Is There a Difference for Cells of the Innate Immune System?
Intracellular Endogenous DNA and Exogenous Bacterial/Viral DNA
Intracellular Endogenous RNA and Exogenous Bacterial/Viral RNA
Conclusion
Intracellular Dyshomeostasis-Associated Molecular Patterns
1.2.4 Endogenous Inducible DAMPs (Cat. III DAMPs)
1.2.4.1 Native Molecules Operating as Inducible DAMPs (IIIA DAMPs)
1.2.4.2 Modified Molecules Operating as Inducible DAMPs (IIIB DAMPs)
1.2.4.3 Native Molecules Operating as Inducible Suppressing DAMPs (IIIC DAMPs)
1.2.4.4 Humoral Pattern Recognition Molecules Operating as Inducible DAMPs or SAMPs (IIID DAMPs)
1.2.4.5 Damage-Associated Molecules Operating Context-Dependently as SAMPs or DAMPs
1.2.5 Exogenous DAMPs (Cat. IV DAMPs)
1.2.5.1 Viral Vector-Based Vaccines
1.2.5.2 Nucleic Acid Vaccines
DNA Vaccines
RNA Vaccines
1.2.5.3 Nanoparticles
1.2.5.4 Airborne Particulate Matter
1.2.6 Résumé
1.3 Some Principles of the Action of DAMPs in Shaping Antigen-Related Disorders
1.3.1 Emission of Three Signals by Activated Antigen-Presenting Cells
1.3.2 History of Costimulation: The Signal 2
1.3.3 The Concept of DAMP-Promoted Activation of APCs
1.4 Cytotoxic T Lymphocyte- and Antibody-Driven Induction of Regulated Cell Death Leading to Emission of DAMPs: “The Adaptive Immune System Calls in the Cavalry”
1.4.1 Introductory Remarks
1.4.2 Antibodies
1.4.3 Cytotoxic CD8+ T Lymphocytes
1.4.4 Cytotoxic B Lymphocytes
1.4.5 The Hypothetical Model of a DAMP-Driven Positive Feed-Forward Loop in Adaptive Immune Responses
1.5 DAMPs and SAMPs in Diagnosis and Prognosis
1.5.1 Introductory Remarks
1.5.2 DAMPs and SAMPs as Prognostic and Predictive Biomarkers
1.5.3 Résumé
1.6 Use of DAMPs and SAMPs as Therapeutic Targets or Therapeutics
1.6.1 Introductory Remarks
1.6.2 DAMPs and SAMPs as Therapeutic Targets
1.6.3 SAMPs as Therapeutics in Chronic Inflammatory Processes
1.6.4 DAMPs as Therapeutics to Boost Innate Resistance
1.6.4.1 General Remarks
1.6.4.2 Administration of DAMPs in Vaccination Procedures
1.6.4.3 Induction of DAMPs in Antitumor Therapy
1.6.4.4 Concluding Remark
1.6.5 Résumé
References
Part II: Infections
2: Infectious Agents: From the Red Queen Paradigm to Some of Their Genuine Traits
2.1 Introduction
2.2 To Start with Some Infection Enigmas
2.3 Pathogenetic Actions on the Side of the Infectious Agent: The Capacity of a Pathogen to Induce DAMPs in the Host as a Conceptual Definition of Virulence
2.3.1 Pathogenicity and Virulence in Light of Major Paradigms in Microbiology and Immunology
2.3.2 Concepts of Pathogenicity and Virulence as a Consequence of Infectious Agent-Induced Damage to Host Cells: A Unifying Approach?
2.3.3 The Role of Virulence Factors: Serving the Fitness of Pathogens but, Simultaneously, Evoking DAMP-Promoted Host Defense Responses
2.3.4 Some Thoughts on the Evolutionary Role of DAMPs and Innate Immune Recognition Receptors
2.3.5 The Red Queen Paradigm
2.4 Pathogenetic Actions on the Side of the Host: Quality and Quantity of Innate/Adaptive Immune Defense Responses to Infectious Agent-Induced Damage
2.5 The Pathogenesis of Infectious Diseases: A Brief Synopsis Ahead
2.5.1 Introductory Remarks
2.5.2 The Early Begin of the Disease: Recognition of Pathogens and the Harm They Induce
2.5.3 Infectious Diseases as Clinical Manifestation of the Innate Immune Defense Program of the Host Against the Pathogenic Invaders
2.5.4 Model Integration of DAMPs and SAMPs in Regulated and Dysregulated Inflammatory Defense Responses Determining the Pattern of Infectious Diseases
2.5.5 Résumé
2.6 Some Characteristics of Bacteria
2.6.1 Introductory Remarks
2.6.2 Only a Brief Excerpt from the Fascinating History of Microbiology
2.6.3 The Continuous Fight Against Pathogenic Members of the Immense Bacterial World
2.6.4 Structure of Bacteria
2.6.5 Bacterial Taxonomy
2.6.5.1 General Remarks
2.6.5.2 Phenotypic Classification of Bacteria
2.6.5.3 Genotypic Classification of Bacteria
2.6.5.4 Concluding Remarks
2.6.6 Bacterial Cell Division
2.6.6.1 General Remarks
2.6.6.2 Principles of Bacterial DNA Replication
2.6.6.3 Extracellular and Intracellular Bacterial Replication: The Cradle of DAMPs Emission
2.7 Some Characteristics of Viruses
2.7.1 A Few Historical Remarks
2.7.2 Viral Infections: From a Simple Common Cold to Fatal Sepsis
2.7.3 Some Features of Viruses
2.7.4 Structure and Taxonomy of Viruses (in Brief)
2.7.4.1 General Remarks
2.7.4.2 The Infectious Particle: Viral Genome and Associated Proteins
2.7.4.3 The Baltimore Classification Scheme
2.7.4.4 Concluding Remarks
2.7.5 Replication Cycle of Viruses: The Seed for the Generation of DAMPs
2.7.5.1 General Remarks
2.7.5.2 Attachment → Penetration/Fusion → Uncoating
2.7.5.3 Replication Strategies of DNA Viruses
BCI, Double-Stranded DNA Viruses
BCII, Single-Stranded DNA Viruses
2.7.5.4 Replication Strategies of RNA Viruses
BCIV, Negative-Sense Single-Stranded RNA Viruses
BCIV, Positive-Sense Single-Stranded RNA Viruses
2.7.5.5 Assembly, Maturation, and Release
2.7.5.6 Life Cycle of the SARS-CoV-2 (here, Delta Variant)
Attachment → Penetration/Fusion → Uncoating of SARS-CoV-2
Replication, Maturation, and Egress of SARS-CoV-2
2.7.5.7 Concluding Remarks
2.8 Fungal Infections
2.8.1 Introductory Remarks
2.8.2 Structure of Fungi
2.8.3 Classification of Fungi
2.8.4 Reproduction of Fungi
2.9 Parasitic Infections
2.9.1 Introductory Remarks
2.9.2 Protozoans
2.9.2.1 General Remarks
2.9.2.2 Structure and Classification
2.9.2.3 Life Cycle Stages and Reproduction
2.9.3 Helminths
2.9.3.1 General Remarks
2.9.3.2 Structure and Classification
