A Potential Role for Epigenetically Mediated Trained Immunity in Food Allergy

Abstract

The prevalence of IgE-mediated food allergy is increasing at a rapid pace in many countries. The association of high food allergy rates with Westernized lifestyles suggests the role of gene-environment interactions, potentially underpinned by epigenetic variation, in mediating this process. Recent studies have implicated innate immune system dysfunction in the development and persistence of food allergy. These responses are characterized by increased circulating frequency of innate immune cells and heightened inflammatory responses to bacterial stimulation in food allergic patients. These signatures mirror those described in trained immunity, whereby innate immune cells retain a "memory" of earlier microbial encounters, thus influencing subsequent immune responses. Here, we propose that a robust multi-omics approach that integrates immunological, transcriptomic, and epigenomic datasets, combined with well-phenotyped and longitudinal food allergy cohorts, can inform the potential role of trained immunity in food allergy.

Keywords: Immunology; Omics; Systems Biology.

Graphical abstract

Figure 1

Proposed Role of TRIM in Chronic Inflammatory Diseases Sterile inflammation is a hallmark of autoimmune diseases, autoinflammatory diseases, and inflammatory diseases such as atherosclerosis. Several danger-associated molecular patterns (DAMPs) have been shown to induce inflammation in innate immune cells. Metabolic intermediates including oxidized low-density lipoprotein (ox-LDL) and mevalonate induce epigenetic modifications and metabolic rewiring in monocytes and macrophages, resulting in a hyperinflammatory, hypermetabolic state. These are produced in high levels in atherosclerosis and hyper-IgD syndrome, respectively, and therefore TRIM may play an integral role in the chronic inflammation seen in these diseases. Other DAMPs have been proposed as inducers of TRIM in autoimmunity, including citrullinated histones in RA, and monosodium urate in SLE patients with cardiovascular comorbidities. The epigenetic reprogramming in TRIM results in an increased production of pro-inflammatory cytokines, which is also consistently reflected in the serum levels of patients with autoimmune and autoinflammatory diseases.

Figure 2

Transcription Factors Remodel DNA Accessibility and Epigenetic Marks to Establish Cell Identity and Response to Exogenous Signals (A) LDTFs establish cell-type-specific DNA accessibility landscapes. (B) Exposure of cells to environmental signals such as MAMPs and DAMPs induces remodeling of chromatin by SDTF and chromatin remodeling complexes. This remodeling generally occurs at intermediately accessible regions, with constitutively active promoters and heterochromatin not affected. The newly established active or inactive regions influence the cell's response to future environmental signals.

Figure 3

The Potential Role of Microbial Exposures and the Trained Immune Phenotype in Skewing the Th2 Phenotype (A) As shown by the proinflammatory response to LPS in allergic cells that have not had sufficient microbial exposures, causing epigenetic and metabolic rewiring of naive CD4 T cells, leading to improper development of the Th1 pathway and bias toward the Th2 phenotype. (B) The possible preventative role of BCG and microbial exposures in allergy, by inducing production of anti-inflammatory cytokines to ensure appropriate development of Th1/Th2 balance.