New insights into mechanisms of mucosal mast cells in food allergies

Food allergy, or the aggressive immune system reaction following the consumption of a certain food or food ingredient, typically involves immunoglobulin E (IgE) antibodies and can be potentially life-threatening. Often, the immune response to a food protein can be rapid and severe, requiring emergency care. In recent years, scientific studies have revealed that mucosal mast cells (MMCs), which are immune cells that arise from bone marrow, are excessively produced and play a key role in the severity and sudden onset of food allergy symptoms.

However, the precise mechanisms by which MMCs proliferate excessively are yet to be elucidated. To reveal the underlying mechanism behind the overproduction of MMCs during IgE-mediated food allergy, a team of researchers from Juntendo University, Japan, has focused their efforts on studying intestinal mast cell hyperplasia (increased proliferation) in a mouse model of food allergy.

The research team comprised Associate Professor Nobuhiro Nakano and Dr. Jiro Kitaura from Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Japan, along with Dr. Kenji Oishi and Dr. Toshiaki Shimizu from the Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Japan. Their research findings were published online in Allergy on January 27, 2025.

“Building on our previous research findings, we developed a method to generate mucosal mast cells from bone marrow cells in an in vitro cell culture system. Remarkably, the mast cells generated using our method expressed major histocompatibility complex class II (MHCII) on their cell surface. Despite MHCII being important for presenting antigens, the role of mast cells as antigen-presenting cells has been unclear. This inspired our research team to investigate the role of mucosal mast cells in the pathogenesis of food allergy,” says Nakano, sharing the motivation behind the present research.

Initially, the researchers generated an IgE-mediated food allergy model using ovalbumin in wild-type BALB/c mice and found that MHCII molecules are expressed on the surface of some MMCs in the intestinal mucosa of the food-allergic mice. Next, they generated mice with MHCII-deficient MMCs and mice with wild-type MMCs and developed an IgE-mediated food allergy model using ovalbumin in these mice. Nakano and co-researchers evaluated the degree of intestinal MMC hyperplasia and the severity of hypothermia in the mice model. Notably, in mice with MHCII-deficient MMCs, the excessive proliferation of intestinal MMCs and hypothermia was suppressed.

Driven by their findings, Nakano and colleagues delved into the finer aspects of the immune response in the IgE-mediated food allergy model. They generated induced MMCs by in vitro differentiation of bone marrow cells derived from mice. In vitro antigen presentation assays revealed that the induced MMCs expressing MHCII molecules were able to ingest the food antigens directly or via antigen-specific IgE and then activate specific T helper cells by antigen presentation.

Further experiments showed that the activated T helper cells were involved in triggering a cascade of molecular interactions by secretion of key interleukins, which are cytokine messenger molecules that stimulate the immune system. Specifically, interleukin-4 (IL-4) and IL-5 were secreted, which significantly enhanced the production of the mast cell growth factor IL-9 by MMCs. Ultimately, excess IL-9 caused the overproduction of MMCs, resulting in exaggerated food allergy symptoms.

“At present, IgE-mediated food allergies are quite prevalent across different regions of the world, but pharmacological agents to manage food allergies are limited,” highlights Nakano. “Our findings can aid the development of medications to alleviate the symptoms of food allergies by inhibiting the excessive proliferation of mucosal mast cells,” concludes Nakano.

In summary, this study unveils the intricate molecular mechanisms involved in immune response during food allergies and sheds light on potential therapeutic strategies to target MHCII-expressing MMCs.