2.9.3.3 Life Cycle Stages and Reproduction
2.10 Outlook
References
3: Virulence of Pathogens and the Counteracting Responses of the Host
3.1 Introduction
3.2 Bacterial Virulence
3.2.1 Introductory Remarks
3.2.2 Nondamaging Bacterial Virulence Factors Paving the Way to Induce Injury
3.2.2.1 General Remarks
3.2.2.2 Bacterial Adherence and Host Colonization
3.2.2.3 Biofilm Formation
3.2.2.4 Capsules
3.2.2.5 Concluding Remarks
3.2.3 Indirectly Damaging Bacterial Virulence Factors
3.2.3.1 General Remarks
3.2.3.2 RNA-Dependent Regulation of Bacterial Virulence
3.2.3.3 Siderophores: Molecules Damaging Host Cells by Iron Deprivation
3.2.3.4 Secretion Systems Contributing to Bacterial Virulence
3.2.3.5 Bacterial Extracellular Membrane Vesicles Encapsulating Virulence Factors
3.2.3.6 Concluding Remarks
3.2.4 Directly Damaging Bacterial Virulence Factors of Extracellular Bacteria
3.2.4.1 General Remarks
3.2.4.2 Bacterial Exotoxins
Pore-Forming Toxins: Sophisticated and Largely Spread Virulence Factors Causing Cell Disruption
AB Toxins Causing Stress Responses and Cell Death
Bacterial Effector Proteins Causing Intracellular Dyshomeostasis and Regulated Cell Death
Receptor-Triggered Intracellular Signaling Leading to Cellular Dyshomeostasis
3.2.4.3 Bacterial Endotoxins
3.2.4.4 Concluding Remarks
3.2.5 Intracellular Bacteria: Production of Indirectly and Directly Damaging Virulence Factors
3.2.5.1 General Remarks
3.2.5.2 Production of Virulence Factors by Bacteria Inside Nonphagocytic Cells
3.2.5.3 Production of Virulence Factors by Bacteria Inside Phagocytes
3.2.5.4 Concluding Remarks
3.2.6 Mechanisms of Bacteria to Subvert Host Defense Responses
3.2.7 Résumé
3.3 Viral Virulence
3.3.1 The Virulence Program of Viruses
3.3.2 Virulence Factors in Terms of Molecular Perturbations in Viral Replication Cycle
3.3.3 Viroporins: A Peculiar Viral Virulence Factor
3.3.4 Virulence Secondary to Viral Invasion: Mechanisms to Subvert Host Defense Responses
3.3.5 Résumé
3.4 Fungal Virulence
3.4.1 Introductory Remarks
3.4.2 Host Membrane Distension and Disruption by Mechanical Forces
3.4.3 Fungal Toxins
3.4.4 Fungal Extracellular Vesicles
3.4.5 Résumé
3.5 Parasitic Virulence
3.5.1 Protozoan Virulence
3.5.2 Helminthic Virulence
3.6 Cell-Autonomous Stress Responses During Infections
3.6.1 Introductory Remarks
3.6.2 Extracellular Vesicle Formation upon Pathogen-Mediated Cell Stress
3.6.3 Autophagy in Defense Against Pathogens
3.6.3.1 General Remarks
3.6.3.2 Xenophagy of Intracellular Bacteria and Viruses
3.6.3.3 Concluding Remarks
3.6.4 Oxidative Stress and Antioxidative Stress Responses
3.6.5 The Heat Shock Response
3.6.6 Endoplasmic Reticulum Stress and the Unfolded Protein Response
3.6.6.1 General Remarks
3.6.6.2 Dyshomeostatic DAMP-Triggered Pro-Death Pathways of the Unfolded Protein Response
3.6.6.3 Bacterium-Induced ER Stress→Unfolded Protein Response
3.6.6.4 Virus-Induced ER Stress→Unfolded Protein Response
3.6.6.5 The Integrated Stress Response
3.6.7 DNA Damage Response
3.6.7.1 General Remarks
3.6.7.2 Activation of the DNA Damage Response by Infections
Viral Activation of the DDR
Bacterial Activation of the DDR
3.6.7.3 Concluding Remarks
3.6.8 Résumé
3.7 Regulated Cell Death as Prolific Sources of DAMPs: A Powerful Host Defense Program Against Infection
3.7.1 Introductory Remarks
3.7.2 Subroutines of Regulated Cell Death
3.7.3 Apoptosis→Secondary Necrosis: The Failure to Clear a Dying Cell
3.7.4 Necroptosis: A Cellular Suicide for Host Defense
3.7.4.1 General Remarks
3.7.4.2 Activation of the Necroptotic Program and Cell Lysis
3.7.4.3 The Release of DAMPs in Necroptosis
3.7.4.4 Necroptosis in Bacterial Infections
Damaging Bacterial Virulence Factors as Inducers of Necroptosis
The Red Queen Paradigm in Necroptosis
3.7.4.5 Necroptosis in Viral Infections with Reference to Influenza A Virus
Emission of DAMPs in IAV-Induced Necroptosis: A Paradigm for Host Immune Defense Responses Against Pathogens
3.7.4.6 First Hints of Necroptosis Induction in Coronavirus Infection
3.7.4.7 Necroptosis in Fungal Infections
3.7.4.8 Concluding Remarks
3.7.5 Pyroptosis: The Result of Pathogen-Induced Activation of Inflammasomes
3.7.5.1 General Remarks
3.7.5.2 Types of Inflammasomes
3.7.5.3 Activation of the Inflammasome-Mediated Pyroptotic Program and Cell Lysis
3.7.5.4 Bacterium-Triggered Activation of Pyroptosis
Canonical Activation of NLRP3 Inflammasome-Driven Pyroptosis
Noncanonical Activation of NLRP3 Inflammasome
AIM2 Inflammasome
The NAIP-NLRC4 Inflammasome
NLRP1 and Pyrin Inflammasome
3.7.5.5 Virus-Triggered Activation of Pyroptosis
Activation of the NLRP3 Inflammasome
The NLRP3 Inflammasome→Pyroptosis Pathway in Influenza A Virus and COVID-19 Infection
Perspectives of Pyroptosis for the Pathogenesis of COVID-19 Infection
The AIM2-Driven Pyroptosis Pathway
3.7.5.6 Fungal-Triggered Activation of Pyroptosis
3.7.5.7 Pyroptosis in Parasitic Infections
3.7.6 PANoptosis: A Unique Inflammatory Cell Death Pathway Integrating Other Cell Death Trajectories
3.7.7 Formation of NETs and NETosis
3.7.7.1 General Remarks
3.7.7.2 Pathways in Lytic and Nonlytic NET Formation
Lytic NET Formation (Suicidal NETosis)
Nonlytic (Vital) NET Formation
3.7.7.3 NETs and NETosis in Bacterial Infections
3.7.7.4 NETs and NETosis in Viral Infections
3.7.7.5 NETs and NETosis in Protozoan Infections
3.7.7.6 NETs and NETosis Induced by Immune Complexes
3.7.7.7 Concluding Remarks
3.7.8 Ferroptosis: An Iron-Dependent, Oxidative Form of Regulated Necrosis
3.7.8.1 General Remarks
