SHOULDN'T FOOD CAUSE IMMUNE RESPONSES?

image credits: https://www.health.com/too-much-protein-7486494

The immune system acts against foreign particles, right? Well, we voluntarily ingest foreign particles every day for our survival. Although, the immune system does not react to most of the food we eat, if it does we consider it an anomaly and call it Hypersensitivity or Allergies. This discrimination function of the immune system is termed “Immune Tolerance.” When the immune system is incapable of this function, it also attacks self cells causing Autoimmune disorders apart from hypersensitive reactions. Sung-Wook Hong et.al studied this tolerance mechanism in 2022 in their paper titled “Immune tolerance of food is mediated by layers of CD4+ T cell dysfunction” published in Nature.

The concept presented in their paper suggests that immune tolerance is not because of the absence of an immune response produced against antigens from food. Instead, the responses are indeed produced but they fail and are hyposensitive. They have proved this by a sensitive cell enrichment method, in which the polyclonal CD4+ T cells are activated by food peptides and are proliferated weakly in the secondary lymphoid organs of the gut-liver axis. This weak proliferation was due to the action of T-regulatory cells. The food peptides in the experiment also included a natural one from gliadins which is the trigger in celiac disease (CD). In patients with CD, once gliadins enter their lamina propria through the epithelial barrier of the intestinal mucosa, they are deamidated by the tissue transglutaminase enzyme which makes it immunogenic, it is then taken up by Antigen-presenting cells (APCs) which display the gliadin peptide by HLA class II molecules on their surface. These APCs interact with gliadin-specific CD4+ T helper 1 cells and produce inflammatory cytokines.

Villous Atrophy in celiac disease
image credits: https://bgapc.com/how-to-know-if-you-have-celiac-disease/

The study also observed a weak antibody response was produced by T follicular helper cells which differentiated from a few of the food-specific T cells. Most of the T helper cells generated did not have the standard markers seen in the T helper lineage and resembled naive T follicular-helper-like anergic cells. These cells could not form T helper 1 cells that can cause inflammatory reactions. 

The interesting fact here is, that many of those T helper lineage-negative cells turned into T regulatory cells themselves by an interleukin 2 dependant mechanism. Finally, their results show that the naive CD4+ T cells corresponding to the exposure of food antigens do respond against them by forming a complex set of noncanonical hyporesponsive T helper cell subsets which are not enough or cannot cause inflammation and thus gut pathology, but they have the potential to generate T regulatory cells that could suppress it. This mechanism of the adaptive immune system protects gastrointestinal health by tolerating food antigens. The prospects of this research could benefit the treatments and cure for food allergies, inflammatory bowel diseases, and the creation of orally active vaccines.

REFERENCE:

1. Hong SW, Krueger PD, Osum KC, Dileepan T, Herman A, Mueller DL, Jenkins MK. Immune tolerance of food is mediated by layers of CD4+ T cell dysfunction. Nature. 2022 Jul 28;607(7920):762-8.
2. Liu EG, Yin X, Swaminathan A, Eisenbarth SC. Antigen-presenting cells in food tolerance and allergy. Frontiers in immunology. 2021 Jan 8;11:616020.

COVER IMAGE CREDIT: Image credits: https://health.clevelandclinic.org/allergy-or-intolerance-how-to-tell-the-difference