The Revolution of Epigenetics in the Field of Autoimmunity

Biologics: Targets and Therapy, 2012

The lack of complete concordance of autoimmune disease in identical twins suggests that nongenetic factors play a major role in determining disease susceptibility. In this review, we consider how epigenetic mechanisms could affect the immune system and effector mechanisms in autoimmunity and/or the target organ of autoimmunity and thus affect the development of autoimmune diseases. We also consider the types of stimuli that lead to epigenetic modifications and how these relate to the epidemiology of autoimmune diseases and the biological pathways operative in different autoimmune diseases. Increasing our knowledge of these epigenetic mechanisms and processes will increase the prospects for controlling or preventing autoimmune diseases in the future through the use of drugs that target the epigenetic pathways.

Journal of Developmental Origins of Health and Disease, 2011

Recent advances in epigenetics have enhanced our knowledge of how environmental factors (UV radiation, drugs, infections, etc.) contribute to the development of autoimmune diseases (AID) in genetically predisposed individuals. Studies conducted in monozygotic twins discordant for AID and spontaneous autoimmune animal models have highlighted the importance of DNA methylation changes and histone modifications. Alterations in the epigenetic pattern seem to be cell specific, as CD4+ T cells and B cells are dysregulated in systemic lupus erythematosus, synovial fibroblasts in rheumatoid arthritis and cerebral cells in multiple sclerosis. With regard to lymphocytes, the control of tolerance is affected, leading to the development of autoreactive cells. Other epigenetic processes, such as the newly described miRNAs, and post-translational protein modifications may also be suspected. Altogether, a conceptual revolution is in progress, in AID, with potential new therapeutic strategies target...

Journal of Autoimmunity, 2010

Advances in genetics, such as sequencing of the human genome, have contributed to identification of susceptible genetic patterns in autoimmune diseases (AID). However, genetics is only one aspect of the diseases that does not reflect the influence of environment, sex or aging. Epigenetics, the control of gene packaging and expression independent of alterations in the DNA sequence, is providing new directions linking genetics and environmental factors. Recent findings have contributed to our understanding of how epigenetic modifications could influence AID development, showing differences between AID patients and healthy controls but also showing how one disease differs from another. With regards to epigenetic abnormalities, DNA methylation and histone modifications could be affected leading to large spatial and temporal changes in gene regulation. Other epigenetic processes, such as the influence of the ionic milieu around chromatin and DNA supercoiling stresses may be suspected also. The newly described role of microRNAs in control of gene expression is important by promoting or suppressing autoreactivity in AID. As a consequence control of cellular processes is affected becoming conducive, for example, to the development of autoreactive lymphocytes in systemic lupus erythematosus, synoviocyte proliferation in rheumatoid arthritis, or neural demyelination in multiple sclerosis. Application of epigenetics to AID is in its infancy and requires new hypotheses, techniques, tools, and collaborations between basic epigenetic researchers and autoimmune researchers in order to improve our comprehension of AID. From this will arise new therapeutics, means for early intervention, and perhaps prevention.

Frontiers in Cell and Developmental Biology

Editorial on the Research Topic Epigenetic aspects of autoimmune diseases Genetics, environmental factors, and epigenetics all contribute to autoimmune disease onset and progression (Gulati and Brunner, 2018). Most of the earlier research on autoimmune diseases focused on genetics and environmental factors. Research into genetics, in attempting to identify specific risk alleles has had limited success, for example, identifying HLA-DRB1, a complex of genes coding for cell surface proteins, has emerged as a risk allele for autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) (Niu et al., 2015). However, genetic findings have not been sufficient to explain the majority of RA and SLE cases, autoimmune diseases in general, or the typical delay in initial onset, occurring later in life (early to mid-adulthood), in most autoimmune diseases. Even with identification of a risk allele, it is not clear if it is a cause of the disease or just a subsidiary factor. Likewise, environmental factors (e.g., viruses, toxins, bacteria, etc.) also present confusion as to their role since a variety of environmental factors and combinations can be involved in triggering onset of an autoimmune disease (Arleevskaya et al., 2016; Arleevskaya et al., 2020). For example, Epstein-Barr virus (EBV) is suspected of a role in autoimmune diseases, especially multiple sclerosis (MS) (Bjornevik et al., 2022). However, almost all adults have had exposure to EBV but only a small percentage develop MS and onset can be many years after initial infection with EBV. It may be that another environmental factor and/or a genetic risk allele needs to be involved, such as an especially heavy cellular viral load of EBV that may occur by viral binding and entry using HLA-DR cell surface proteins as opposed to other HLA types (Agostini et al., 2018). Research into the involvement of epigenetics in autoimmune diseases has been steadily increasing in the past two decades. Epigenetics is the control of gene expression or suppression without changing the underlying DNA sequence of the gene (Renaudineau et al., 2011). Epigenetics can involve methylation of DNA, which typically suppresses the underlying gene, or demethylation of the DNA as a step towards expression (Fali et al., 2014). Coordinated with the DNA methylation state are