3.7.8.2 The Defense Response to Oxidative Stress Depending on Increasing Stress Intensity
3.7.8.3 Update of Ferroptosis Activation Mechanisms
3.7.8.4 Ferroptosis in Infections: First Reports
3.7.9 Parthanatos
3.8 Outlook and Future Perspectives
References
4: The DAMP-Driven Host Immune Defense Program Against Pathogens
4.1 Introduction
4.2 MAMPs and DAMPs as Key Players in Defense Responses to Pathogens
4.2.1 Introductory Remarks
4.2.2 Microbe-Associated Molecular Patterns
4.2.2.1 General Remarks
4.2.2.2 Pathogen Membrane Components Acting as MAMPs
4.2.2.3 Pathogen-Derived Nucleic Acids Acting as MAMPs: Or Better—Exogenous DAMPs
4.2.3 Damage-Associated Molecular Patterns
4.2.4 Résumé
4.3 Sensing of MAMPs and DAMPs by Pattern Recognition Molecules Triggering Innate Immune Pathways in Infections
4.3.1 Introductory Remarks
4.3.2 Cellular Pattern Recognition Molecules and Signaling Pathways Used to Sense Pathogens and to Cope with Stress and Injury Caused by Them: An Overview
4.3.2.1 General Remarks
4.3.2.2 Cell Surface Toll-Like Receptors
Signaling Pathways and the Supramolecular Organizing Centers
The Myddosome
The Putative Triffosome
Prompt Induction of the Pyroptotic Pathway by Simultaneous Engagement of TLRs and NLRP3
4.3.2.3 Nucleic Acid Sensors
Endolysosomally Localized Transmembrane Toll-Like Receptors
Cytosolic RNA Sensors
Cytosolic DNA Sensors with Special Attention to Cyclic GMP-AMP Synthase
4.3.2.4 NOD-Like Receptors
4.3.2.5 C-Type Lectin Receptors
4.3.3 Detection of Invading Bacteria: Receptor Molecules and their Helpers
4.3.4 Detection of Viruses: The Impressive Arsenal of Different Receptors Implicated in Antiviral Defense
4.3.4.1 General Remarks
4.3.4.2 Detection of Viruses Before Cell Entry
4.3.4.3 Detection of Intracellular Viral Nucleic Acids
RNA Virus-Triggered Signaling Pathways
DNA Virus-Triggered Signaling Pathways
4.3.4.4 Nuclear Innate Sensors Detecting Viral DNA
4.3.4.5 Concluding Remarks
4.3.5 Production of Inducible DAMPs Upon Bacteria and Virus Detection: The Type I Interferon and Tumor Necrosis Factor Systems
4.3.6 Detection of Fungi by Cellular Pattern Recognition Molecules
4.3.7 Detection of Parasites by Cellular Pattern Recognition Molecules
4.3.8 Humoral Innate Immune Sensing of Pathogens
4.3.9 Epigenetic Regulation of Innate Immune Responses to Infections
4.3.9.1 Trained Immunity in Infections
4.4 MAMP/DAMP-Mediated Regulation of Defense Responses to Pathogens
4.4.1 Introductory Remarks
4.4.2 Multiple-Level Mechanisms to Regulate Infectious Inflammation
4.4.3 MAMP/DAMP-Triggered Initiation and Promotion of Infectious Inflammation
4.4.3.1 General Remarks
4.4.3.2 PRM-Bearing Cells Regulating Proinflammatory Responses to Pathogens
4.4.3.3 Impact of Phagocytosis on Pathogen Elimination
4.4.3.4 Humoral Innate Immune Effector Responses: The Complement System
4.4.4 The Model of SAMP-Driven Resolution of Inflammation
4.4.4.1 General Remarks
4.4.4.2 Death of Inflammatory Cells and the Process of Efferocytosis
4.4.4.3 Participation of M2 Macrophages and N2 Neutrophils in Inflammation Resolution
4.4.4.4 SAMP-Driven Resolution of Inflammation in Infectious Disorders
4.4.4.5 Concluding Remarks
4.5 Innate Lymphoid Cells and Unconventional T Cells in Infections
4.5.1 Introductory Remarks
4.5.2 Innate Lymphoid Cells
4.5.2.1 General Remark
4.5.2.2 Natural Killer Cells in Viral Infections
4.5.2.3 Natural Killer Cells in Bacterial Infections
4.5.2.4 Natural Killer Cells in Fungal Infections
4.5.2.5 Innate Lymphoid Cells Group 2 in Parasite Infections
4.5.2.6 Concluding Remarks
4.5.3 Unconventional T Cells
4.5.3.1 General Remarks
4.5.3.2 Invariant Natural Killer T Cells
4.5.3.3 Mucosa-Associated Invariant T Cells
4.5.3.4 Gammadelta T Cells
4.6 DAMP-Shaped Adaptive Immune Responses to Pathogens
4.6.1 Introductory Remarks
4.6.2 Pathogen-Derived Antigens
4.6.3 Uptake, Processing, and Presentation of Bacterial and Viral Antigens by Dendritic Cells
4.6.3.1 General Remarks
4.6.3.2 Bacterial Antigens
4.6.3.3 Viral Antigens
4.6.4 Maturation of Immunostimulatory Dendritic Cells in Infection
4.6.4.1 General Remarks
4.6.4.2 The Professional Properties of Matured Dendritic Cells
4.6.4.3 Bacterial Infections
4.6.4.4 Viral Infections and Viral Vaccines
Viral Vector DNA Vaccine and Dendritic Cell Maturation
mRNA Vaccine and Dendritic Cell Maturation
4.6.4.5 Fungal and Protozoan Infections
4.6.4.6 Concluding Remarks
4.6.5 Cellular Adaptive Immune Responses
4.6.5.1 General Remarks
4.6.5.2 CD4+ T Cell Immune Responses
4.6.5.3 Function of CD4+ Th1 Cells
4.6.5.4 Efferent Arm of the Adaptive Immune Response
4.6.6 Humoral Adaptive Immune Responses
4.6.7 Immune Complexes Triggering NET Formation and NETosis in Infections: An Emerging Concept
4.6.7.1 General Remarks
4.6.7.2 Immune Complexes and Their Interaction with Fc Gamma Receptors on Neutrophils
4.6.7.3 Functional Diversification of Immunoglobulin G Through Fc Glycosylation
4.6.7.4 Impact of Changes in IgG Fc Glycosylation State on Neutrophil Effector Functions in Infections
4.6.7.5 Immune Complexes Interacting with FcRs as Powerful Inducers of NET Formation and NETosis
4.6.7.6 Immune Complex-Triggered NETs/NETosis in Infections: From Facts to a Preliminary Working Hypothesis
4.6.8 Innate and Adaptive Immune Memory
4.7 Conclusions and Future Perspectives
4.7.1 Introductory Remarks
4.7.2 Interplay Between MAMPs and DAMPs
4.7.3 The Changing Role of MAMPs in Pathogen-Induced Inflammation/Immunity
4.7.3.1 The Microbiota
4.7.3.2 MAMPs in the Absence of Injury-Induced DAMPs: Promotion of Intestinal Homeostasis and Tolerance Instead of Inflammation
