The Epigenetics of Autoimmune Diseases

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ISBN: 9780470758618 | 0470758619
Cover: Hardcover
Copyright: 10/5/2009

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This book covers the latest discoveries and developments in epigenetics and their significance in a variety of autoimmune diseases including rheumatoid arthritis, autoimmune anaemia, type-1 diabetes, multiple sclerosis, autoimmune gastritis, thyroiditis, and systemic lupus erythematosus. The chapters are written by world-class experts in their respective fields and divided into four parts:(i) Transcription factors - partners of immune tolerance to self.(ii) Epigenetic modifiers of autoimmunity.(iii) Influence of environmental factors on epigenetics of autoimmunity.(iv) Stress responses that break immune silence.

Contributors
Transcription Factors: Partners Of Immune Tolerance To Self.
Transcriptional Regulation of T Cell Tolerance
Introduction
T cell anergy
Ca2+/calcineurin/NFAT signalling in T cell anergy
Transcriptional programme of T cell anergy
Transcriptional repression in T cell anergy: epigenetic modification of the Il2 promoter
Regulatory T cells
Transcriptional control of Treg development and function
References
Epigenetic Regulation of Foxp3 Expression in Regulatory T Cells
Introduction
Naturally occurring CD25+CD4+ Tregs
The transcription factor FOXP3: determining Treg function and identity
Molecular regulation of FOXP3
Tregs as a stable lineage: indications of epigenetic imprinting
Induced Tregs: stable suppressors or transient immuno-modulators?
Conclusions
References
The Role of NF-?B in Central Tolerance
Introduction
Canonical and alternative NF-?B pathways
Thymic stroma and central tolerance
NF-?B and regulatory T cell development
NF-?B and thymocyte positive and negative selection
Conclusions and perspectives
Acknowledgement
References
The Role of Act1 in the Control of Autoimmunity
Introduction
Autoimmunity and autoimmune mouse models
Molecular mechanisms of autoimmunity
Act1: a modulator of autoimmunity
Conclusions
References
Regulation of T Cell Anergy and Escape from Regulatory T Cell Suppression by Cbl-b
Introduction
Mechanisms of T cell tolerance induction
Molecular establishment of T cell anergy
Ubiquitin E3 ligases in T cell tolerance
Molecular function and regulation of Cbl-b
Physiological relevance of Cbl-b
The role of Cbl-b in T cell tolerance
Deregulation of Cbl-b in disease
Therapeutic potential of Cbl-b in tumour immunity
Implications for autoimmune disease
References
Indoleamine 2,3-dioxygenase: Transcriptional Regulation and Autoimmunity
Introduction
L-Trp degradation along the kynurenine pathway and immune functions of IDO
IDO immunobiology and therapeutic intervention
Transcriptional regulation of the IDO-encoding gene
Impaired IDO activity and loss of tolerance in autoimmune diseases
IDO-based therapies for autoimmune disease
Acknowledgement
References
Stress Responses That Break Immune Silence.
Chromatin Modifications, Oxidative Stress and Nucleosome Autoantibodies
Introduction
Nucleosome and SLE
Epigenetics and SLE
Oxidative stress in SLE: definition and mechanisms
Oxidative stress, epigenetic alterations and nucleosome immunogenicity
Conclusion
Acknowledgements
References
Stress, Epigenetics and Thyroid Autoimmunity
Introduction
The Th1/Th2 balance in immune-response regulation
Stress hormones and the Th1/Th2 balance
The Th1/Th2 balance in thyroid autoimmunity
Association of stress with thyroid autoimmunity
Stress in the clinical expression of thyroid autoimmunity: a unifying hypothesis
Epigenetic regulation of T cell differentiation and stress hormones
Conclusions
References
Reactive Intermediates, Inflammation and Epigenetics in Lupus
Introduction
Biology of reactive intermediates
RNIs in murine models of lupus
Genetic associations of RNI/ROI and lupus
Conclusions
References
Post-translational Modification of HMGB1 and Its Role in Immune Activation
Introduction
Molecular biology of HMGB1
HMGB1 as an immune mediator
Mechanisms of HMGB1 modification and release
The role of HMGB1 as a mediator of disease and target of therapy
Conclusion
References
Idiosyncratic Drug-Induced Liver Injury: Facts and Perspectives
Introduction
Intrinsic drug toxicity to the liver
Idiosyncratic drug toxicity to the liver
Mechanisms of hypersensitivity reactions to drugs in the liver
Hypersensitivity versus tolerance
Hepatocyte injury as a consequence of allergic hepatitis
Drug-induced liver autoimmunity
Epigenetics of drug-induced liver injury
Acknowledgements
References
Epigenetic Modifiers Of Autoimmunity.
Epigenetic Modifications Associated with T Cell Tolerance
Immunity versus tolerance
Epigenetic regulation of the physical structure of genomic DNA
Epigenetic control of pro-inflammatory cytokine gene transcription
Epigenetic silencing of cytokine genes in tolerant T cells
Targeting epigenetic modifications to cytokine genes in tolerant T cells
Common mechanisms of epigenetic silencing among distinct types of tolerant T cells?
References
DNA Methylation Alterations in Systemic Lupus Erythematosus
Introduction
DNA methylation: an epigenetic determinant of lymphocyte function
