Review articleThe critical role of epigenetics in systemic lupus erythematosus and autoimmunity
Introduction
Autoimmunity refers to the abnormal state that the dysregulated immune system attacks the healthy cells and tissues due to the loss of immunological tolerance to self-antigens. This aberrant state present clinically in the form of a wide spectrum of autoimmune disorders characterized by the presence of autoreactive immune cells and (or) the development of autoantibodies. These autoimmune responses can be widespread and involve multiple organs and systems, resulting in systemic autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatic arthritis, systemic sclerosis and primary Sjögren’s syndrome, a group of disorders also commonly referred to as connective tissue diseases. The pathological damage of autoimmunity can also be limited to specific organs, causing organ-specific autoimmune diseases such as primary biliary cirrhosis, type 1 diabetes mellitus, multiple sclerosis, Hashimoto’s thyroiditis, Graves’ disease, and skin disorders including vitiligo and alopecia areata.
The origins of the loss of immunological tolerance to self-antigens and the mechanisms underlying autoimmunity onset and development are highly complex and remain largely unknown. Both genetic predisposition and environmental factors such as nutrition, infection, chemicals and ultraviolet exposure are considered to participate in the pathogenic process of autoimmunity [1]. However, how each of these genetic or environmental factors causes autoimmunity is still a challenging question. The emergence of epigenetic studies, arising along with the progressing of human genome project since the end of the last century, has provided us with a brand new perspective to understand these complex mechanisms and has shed light on a new era for research of autoimmunity.
Epigenetics refers to the study of potentially heritable changes in gene expression and function that do not involve alterations of the original nucleotide sequence of the DNA. The major epigenetic mechanisms, i.e. DNA methylation, histone modification, and noncoding RNA, play crucial roles in various life processes such as cellular differentiation, growth, development, ageing, and immune response [2]. These epigenetic mechanisms are implicated in the pathogenesis of in a variety of complex diseases, including autoimmune diseases. As an important complement to the genetic studies, epigenetics provides a better understanding of how environmental triggers cause changes to gene expression and disturbance to immune homeostasis. In addition, compared to the multiple mutant genes or chromosome anomalies, the reversible nature of epigenetic abnormalities provides an easier approach to being “corrected” and holds much greater potential for treatment of autoimmune diseases. Indeed, the exponentially increased number of publications on epigenetic research of autoimmune diseases is an example of how attractive and active this field has become [3], [4], [5].
To better explain the significance of epigenetics in autoimmunity, we will herein start with a brief interpretation of how genetic studies fail to completely elucidate the pathogenesis of autoimmune diseases. Taking SLE as a typical and extensively studied example, we will then present a comprehensive review of the epigenetic mechanisms implicated in pathogenesis of autoimmunity, and how these different epigenetic mechanisms interplay with each other and with genetic variants and environmental factors. We will also briefly review the significant epigenetic findings of other autoimmune disorders such as rheumatic arthritis, systemic sclerosis, and primary biliary cirrhosis to further elucidate the diverse roles of epigenetics in autoimmunity.
Section snippets
Advances in genetic studies of autoimmune diseases
The genetic susceptibility to autoimmune diseases is strongly supported by racial difference in incidence rate, familial aggregation, and by twin studies. Take SLE as an example, its occurrence is four times higher in African-Americans as in European-Americans [6], while the genetic differences among SLE patients from these different ancestral backgrounds have been revealed by various studies [7], [8], [9], [10]. Siblings of SLE patients have greater relative risk for the disease than the
Epigenetic mechanisms and their multi-layer roles in autoimmunity: SLE as an example
It is now recognized that DNA methylation, histone modification and noncoding RNAs are the major epigenetic machinery that regulate the chromatin state and expression activity of genes, thus are involved in various kinds of life processes [42]. These epigenetic mechanisms are of critical importance to the human immune system because of the high plasticity of transcriptome in various immune cells, each with particular roles to play in response to various environmental changes and in protecting
Epigenetics and other autoimmune diseases
Abnormalities of epigenetic regulation have also been demonstrated in many other autoimmune diseases. An interesting finding is that the promoter hypomethylation of CD40L has also been identified in CD4+ T cells from female patients with SSc, RA, and PBC, associated with CD40L overexpression [172], [173], [174]. This phenomenon is similar to what has been revealed in SLE and provides insights into the female predominance of these different autoimmune diseases. It also indicates the presence of
Future perspectives
Our understanding of the etiology and pathogenesis of autoimmune diseases has progressed fundamentally through decades of research efforts, especially with the rapid development in the epigenetic field, which we have sought to highlight throughout this review. It is clear that genetic susceptibility, epigenetic alterations and environmental impact all contribute to the pathogenic mechanisms of autoimmunity, however, there is still a large gap between what needs to be elucidated and what we have
Disclosure statement
The authors declare that they have no conflict of interest.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 81220108017, No. 81430074, No. 81301357 and No. 30972745), the Ph.D. Programs Foundation of Ministry of Education of China (No. 20120162130003), the Hunan Provincial Natural Science Foundation of China (13JJ4025 and 14JJ1009), and the National Key Clinical Specialty Construction Project of National Health and Family Planning Commission of the People’s Republic of China.