4.7.4 Recognition of MAMPs and DAMPs in Infections: Simultaneously or Sequentially?
4.7.4.1 Discussion of the Topic in the International Literature
4.7.5 Résumé
References
5: The Pathogenetic Role of DAMPs in Severe Infectious Diseases
5.1 Introduction
5.2 MAMP/DAMP-Triggered Dysregulation of Defense Responses to Pathogens
5.2.1 Introductory Remarks
5.2.2 Chronic/Persistent Inflammatory Responses to Infections
5.2.2.1 General Remarks
5.2.2.2 Nonresolving Persisting Infections
5.2.3 Hyperinflammatory Syndrome Associated with Infections: The Case of Sepsis
5.2.3.1 General Remarks
5.2.3.2 Causes of Sepsis Development
5.2.3.3 Systemic Hyperinflammatory Response Syndrome and Coagulation Activation
5.2.3.4 Induction of Regulated Cell Death by Pathogens
5.2.3.5 Compensatory Anti-inflammatory Response Syndrome
5.3 Exploring DAMPs in Clinical Practice: An Emerging Area of Research in Infectious Diseases
5.3.1 Introductory Remarks
5.3.2 High Mobility Group Box 1
5.3.2.1 General Remarks
5.3.2.2 Bacterial Infections
5.3.2.3 Viral Infections
5.3.2.4 Fungal Infections
5.3.3 S100A Proteins (Calgranulins)
5.3.3.1 General Remarks
5.3.3.2 Bacterial Infections
5.3.3.3 Viral Infections
5.3.3.4 Concluding Remarks
5.3.4 Extracellular Nucleic Acids, Histones, and Nucleosomes
5.3.4.1 General Remarks
5.3.4.2 Bacterial Infections
5.3.4.3 Viral Infections
5.3.5 SAMPs
5.3.6 Résumé
5.4 Pathogenetic Impact of MAMPs and DAMPs on Viral Diseases: The Example of Pneumonia-Related Acute Respiratory Distress Syndrome
5.4.1 Introductory Remarks
5.4.1.1 General Remarks
5.4.1.2 Symptomatology and Clinical Picture of Respiratory Tract Infection → Pneumonia
5.4.1.3 Classification of ALI → ARDS
5.4.2 Demonstration of MAMPs, DAMPs, and SAMPs in Respiratory Virus Infections
5.4.2.1 General Remarks
5.4.2.2 MAMPs
5.4.2.3 DAMPs
5.4.2.4 SAMPs
5.4.3 Change of Viewpoints in the Pathogenesis of ALI → ARDS
5.4.4 Cellular Events in ARDS
5.4.5 MAMP/DAMP/SAMP-Driven Dysregulated Innate Immune Responses in ARDS
5.4.5.1 General Remarks
5.4.5.2 Initiation of Lung Inflammation
5.4.5.3 Resolution of Lung Inflammation
5.4.5.4 Hallmarks of Dysregulated Innate Immune Responses in ARDS
Hyperinflammation: The “Cytokine Storm”
Counterbalancing Inflammation-Hyperresolution → Immunosuppression
Immunothrombosis → Disseminated Intravascular Coagulation
5.4.5.5 Systemic and Remote Organ-Specific Inflammation
5.4.6 The Cytokine Storm as a DAMP-Driven Dysregulated Hyperinflammatory Response
5.4.7 Pathogenetic Role of Nonviral-Induced DAMPs in Respiratory Virus Infection: A Theory
5.4.8 DAMPs and SAMPs as Diagnostics and Prognostics in Respiratory Virus Infection
5.4.8.1 General Remarks
5.4.8.2 DAMPs
5.4.8.3 SAMPs
5.4.8.4 Concluding Remarks
5.4.9 DAMPs and SAMPs as Therapeutic Targets or Therapeutics in Respiratory Virus Infection
5.4.10 Résumé and Future Perspectives
5.5 Pathogenetic Impact of MAMPs and DAMPs on Bacterial Diseases: The Example of Sepsis
5.5.1 Introductory Remarks
5.5.1.1 General Remarks
5.5.1.2 History of Classification/Definition of Sepsis: A Few Remarks
5.5.1.3 Clinical Picture of Sepsis at a Glance
5.5.2 Experimental Sepsis Models
5.5.3 Demonstration of DAMPs
5.5.3.1 General Remarks
5.5.3.2 High Mobility Group Box 1, Heat Shock Proteins, and S100 Proteins
High Mobility Group Box 1
Heat Shock Proteins
S100A Proteins
5.5.3.3 Mitochondria-Derived DAMPs
Mitochondrial DNA
Mitochondrial N-Formyl Peptides
5.5.3.4 Histones
5.5.3.5 DAMPs Derived from the Degraded Endothelial Glycocalyx in Sepsis
5.5.3.6 The Inducible DAMPs C3a and C5a (Anaphylatoxins)
5.5.3.7 Extracellular Vesicles (e.g., Exosomes) in Sepsis
5.5.3.8 Concluding Remarks
5.5.4 Demonstration of SAMPs
5.5.4.1 General Remarks
5.5.4.2 Annexin A1
5.5.4.3 Extracellular Adenosine
5.5.4.4 Specialized Proresolving Mediators
5.5.4.5 Prostaglandin E2
5.5.4.6 Concluding Remarks
5.5.5 Pathophysiology-Pathogenesis of Sepsis
5.5.5.1 General Remarks
5.5.5.2 The Systemic Hyperinflammatory State: Sketching a Scenario Model
DAMP-Promoted Activation of Polymorphonuclear Neutrophils
DAMP-Triggered Activation of Endothelial Cells Leading to Endothelial Barrier Dysfunction
Complement Activation: The Work of the Inducible DAMPs C3a and C5a
Contribution of DAMPs to Immunothrombosis: Hypercoagulability
5.5.5.3 Immunosuppression Reflecting “Inflammation Hyperresolution”: Continuation of the Scenario Model
SAMP-Driven “Hyperresolution” in Sepsis-Associated Immunosuppression
5.5.5.4 Remote Organ-Specific Dysfunction
5.5.6 Epigenetics in Sepsis
5.5.7 DAMPs and SAMPs as Biomarkers
5.5.7.1 General Remarks
5.5.7.2 DAMPs
HMGB1
S100A8/A9 Proteins (Calprotectin)
Mitochondrial DNA
5.5.7.3 SAMPs
5.5.7.4 Concluding Remarks
5.5.8 DAMPs and SAMPs as Therapeutic Targets and Therapeutics
5.5.8.1 General Remarks
5.5.8.2 DAMPs as Therapeutic Targets
High Mobility Group Box 1
S100A8/A9 Proteins
5.5.8.3 Blood Purification Techniques: A New Approach to Eliminating DAMPs on the Horizon
5.5.8.4 SAMPs as Therapeutics and Therapeutic Targets in Sepsis
SAMPs as Therapeutics in the Early Hyperinflammatory Phase
Blockade of SAMPs in the Late Sepsis-Associated Immunosuppressive Phase
5.5.8.5 Concluding Remarks
5.5.9 Résumé and Future Perspectives
5.6 Pathogenetic Impact of MAMPs and DAMPs on Protozoan Diseases: The Example of Malaria
5.6.1 Introductory Remarks
5.6.1.1 General Remarks
5.6.1.2 Clinical Picture of Malaria at a Glance
5.6.2 Demonstration of DAMPs