Journal of Reproductive Immunology, 2014

Epigenetic mechanisms such as DNA methylation, histone modification, and micro RNA signaling regulate the activity of the genome. Virtually all aspects of immunity involve some level of epigenetic regulation, whether it be host defense or in mediating tolerance. These processes are critically important in mediating dynamic responses to the environment over the life course of the individual, yet we are only just beginning to understand how dysregulation in these pathways may play a role in immune disease. Here, we give a brief chronological overview of epigenetic processes during immune development in health and disease.

Journal of Autoimmunity, 2009

World Journal of Immunology, 2015

Autoimmunity is believed to develop when genetically predisposed individuals undergo epigenetic modifications in response to environmental factors. Recent advances in the understanding of epigenetic mechanisms suggest, in autoimmune diseases, a multi-step process involving environmental factors (e.g. , drugs, stress) and endogenous factors (e.g. , cytokines, gender), both leading to the deregulation of the epigenetic machinery (DNA methylation, histone modifications, miRNA), that in turn specifically affects the immune system and/or the target organ(s). Such effect is reinforced in those patients with risk variants mapping to epigenetically-controlled regulators of immune cells. As a consequence, autoreactive lymphocytes and autoantibodies are produced leading to the development of the autoimmune disease. Potential new therapeutic strategies and biomarkers are also addressed.

Biomedicine & Pharmacotherapy, 2017

Recent genome-wide association studies have documented a number of genetic variants to explain mechanisms underlying autoimmune diseases. However, the precise etiology of autoimmune diseases remains largely unknown. Epigenetic mechanisms like alterations in the post-translational modification of histones and DNA methylation may potentially cause a breakdown of immune tolerance and the perpetuation of autoreactive responses. Recently, several studies both in experimental models and clinical settings proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically, data support the impact of epigenetic changes in autoimmune diseases, in some cases based on mechanistical observations. Epigenetic therapy already being employed in hematopoietic malignancies may also be associated with beneficial effects in autoimmune diseases. In this review, we will discuss on what we know and expect about the treatment of autoimmune disease based on epigenetic aberrations.

Deals with the nature of human behaviors, and both internal and external factors that affect these behaviors.

American Journal of Legal History 63(2), 2023

Special symposium issue of the American Journal of Legal History 63(2): Legal systems past and present classify people in ways that entail particular rights, obligations, capacities, and incapacities. Historically, statuses have distinguished free and unfree (and various intermediate statuses); citizen and alien (and often various intermediate statuses); membership in legally recognized religious, ethnic, tribal, or racial groups; marital and other family statuses (spouse, divorcee, dependent, heir, etc.); and many others. Henry Sumner Maine, the nineteenth-century comparative legal historian, proposed that ‘the movement of the progressive societies has hitherto been a movement from Status to Contract’. He envisaged history, at least in the West, as a progressive detachment of individual rights and capacities from the involuntary, inherited statuses connected with family and tribe. Yet in spite of a trend towards liberal individualism in modern secular states, status distinctions still permeate law, though they are usually conceived of and discussed in narrowly circumscribed, compartmentalized forms: status of citizen, immigrant, or alien; minor, dependent, or adult; married or domestic partner; heir; corporate person; member of the military or the clergy; and ‘personal status’ under various colonial or postcolonial regimes. It is rare to see anyone address in broad terms the continuing salience of status in modern Anglo-American legal contexts, though there are rare exceptions. This collection grew out of an interdisciplinary conference on the dynamics of juridical status, organized at Washington and Lee University in November 2019, bringing together scholars of legal history, religious history, legal theory, and political philosophy in the hope that a conversation on this topic that ranged across history and geography as well as various disciplines might yield new insights about the workings of status more generally in law. The five articles included in this symposium issue focus on ancient and medieval historical phenomena involving status, with a geographical span reaching from Europe to India.