The Role of Epigenetics in Autoimmune/Inflammatory Disease

Abstract

Historically, systemic self-inflammatory conditions were classified as either autoinflammatory and caused by the innate immune system or autoimmune and driven by adaptive immune responses. However, it became clear that reality is much more complex and that autoimmune/inflammatory conditions range along an “inflammatory spectrum” with primarily autoinflammatory vs. autoimmune conditions resembling extremes at either end. Epigenetic modifications influence gene expression and alter cellular functions without modifying the genomic sequence. Methylation of CpG DNA dinucleotides and/or their hydroxymethylation, post-translational modifications to amino termini of histone proteins, and non-coding RNA expression are main epigenetic events. The pathophysiology of autoimmune/inflammatory diseases has been closely linked with disease causing gene mutations (rare) or a combination of genetic susceptibility and epigenetic modifications arising from exposure to the environment (more common). Over recent years, progress has been made in understanding molecular mechanisms involved in systemic inflammation and the contribution of innate and adaptive immune responses. Epigenetic events have been identified as (i) central pathophysiological factors in addition to genetic disease predisposition and (ii) as co-factors determining clinical pictures and outcomes in individuals with monogenic disease. Thus, a complete understanding of epigenetic contributors to autoimmune/inflammatory disease will result in approaches to predict individual disease outcomes and the introduction of effective, target-directed, and tolerable therapies. Here, we summarize recent findings that signify the importance of epigenetic modifications in autoimmune/inflammatory disorders along the inflammatory spectrum choosing three examples: the autoinflammatory bone condition chronic nonbacterial osteomyelitis (CNO), the “mixed pattern” disorder psoriasis, and the autoimmune disease systemic lupus erythematosus (SLE).

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

“…In accordance with these results, it has been described that mice with a genetic deletion of the VPAC2 gene exhibit an exacerbation of EAE induced by MOG35-55 compared to wild-type mice, presenting an increased pro-inflammatory cytokine profile (TNF-α, IL-6, IFN-γ, and IL- 17) and reduced production of anti-inflammatory cytokines (IL-10, TGF-β, and IL-4) in the CNS and lymph nodes. In addition, the proliferative index and the in vivo suppressor activity of CD4 + CD25 + FoxP3 + Tregs are markedly reduced in KO VPAC2 mice with EAE [289].…”

“…Most of them were created by modifying endogenous peptides and displayed different affinities and selectivities, with the first descriptions unable to differentiate between the two receptors [56][57][58]. Selective agonists for VPAC1 receptor have been generated, such as [K 15 , R 16 , L 27 ]VIP(1-7)/GRF (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) [59], [Ala 11,22,28 ]VIP [60], [L 22 ]VIP [61], [R 16 ]PACAP(1-23) [62], and LBT-3393 [63]. A selective antagonist is also available: PG97-269 [64].…”

“…According to the Autoimmune Diseases Coordinating Committee of the National Institutes of Health in the United States, the prevalence of autoimmune pathologies is estimated at up to 8% of the population. These pathologies are characterized by a complex etiology combining different genetic, epigenetic, and environmental factors, such as tobacco use or history of infections, which result in the alteration of the regulation of the immune system [14][15][16][17]. These diseases lead to substantial levels of morbidity, a significant reduction in the quality of life, and premature death [18][19][20][21].…”

<p>Towards Precision Medicine in Systemic Lupus Erythematosus</p>

“…In particular (CpG DNA methylation, histone modifications and non-coding RNAs are likely to be critically involved. 56,57 Most of the genes that are associated with SLE, with known function, can be sub-divided according to one of four-key molecular pathways: genes that affect lymphocyte activation; genes related to innate immune activation and signalling; genes related to handling of apoptotic debris, chromatin and IC; genes related to a specific organ damage in SLE. Some genetic variants may fall within more than one category.…”

Epigenetic Regulation in Etiology of Type 1 Diabetes Mellitus

“…The se changes are highly mosaic in a given tissue an d insert a high degree of epigenetic variability between cells [17]. Such epigenetic modifications could alter immune response by masking/unmasking potential an tigens an d by modulating immune reactions of effector cells [18].…”