5.6.3 Demonstration of SAMPs
5.6.4 Pathogenesis of Malaria
5.6.4.1 General Remarks
5.6.4.2 The Pathogenetic Role of DAMPs in Malaria: Sketching a Scenario Model
5.6.5 Résumé
5.7 DAMP/SAMP-Dependent Clinical Outcomes of Infectious Diseases: Sketching a Narrative Summing-Up Model
5.7.1 The Different Clinical Facets of an Infection
5.7.2 Integration of DAMP/SAMP-Driven Immune Responses in Different Clinical Courses of Infections (Exemplified in Part by COVID-19 Pneumonia): A Tentative Proposal
5.7.2.1 General Remarks
5.7.2.2 Controlled Responses
5.7.2.3 Uncontrolled Responses
5.7.3 The Future of DAMPs and SAMPs in Improving Outcomes of Infectious Diseases
References
Part III: Autoimmunity
6: Basic Trajectories in Autoimmunity
6.1 Introduction
6.2 Some Basic Principles in the Development of Autoimmune Diseases
6.2.1 Introductory Remarks: What Is Known Today
6.2.2 The Concept of T Cell and B Cell Tolerance to Self at a Glance
6.2.2.1 General Remarks
6.2.2.2 Some Historical Notes
6.2.2.3 Central T Cell Tolerance to Self and Trajectories to Its Breakdown
Clonal Deletion/Negative Selection
Regulatory T Cell Differentiation
Failures of Central T Cell Tolerance
6.2.2.4 Peripheral T Cell Tolerance to Self: The Tissue Controls Escaped Autoreactive T Cells
6.2.2.5 The Potential of “Healthy” Tissue Cells to Induce Peripheral Tolerance
Anergy
Deletion
Control of Peripheral T Cell Tolerance by Coinhibitory Signals
Generation of Peripherally Tolerogenic DC-Induced Regulatory T Cells
6.2.2.6 The Potential of “Unhealthy”/Damaged Tissue Cells to Initiate Innate Immune Responses.
Initiation, Resolution, and Chronicity of Inflammation
6.2.2.7 Central and Peripheral B Cell Tolerance to Self
Central B Cell Tolerance
Peripheral B Cell Tolerance
6.2.2.8 Concluding Remarks
6.2.3 Development of Autoimmunity in Light of the Danger/Injury Model
6.2.3.1 General Remarks
Traditional Concept of Autoimmunity
Interpretation of Autoimmunity in the Light of the Danger/Injury Model
6.2.3.2 Autoimmunity to Native Bona Fide Self Antigens: A Few Examples
6.2.3.3 Autoimmunity to Altered-Self Antigens (Neoantigens)
6.2.3.4 Falsely Diagnosed Autoimmunity in Infections
6.2.3.5 Presentation of Autoantigens by B Cells
6.2.3.6 Initiation of Autoimmunity by the Coaction of DAMPs: A Tautological Approach
6.2.3.7 Propagation of Autoimmunity by the Coaction of DAMPs
6.2.3.8 Increasing Evidence for the Role of DAMPs in Autoimmunity
6.2.3.9 Concluding Remarks
6.2.4 Immune Complexes Triggering NETosis as a Pivotal Source of DAMPs Emission in Autoimmune Diseases
6.2.4.1 General Remarks
6.2.4.2 Immune Complexes and Their Interaction with Fc Receptors on Neutrophils
Impact of Changes in IgG Fc Glycosylation State on Neutrophil Effector Functions
6.2.4.3 Immune Complexes Interacting with FcγRs as Powerful Inducers of NET Formation and NETosis
Immune Complexes as Potent Inducers of NET Formation in Autoimmunity
6.2.4.4 Immune Complex-Induced NET Formation/NETosis and Subsequent Initiation of a DAMP-Promoted Positive Feed-Forward Loop Orchestrating Autoimmune Responses: A Hypothetical Scenario
6.2.5 Autoimmune Mechanisms of Tissue Destruction: Another Source of DAMPs Emission
6.2.5.1 General Remarks
6.2.5.2 Autoreactive Cytotoxic T Cells
6.2.5.3 Autoantibodies, Antibody-Dependent Cell-Mediated Cytotoxicity, and Complement
Antibody-Dependent Cell-Mediated Cytotoxicity
Complement Activation
Immune Complexes
6.2.5.4 Concluding Remarks
6.2.6 Résumé
6.3 The Role of the Environment in the Etiopathogenesis of Autoimmune Diseases
6.3.1 Introductory Remarks
6.3.2 Models of Environmental Factor-Promoted Generation of Autoantigens
6.3.2.1 General Remarks
6.3.2.2 Presentation of “Cryptic” Self Peptides by MHC-I Molecules Enhanced by Inducible DAMPs
6.3.2.3 Molecular Mimicry: Host Self Epitopes Resembling Microbial Antigenic Determinants
6.3.2.4 Epitope Spreading
6.3.2.5 Bystander Activation
6.3.2.6 The Model of Regulated Cell Death as a Productive Source of Autoantigens
Principles of Autoantigen Release from Necrotic Cells and the Role of Posttranslational Modifications
6.3.2.7 Concluding Remarks
6.3.3 Environmental Factors Promoting the Emission of DAMPs Through Induction of Regulated Cell Death
6.3.3.1 General Remarks
6.3.3.2 Infections
6.3.3.3 Xenobiotics
6.3.3.4 Vaccines
6.3.3.5 Heavy Metals
6.3.3.6 Lifestyle Habits, for Example, Cigarette Smoking
6.3.3.7 Ultraviolet Radiation
6.3.3.8 Nutrition (Gluten, Iodine, and Vitamin D)
6.3.3.9 Oral Contraceptives and Postmenopausal Hormone Therapy
6.3.3.10 Air Pollution
6.3.3.11 Concluding Remarks
6.3.4 Role of the Microbiota in the Pathogenesis of Autoimmune Diseases
6.3.4.1 General Remarks
6.3.4.2 Changes in the Composition of the Commensal Community Preceding the Onset of Disease
6.3.4.3 Mechanisms of Commensal Involvement in the Promotion of Autoimmunity
6.3.4.4 Concluding Remarks
6.3.5 Résumé
6.4 Hereditary Factors in the Etiopathogenesis of Autoimmune Diseases
6.4.1 Introductory Remarks
6.4.2 Genetics
6.4.2.1 General Remarks
6.4.2.2 Genetic Factors Associated with Autoimmune Diseases
The MHC/HLA System
The Non-MHC/HLA System
6.4.2.3 Genetic Defects in Insufficient Clearance of Dying Cells and NETs
6.4.2.4 Concluding Remarks
6.4.3 Epigenetics
6.4.3.1 General Remarks
6.4.3.2 Epigenetics: The Link Between Environmental and Genetic Factors
Chromatin Architecture
Epigenetic Mechanisms Regulate Gene Expression