DNA methylation changes in lupus
Epigenetic regulation as a therapeutic target
Future aims for epigenetic research into lupus
Acknowledgements
References
Long-Range Histone Acetylation Patterns in the Development of Autoimmunity
Introduction
The histone code hypothesis
Epigenetic defects as a mechanism of disease
Analysis of the histone code
Long-range histone acetylation patterns in Th cell differentiation
Long-range histone acetylation and autoimmunity
Perspectives
Acknowledgements
References
Roquin Defects Reveal a Role for the microRNA Machinery in Regulating Autoimmunity
Introduction
RNA silencing through the miRNA machinery
miRNAs regulate lymphoid cell development and immune responses
miRNAs as single drivers of immunodeficiency or inflammation
miRNAs regulate autoimmunity
Roquin regulates miRNA-mediated silencing of T cells and represses lupus
Concluding remarks
Acknowledgements
References
Autoimmune Response to Post-translationally Modified (Citrullinated) Proteins: Prime Suspect in the Pathophysiology of Rheumatoid Arthritis
Introduction
RA is associated with B cell autoreactivity to citrullinated proteins
Both ACPA and citrullinated antigenic targets are present in the RA synovium
Autoreactivity to citrullinated proteins probably plays a role in RA synovitis
The way ACPA could promote joint inflammation
Joint-expressed citrullinated autoantigen targets possibly involved in a pro-inflammatory effect of ACPA
Initial triggering of the autoimmune response to citrullinated proteins
Goals for future research
Acknowledgements
References
Hormones: Epigenetic Contributors to Gender-Biased Autoimmunity
Introduction
Oestrogen receptors
Oestrogen and autoimmunity
Foxp3 and ERs
ERs and histone modifications
The histone code
Co-activators
Pioneer factors
Co-repressors
ERs and cell proliferation
Epigenetic changes in disease
ERs and SLE
Co-activators and phosphorylation
Endocrine disruptors
Perspectives and future directions
Acknowledgements
References
Epigenetics and Systemic Sclerosis
Introduction
Vascular alterations in SSc
Tissue hypoxia, oxidative stress and SSc
Respiratory burst and post-translational modifications in SSc
The epigenome and its environmental reprogramming
Epigenetics and SSc
Conclusions
References
Epigenetic Regulation of B Lymphocyte Development and Repertoire Selection: Relevance to Autoimmunity
Introduction
Initiation of B cell fate choice
Checkpoints of B cell tolerance to self
Negative regulation of immunoglobulin gene joining
B cell fate commitment and immunoglobulin gene accessibility
Changes in chromatin structure during B cell development
Epigenetic changes through association of different immunoglobulin loci
Epigenetic factors that allow full utilization of the immunoglobulin repertoire
Multistep regulation of B cell maturation
Altered B cell functions in systemic autoimmunity
Impaired B cell tolerance to self in systemic autoimmunity
Epigenetic factors underlying impaired B cell tolerance
Future prospects
Acknowledgement
References
Towards Novel Epigenetic-Based Immuno-Intervention Strategies In Autoimmune Disease.
Protective Effects of Epigenetic Modifications in Experimental Inflammatory Bowel Disease
Introduction
Mechanisms of protein acetylation and deacetylation
Anti-inflammatory effect of epigenetic modifications in vitro
Impact of HDAC inhibition in models of experimental colitis
Perspectives
References
Epigenetic Regulation of Autoimmune Diseases through Deacetylase Inhibition
Introduction
Regulatory T cells
Epigenetic regulation of FOXP3 expression
FOXP3 acetylation and function
Protein lysine deacetylation
HDAC inhibitors in autoimmune disease
Dietary butyrate promotes lysine acetylation by inhibiting deacetylases
The HDAC inhibitor butyrate affects TGF-? signalling and increases Smad3 levels
HDAC inhibitors affect immune-cell proliferation and conversion of antigen triggered T cells into an unresponsive state
Conclusions
References
Histone Deacetylases and Autoimmunity
Introduction
Chromatin acetylation and deacetylation
Histone deacetylases and histone acetyltransferases
Histone acetylation, deacetylation and transcription factors in autoimmunity
Acetylation state and lymphocyte functions
HDACs and their inhibition in autoimmune disease
Conclusions
Acknowledgements
References
Histone Deacetylase Inhibitors as a Therapeutic Modality in Multiple Sclerosis
Introduction
Linking the histone code with MS
Neuronal traits are modulated by HDAC transcription factor complexes
Motor neurone genes modulated by HDACs
The transcription factor E2F1, HDACs and neuronal survival mechanisms
HDACs play important roles in stem cell neuronal differentiation
HDIs lead to acetylation of the Sp1 transcription factor
Immune-system effects of HDIs
HDACs and pro-inflammatory and stress-related pathways in immune settings
HATs, HDACs and the NF-?B pathway
HATs, HDACs and ER stress
Clinical trials and caveats of HDIs
Do HDIs target genes or help chaperone activity as their primary response?
Future directions
References
Index
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The Epigenetics of Autoimmune Diseases

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