References (240)
- et al.
Genes, epigenetic regulation and environmental factors: which is the most relevant in developing autoimmune diseases?
Autoimmun. Rev.
(2012) - et al.
Epigenetic dynamics in immunity and autoimmunity
Int. J. Biochem. Cell Biol.
(2015) - et al.
Epigenetic mechanisms in systemic lupus erythematosus and other autoimmune diseases
Trends Mol. Med.
(2011) - et al.
Widely divergent transcriptional patterns between SLE patients of different ancestral backgrounds in sorted immune cell populations
J. Autoimmun.
(2015) - et al.
Studies of twins with systemic lupus erythematosus. A review of the literature and presentation of 12 additional sets
Am. J. Med.
(1975) - et al.
Immunogenetics of systemic lupus erythematosus: a comprehensive review
J. Autoimmun.
(2015) - et al.
The genomics of autoimmune disease in the era of genome-wide association studies and beyond
Autoimmun. Rev.
(2012) The genetics of human autoimmune disease: a perspective on progress in the field and future directions
J. Autoimmun.
(2015)- et al.
Immunogenetics of systemic sclerosis: defining heritability, functional variants and shared-autoimmunity pathways
J. Autoimmun.
(2015) - et al.
Immunogenetics of juvenile idiopathic arthritis: a comprehensive review
J. Autoimmun.
(2015)
The immunogenetics of Psoriasis: a comprehensive review
J. Autoimmun.
The immunogenetics of multiple sclerosis: a comprehensive review
J. Autoimmun.
Immunogenetics of autoimmune thyroid diseases: a comprehensive review
J. Autoimmun.
Immunogenetics of rheumatoid arthritis: understanding functional implications
J. Autoimmun.
Immunogenetics of type 1 diabetes: a comprehensive review
J. Autoimmun.
The immunogenetics of Behcet’s disease: a comprehensive review
J. Autoimmun.
Understanding inflammatory bowel disease via immunogenetics
J. Autoimmun.
Five years of GWAS discovery
Am. J. Hum. Genet.
Heritability versus the role of the environment in autoimmunity
J. Autoimmun.
DNA methylation of transcriptional enhancers and cancer predisposition
Cell
DNA methylation and mRNA and microRNA expression of SLE CD4+ T cells correlate with disease phenotype
J. Autoimmun.
Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naive CD4+ T cells from lupus patients
J. Autoimmun.
Increased 5-hydroxymethylcytosine in CD4(+) T cells in systemic lupus erythematosus
J. Autoimmun.
T cell CD40LG gene expression and the production of IgG by autologous B cells in systemic lupus erythematosus
Clin. Immunol.
Overexpression of X-linked genes in T cells from women with lupus
J. Autoimmun.
Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation
Immunity
Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene
Immunity
Genome-wide analysis identifies Bcl6-controlled regulatory networks during T follicular helper cell differentiation
Cell Rep.
CD4(+) T cells epigenetically modified by oxidative stress cause lupus-like autoimmunity in mice
J. Autoimmun.
T cell PKCdelta kinase inactivation induces lupus-like autoimmunity in mice
Clin. Immunol.
The catalytic subunit of protein phosphatase 2A (PP2Ac) promotes DNA hypomethylation by suppressing the phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/phosphorylated ERK/DNMT1 protein pathway in T-cells from controls and systemic lupus erythematosus patients
J. Biol. Chem.
MicroRNA-29b contributes to DNA hypomethylation of CD4+ T cells in systemic lupus erythematosus by indirectly targeting DNA methyltransferase 1
J. Dermatol. Sci.
Epigenetics and SLE: RFX1 downregulation causes CD11a and CD70 overexpression by altering epigenetic modifications in lupus CD4+ T cells
J. Autoimmun.
The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells
Immunity
DNA methylation in T cells from idiopathic lupus and drug-induced lupus patients
Autoimmun. Rev.
Epigenetic perspectives in systemic lupus erythematosus: pathogenesis, biomarkers, and therapeutic potentials
Clin. Rev. Allergy Immunol.
Autoimmune disease in the epigenetic era: how has epigenetics changed our understanding of disease and how can we expect the field to evolve?
Expert Rev. Clin. Immunol.
Unraveling the genetics of systemic lupus erythematosus
Springer Semin. Immunopathol.
Genetic ancestry, serum interferon-alpha activity, and autoantibodies in systemic lupus erythematosus
J. Rheumatol.
Activation of the interferon pathway is dependent upon autoantibodies in African-American sle patients, but not in European-American SLE patients
Front. Immunol.
Identification of novel genetic susceptibility loci in African American lupus patients in a candidate gene association study
Arthritis Rheum.
Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort
Arthritis Rheum.
High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus
Genes Immun.
A revised estimate of twin concordance in systemic lupus erythematosus
Arthritis Rheum.
A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap
PLoS Genet.
Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci
Nat. Genet.
Clinical implications of shared genetics and pathogenesis in autoimmune diseases
Nat. Rev. Endocrinol.
Advances in lupus genetics and epigenetics
Curr. Opin. Rheumatol.
Genetics of the type I interferon pathway in systemic lupus erythematosus
Int. J. Clin. Rheumtol.
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