Crosstalk Between Epigenetic Modifications and Metabolism in Autoimmune Diseases
6.4.3.3 Epigenetics at the Level of Altered-Self Antigen Formation (“Autoantigenesis”)
6.4.3.4 Impact on the Innate Immune Arc
Trained Immunity Reprogramming Innate Immunity in Health and Disease
6.4.3.5 Impact on the Adaptive Immune Arc
6.4.3.6 The Model of DAMP-Triggered Epigenetic Changes in Autoimmune Diseases
6.4.4 Résumé
6.5 Outlook and Future Perspectives
References
7: DAMPs in Systemic Autoimmune Diseases
7.1 Introduction
7.2 Systemic Lupus Erythematosus
7.2.1 Introductory Remarks
7.2.1.1 General Remarks
7.2.1.2 Clinical Picture and Classification
7.2.2 Experimental Animal Models
7.2.3 Pathogenesis-Orchestrating Interrelationship Between Environmental Triggers, Genetic Predisposition, and Epigenetic Modifications
7.2.3.1 General Remarks
7.2.3.2 Environmental Factors and the Role of Regulated Cell Death
7.2.3.3 Genetics
HLA Region in Relation to SLE Susceptibility
Polygenic Influences on Type I IFN
Polygenic Influences on the Nuclear Factor-Kappa B Pathway
Monogenic Deficiencies in SLE
Gene Loci Mediating T and B Cell Signaling
Programmed Cell Death 1 Gene Polymorphisms
7.2.3.4 Epigenetics
Trained Immunity: An Example of Epigenetic Modifications
Epigenetic Modifications in Adaptive Immunity
The Lesson from the Basics of Epigenetics
Epigenetic Modifications in SLE
Epigenetic Modification at the Level of Altered-Self Antigens
Epigenetic Modification at the Level of Innate Immune Cells (Macrophages and Dendritic Cells)
Epigenetic Modification at the Level of Adaptive Immune T Cells and B Cells
7.2.3.5 Concluding Remarks
7.2.4 Pathogenetic Principles of Autoantigen Formation and Emission of DAMPs
7.2.4.1 General Remarks
Nucleic Acids and Nuclear Proteins in SLE Acting as Autoantigens and Endogenous Nuclear DAMPs
7.2.4.2 Defective Clearance of Dying Cells: A Source of Autoantigens in SLE
7.2.4.3 Defective Clearance of Dying Cells: A Prolific Source of Costimulation-Mediating DAMPs
7.2.4.4 Concluding Remarks
7.2.5 DAMP-Promoted, Pattern Recognition Molecule-Mediated Autoinflammatory Pathways
7.2.5.1 General Remarks
7.2.5.2 DAMP-Triggered, Endosomal Toll-Like Receptor-Mediated Signaling
7.2.5.3 Cytosolic DNA → cGAS → STING-Mediated Signaling
7.2.5.4 DAMPs Involved in Activation of the NLRP3-Mediated Pyroptotic Pathway
7.2.5.5 Evidence for a Role of DNA-Activated AIM2-Mediated Pathway
7.2.6 Is There an Insufficient Inflammation-Resolving Role of SAMPs in SLE?
7.2.7 DAMPs and Their Cognate Pattern Recognition Receptors Triggering Maturation of Dendritic Cells, Production of Type 1 Interferons, and Activation of B Cells
7.2.7.1 General Remarks
7.2.7.2 Activation of Conventional Dendritic Cells
Conventional Dendritic Cell-Promoted Priming of Follicular Helper T Cells
7.2.7.3 Activation of Plasmacytoid Dendritic Cells
7.2.7.4 Production of Type I Interferons: Powerful Inducible DAMPs in SLE
Signaling Through Type I IFN Receptor
Effects of Type I IFN on the Immune System
7.2.7.5 Activation of Follicular Dendritic Cells
7.2.7.6 Activation of Autoantigen-Presenting B Cells: The Begin of B Cell Pathobiology
B Cell Receptor-Mediated, Autoantigen-Triggered Activation of B Cells
Nuclear DAMP (RNA)-Triggered, Toll-Like Receptor-Promoted Activation of B Cells
7.2.7.7 Concluding Remarks
7.2.8 The Autoreactive T Cell Response
7.2.8.1 General Remarks
7.2.8.2 CD4+ Th1 and CD4+ Th17 Cells
7.2.8.3 Follicular CD4+ Helper T Cell Responses: The Help for B Cell Activation
7.2.8.4 Regulatory T Cells
Defects in Peripheral Tolerance
Follicular Regulatory T Cells
7.2.9 The Autoreactive B Cell Response
7.2.9.1 General Remarks
7.2.9.2 B Cell Pathobiology at a Glance
7.2.9.3 A Model of B Cell Activation as an Interplay Between DCs, T Cells, and B Cells
7.2.9.4 B Cell-Derived Production of Autoantibodies in SLE
Extrafollicular Pathway of Autoantibody Production in SLE
Aberrant Glycosylation of Autoantibodies in SLE
Induction of NET Formation and NETosis by Autoantibodies and Associated Immune Complexes
7.2.9.5 Concluding Remarks
7.2.10 Organ-Specific Tissue Injury
7.2.10.1 General Remarks
7.2.10.2 Lupus Nephritis
7.2.10.3 Skin Injury
7.2.10.4 Attribution of Neuropsychiatric Manifestations
7.2.10.5 Concluding Remarks
7.2.11 Summarizing Hypothetical Model to SLE Pathogenesis: Immune Complex-Induced NETs and NETosis and the DAMP-Promoted Positive Feed-Forward Loop as Drivers of Type I Interferon Secretion by Plasmacytoid Dendritic Cells
7.3 Rheumatoid Arthritis
7.3.1 Introductory Remarks
7.3.1.1 General Remarks
7.3.1.2 Clinical Picture and Classification
7.3.2 Experimental Animal Models
7.3.3 The Pathogenesis of Rheumatoid Arthritis: Cellular Events
7.3.4 Pathogenesis-Orchestrating Interrelationship Between Environmental Triggers, Genetic Predisposition, and Epigenetic Modifications
7.3.4.1 General Remarks
7.3.4.2 Environmental Factors and the Role of Regulated Cell Death
7.3.4.3 Genetics
7.3.4.4 Epigenetics
Posttranslational Modifications at the Level of Altered-Self Antigens: Citrullination
Epigenetic Modifications at the Level of Fibroblast-Like Synoviocytes
Trained Immunity in Rheumatoid Arthritis
7.3.4.5 Concluding Remarks
7.3.5 Pathogenetic Principles of Autoantigen Formation and Emission of DAMPs
7.3.5.1 General Remarks
7.3.5.2 Autoantigens
7.3.5.3 DAMPs
HMGB1, S100A Proteins (Calgranulins), Heat Shock Proteins
Extracellular Endogenous Histones, Nucleosomes, and Nucleic Acids
