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Review
. 2017 Mar 22:8:318.
doi: 10.3389/fimmu.2017.00318. eCollection 2017.

Genetic and Epigenetic Determinants in Autoinflammatory Diseases

Damiana Álvarez-Errico  1 , Roser Vento-Tormo  1 , Esteban Ballestar  1
Affiliations
Review

Genetic and Epigenetic Determinants in Autoinflammatory Diseases

Damiana Álvarez-Errico et al. Front Immunol. .

Abstract

The concept of autoinflammation has evolved over the past 20 years, beginning with the discovery that mutations in the Mediterranean Fever (MEFV) gene were causative of Familial Mediterranean Fever. Currently, autoinflammatory diseases comprise a wide range of disorders with the common features of recurrent fever attacks, prevalence of hyperreactive innate immune cells, and signs of inflammation that can be systemic or organ specific in the absence of pathogenic infection of autoimmunity. Innate immune cells from the myeloid compartment are the main effectors of uncontrolled inflammation that is caused in great extent by the overproduction of inflammatory cytokines such as IL-1β and IL-18. Defects in several signaling pathways that control innate immune defense, particularly the hyperreactivity of one or more inflammasomes, are at the core of pathologic autoinflammatory phenotypes. Although many of the autoinflammatory syndromes are known to be monogenic, some of them are genetically complex and are impacted by environmental factors. Recently, epigenetic dysregulation has surfaced as an additional contributor to pathogenesis. In the present review, we discuss data that are currently available to describe the contribution of epigenetic mechanisms in autoinflammatory diseases.

Keywords: DNA methylation; Familial Mediterranean Fever; autoinflammatory diseases; cryopyrin-associated periodic syndromes; epigenetics; non-genetic factors.

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Figures

Figure 1
Figure 1
Control of innate immune cell function. Monocyte cell membrane receptors as TLR4 and IL-1R allow communication between the cell and the environment. Engagement of the receptors by their ligands (LPS or IL-1β) triggers cell signaling cascades, allowing transcription factors, particularly NF-κB translocation into the nucleus, where it recognizes specific regions of the DNA and recruits other transcription factors, as well as epigenetic enzymes, like TET2 (protein involved in DNA demethylation in myeloid cells). Both the binding of transcription factors to the DNA and the epigenetic modifications of the DNA will increase the expression of inflammatory genes, like the inflammasome complex components. Posttranscriptional modifications of inflammasome proteins play a crucial role in the formation of the inflammasome complex, leading to the activation of caspase-1, which then is able to process the proinflammatory cytokines IL1-β and IL-18 into mature bioactive IL-1β and IL-18 cytokines that are secreted to the external media, creating an inflammatory microenvironment. Importantly, IL-1β is able to amplify its own signal through the binding to IL-1R.
Figure 2
Figure 2
Genetics of autoinflammatory diseases. Different inflammasome complexes are activated by different stimulus recognized by specific sensor molecules. Mutations of genes coding inflammasome proteins have been identified in autoinflammatory disorders. Gain-of-function mutations in NLRP3 gene have been detected in cryopyrin-associated periodic syndromes (CAPS), and mutations in NLRC4 gene have been observed in macrophage activation syndrome (MAS). The mechanistic explanation of the exacerbated inflammatory response for patients with Familial Mediterranean Fever (FMF) has recently been described. Mutation of pyrin in FMF patients causes a decrease in pyrin phosphorylation and deregulation of the inflammasome assembly. Higher amounts of inflammasome complex in the different diseases are associated with increased production of mature IL-1β and IL-18 inflammatory cytokines.
Figure 3
Figure 3
Epigenetics of autoinflammatory diseases. Epigenetic changes have been described in several autoinflammatory diseases. For example, in the case of chronic recurrent multifocal osteomyelitis (CRMO), a failure of histone H3 phosphorylation at serine residue 10 (H3S10p) in the promoter region impairs IL-19 and IL-10 expression. Also, neonatal-onset multisystem inflammatory disease (NOMID) patients are associated with an increase of miR 9-1, miR 199a-2, miR 203, and miR 320a and a decrease of miR 29c and miR 103-2 in their skin. Finally, changes on DNA demethylation dynamics have been recently described in cryopyrin-associated periodic syndromes (CAPS) and Familial Mediterranean Fever (FMF).
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