Extracellular Matrix Compounds and Molecules Acting as Altered-Self Antigens and Qualifying as DAMPs
Inducible DAMPs (TNF, IL-1β)
7.3.5.4 SAMPs
7.3.5.5 Concluding Remarks
7.3.6 DAMPs Triggering Synovial Autoinflammatory Responses
7.3.6.1 General Remarks
7.3.6.2 Synovial Membrane Inflammation
DAMPs Activating the NLRP3 Inflammasome
7.3.6.3 Synovial Tissue Proliferation (Pannus) and Destructive Joint Inflammation
7.3.6.4 Concluding Remarks
7.3.7 Evidence for SAMPs to Drive Synovial Inflammation-Resolving Responses
7.3.8 DAMPs Promoting Maturation of Antigen-Presenting Cells
7.3.8.1 General Remarks
7.3.8.2 Synovial Dendritic Cells as Antigen-Presenting Cells
Activation of Synovial Dendritic Cells
7.3.8.3 Fibroblast-Like Synoviocytes and B Cells as Nonprofessional Antigen-Presenting Cells
7.3.8.4 Concluding Remarks
7.3.9 The Autoreactive T Cell Response
7.3.9.1 General Remarks
7.3.9.2 T Cell Pathobiology
7.3.10 The Autoreactive B Cell Response
7.3.10.1 General Remark
7.3.10.2 The Pathogenetic Role of B Cell in the Synovium
Interaction of cDC ↔ Tfh ↔ B cell ↔ FDC in Synovial B Cell Activation
7.3.10.3 Autoantibodies in Seropositive Rheumatoid Arthritis
Anti-Citrullinated Protein Antibodies
Rheumatoid Factor
Complement Activation
7.3.10.4 Concluding Remarks
7.3.11 Summarizing Hypothetical Model to Rheumatoid Arthritis Pathogenesis: The DAMP-Driven Positive Feed-Forward Loop of Innate/Adaptive Autoimmune Responses
7.4 DAMPs and SAMPs as Biomarkers, Therapeutic Targets, and Therapeutics in Systemic Autoimmune Disorders
7.4.1 Introductory Remarks
7.4.2 DAMPs and SAMPs as Diagnostic and Prognostic Biomarkers in Systemic Lupus Erythematosus
7.4.2.1 General Remarks
7.4.2.2 DAMPs
7.4.2.3 SAMPs
7.4.2.4 Concluding Remarks
7.4.3 Avoidance, Blockade, or Removal of DAMPs and Administration of SAMPs as Therapeutic Options in Systemic Lupus Erythematosus
7.4.3.1 General Remarks
7.4.3.2 Administration of Autoantigen in the Absence of DAMPs
7.4.3.3 DAMPs as Therapeutic Targets
High Mobility Group Box 1
Interventions with Nucleic Acid
Nucleic Acid Scavenging
7.4.3.4 SAMPs as Therapeutics
7.4.3.5 Concluding Remarks
7.4.4 DAMPs and SAMPs as Diagnostic and Prognostic Biomarkers in Rheumatoid Arthritis
7.4.4.1 General Remarks
7.4.4.2 DAMPs
7.4.4.3 SAMPs
7.4.5 Avoidance, Blockade, or Removal of DAMPs and Administration of SAMPs as Therapeutic Options in Rheumatoid Arthritis
7.4.5.1 General Remarks
7.4.5.2 Administration of Autoantigen in the Absence of DAMPs
Administration of Tolerogenic Dendritic Cells
DNA Vaccines and Application of Regulatory T Cells: Not Yet Clinically Realized
7.4.5.3 DAMPs as Therapeutic Targets
High Mobility Group Box 1
S100A8/A9 Proteins
7.4.5.4 SAMPs as Therapeutics
7.4.6 Résumé
7.5 Outlook and Future Directions
References
8: DAMPs in Organ-Specific Autoimmune Diseases
8.1 Introduction
8.2 Multiple Sclerosis
8.2.1 Introductory Remarks
8.2.1.1 General Remarks
8.2.1.2 Clinical Picture, Classification, and Prevalence
8.2.1.3 Neuroimmunology and Neuropathology
8.2.2 Experimental Animal Models
8.2.2.1 General Remarks
8.2.2.2 Experimental Autoimmune Encephalomyelitis Supporting the “Outside-In” Paradigm
8.2.2.3 Cuprizone Model of Toxic Demyelination Supporting the “Inside-Out” Paradigm
8.2.3 Pathogenesis-Orchestrating Interrelationship Between Environmental Triggers, Genetic Predisposition, and Epigenetic Modifications
8.2.3.1 General Remarks
8.2.3.2 Environmental Factors and the Role of Regulated Cell Death
8.2.3.3 Environmental Factors in Multiple Sclerosis Promoting Oxidative Stress
8.2.3.4 Induction of Regulated Cell Death in the CNS: What Evidence Exists to Date for Multiple Sclerosis?
Non-Immune-Mediated Induction of Regulated Cell Death
T Cell- and B Cell-Mediated Induction of Regulated Cell Death
8.2.3.5 Genetic Factors
8.2.3.6 Epigenetic Factors
8.2.3.7 Concluding Remarks
8.2.4 A Special Note to the Role of the Microbiota in Multiple Sclerosis
8.2.5 Pathogenetic Principles of Autoantigen Formation and Emission of DAMPs
8.2.5.1 General Remarks
8.2.5.2 Putative Autoantigens in Multiple Sclerosis
Epitope Spreading
Molecular Mimicry
8.2.5.3 DAMPs in Multiple Sclerosis
Constitutively Expressed Native and Modified Molecules (Cat. I DAMPs)
Cell-Free Circulating DNA
Inducible DAMPs (Cat. III DAMPs)
8.2.5.4 SAMPs in Multiple Sclerosis
Specialized Proresolving Lipid Mediators
Annexin A1 and Alpha B-Crystallin (HSPB5)
8.2.5.5 Concluding Remarks
8.2.6 DAMPs and Their Cognate Pattern Recognition Receptors Triggering Neuroinflammatory Responses
8.2.6.1 General Remarks: The Microglia as Sentinels to Sense Any Perturbations in the Brain
8.2.6.2 PRR-Mediated Neuroinflammation and the Inflammasome in Multiple Sclerosis
8.2.6.3 Evidence for an Insufficient Inflammation-Resolving Role of SAMPs in Multiple Sclerosis
8.2.7 DAMPs and Their Cognate Pattern Recognition Receptors Triggering Activation of Antigen-Presenting Cells
8.2.7.1 General Remarks
8.2.7.2 Activation of APCs in Light of the “Inside-Out” Paradigm
Recruitment, Migration, and Activation of Conventional Dendritic Cells in the CNS
8.2.7.3 Activation of APCs in Light of the “Outside-In” Paradigm
8.2.7.4 B Cells as Antigen-Presenting Cells
8.2.7.5 Concluding Remarks
8.2.8 The Autoreactive T Cell and B Cell Responses
8.2.8.1 General Remarks
8.2.8.2 T Cells
T Cell Subsets in the CNS
Reactivation of T Cells in the CNS and the Cytotoxic Function of CD8+ T Cells
B Cells
8.2.9 Hypothetical Model to Reconcile the “Inside-Out” and the “Outside-In” Paradigms in Multiple Sclerosis Pathogenesis: The DAMP-Driven Positive Feed-Forward Loop of Chronic Inflammatory Demyelinating Processes
8.2.9.1 General Remarks
8.2.9.2 DAMP-Driven Positive Feed-Forward Loop Seen from the” Inside-Out” Model
8.2.9.3 DAMP-Driven Positive Feed-Forward Loop Seen from the “Outside-In” Model
8.2.9.4 Concluding Remarks
8.3 Type 1 Diabetes Mellitus
8.3.1 Introductory Remarks
8.3.2 Experimental Animal Models
8.3.2.1 General Remarks
8.3.2.2 The Non-Obese Diabetic Mouse Model
8.3.2.3 Other Models of Type 1 Diabetes Mellitus
8.3.2.4 Concluding Remarks
8.3.3 Pathogenesis-Orchestrating Interrelationship Between Environmental Triggers, Genetic Predisposition, and Epigenetic Modifications
8.3.3.1 General Remarks
8.3.3.2 Environmental Factors with Focus on Induction of Endoplasmic Reticulum Stress
Stress of the Endoplasmic Reticulum Triggering Subroutines of RCD
ER Stress in β-Cells in Type 1 Diabetes Mellitus
8.3.3.3 Preliminary Evidence for ER Stress-Triggered RCD as a Potential Mechanism of Linking β-Cell Death-Via Release of DAMPs—To Innate/Adaptive Autoimmune Responses in Type 1 Diabetes Mellitus
8.3.3.4 Genetic Factors
8.3.3.5 Epigenetic Modifications
8.3.3.6 Concluding Remarks
8.3.4 Pathogenetic Principles of Autoantigen Formation and Emission of DAMPs
8.3.4.1 General Remarks
8.3.4.2 Autoantigens in Type I Diabetes Mellitus
Enzymatic Posttranslational Processes
Non-Enzymatic Posttranslational Processes
Posttranslational Modification in Antigen Processing and Presentation
Epitope Spreading in Autoimmune T1DM
8.3.4.3 DAMPs in Type I Diabetes Mellitus
8.3.4.4 Concluding Remarks
8.3.5 DAMPs and Their Cognate Pattern Recognition Receptors Triggering Islet Inflammation
8.3.5.1 General Remarks
8.3.5.2 Pattern Recognition Receptors → Proinflammatory Signaling Pathways
Toll-Like Receptors
NOD-Like Receptors
8.3.5.3 Concluding Remarks
8.3.6 DAMP/PRR-Activated Antigen-Presenting Cells Promoting Activation of T and B Cells
8.3.6.1 General Remarks
8.3.6.2 DAMP-Promoted Activation of Dendritic Cells
8.3.6.3 Activation of Naïve CD4+ T Cells Via Islet Bona Fide Self Antigens and Altered Neoepitopes
8.3.6.4 Concluding Remarks
8.3.7 The Autoreactive T Cell and B Cell Responses
8.3.7.1 General Remarks
8.3.7.2 T Cells
The CD4+ T Helper Type 1 Cells
The CD4+ T Helper Type 2 Cells
The CD4+ T Helper Type 17 Cells
The Follicular CD4+ Helper T Cells
Cytotoxic CD8+ T Cells
8.3.7.3 B Cells and Autoantibodies
8.3.8 Insulitis and Islet β-Cell Destruction
8.3.8.1 General Remarks
8.3.8.2 Insulitis (as Seen in Light of the Danger/Injury Model)
8.3.8.3 Pancreatic β-Cell Death
8.3.9 Summarizing Hypothetical Model to T1DM Pathogenesis: Is the End-Stage Diabetes the Result of a DAMP-Driven Positive Feed-Forward Loop?
8.4 DAMPs and SAMPs as Biomarkers, Therapeutic Targets, and Therapeutics in Organ-Specific Autoimmune Disorders
8.4.1 Introductory Remarks
8.4.2 DAMPs and SAMPs as Diagnostic and Prognostic Biomarkers in Multiple Sclerosis
8.4.2.1 General Remarks
8.4.2.2 DAMPs
HMGB1
Cell-Free Circulating DNA
S100A8/A9 Proteins
8.4.2.3 SAMPs
8.4.2.4 Concluding Remarks
8.4.3 Avoidance, Blockade, or Removal of DAMPs and Administration of SAMPs as Therapeutic Options in Multiple Sclerosis
8.4.3.1 General Remarks
8.4.3.2 Administration of Autoantigen (Peptide) in the Absence of DAMPs
8.4.3.3 DAMPs as Therapeutic Targets
8.4.3.4 SAMPs as Therapeutics
8.4.3.5 Concluding Remarks
8.4.4 DAMPs and SAMPs as Diagnostic and Prognostic Biomarkers in Islet Transplantation (as a Substitute for Type 1 Diabetes Mellitus)
8.4.4.1 General Remarks
8.4.4.2 DAMPs in Islet Transplantation
HMGB1
S100A8/A9 Proteins
miRNA-375 and Cell-Free cfDNA
8.4.5 Blockade or Removal of DAMPs and Administration of SAMPs as Therapeutic Options in Islet Transplantation (as a Substitute for Type 1 Diabetes Mellitus)
8.4.5.1 General Remarks
8.4.5.2 DAMPs as Therapeutic Targets
8.4.5.3 SAMPs as Therapeutics
8.4.6 Résumé
8.5 Outlook and Future Directions
References
Part IV: Transplants and Cancer
9: The Undesirable and Desirable Functions of DAMPs in Allograft and Tumor Rejection
9.1 Introduction
9.2 Allograft Rejection
9.2.1 Introductory Remarks
9.2.2 Allograft Injury-Induced DAMPs as Main Players in Triggering Innate Alloimmune Responses
9.2.2.1 General Remarks
9.2.2.2 Some Potential Injuries to a Donor Organ Precipitating Regulated Cell Death as a Source of DAMPs
Oxidative Injury to the Donor Organ Under Brain-Dead Conditions
Postischemic Reperfusion Injury to Allograft in the Recipient
Acute Allograft Rejection Episode: The Role of Cytotoxic T Cells in Promoting Regulated Cell Death
Infections
Donor-Specific HLA Antibodies
9.2.2.3 Brief Narrative Synopsis on DAMP-Promote Innate Alloimmunity
9.2.3 Chronic Allograft Dysfunction - Chronic Allograft Rejection
9.2.3.1 General Remarks
9.2.4 DAMPs as Biomarkers and Therapeutic Targets
9.3 Tumor Rejection
9.3.1 Introductory Remarks
9.3.1.1 Immunosurveillance and Immunoediting
9.3.2 Immunogenic Cell Death and the Secretion/Release of DAMPs
9.3.2.1 General Remarks
9.3.3 ICD-Associated Secretion and Release of DAMPs Triggering Antitumor Immune Response
9.3.4 Immunogenic Cell Death-Induced DAMPs for Future Cancer Therapy
9.4 Outlook
References
Part V: Epilogue
10: Approaching the DAMPome: Evolution in Medicine?