Science Update

Recent Study Finds New Pathogenic Mechanism of Non-IgE-Mediated Food Allergies

According to a recent pilot study published in Allergy and Asthma Proceedings, induction of neutrophil extracellular traps (NETs) containing pro-inflammatory mitochondrial DNA may be a new pathogenic mechanism of innate, immune-mediated, non-immunoglobulin E (non-IgE)-mediated food allergies. A food allergy is defined as the immune-mediated adverse reaction to specific dietary antigens, and it is classified as either an IgE-mediated food allergy or a non-IgE-mediated food allergy.

The non-IgE-mediated food allergy primarily affects the gastrointestinal mucosa, whereas the IgE-mediated food allergy can elicit fatal outcomes. The formation of NETs is another method by which neutrophils kill pathogens and control microbial infections. However, these structures also impart deleterious effects seen in various autoimmune and inflammatory conditions. In addition to the primary function of mitochondria to meet energy requirements of the cell, this organelle functions as an active regulator of the innate immune response against sterile and infectious insults.

The aim of the current study was to convey the findings and relevance of previous studies that showed mitochondrial DNA in the form of NETs. The NET-induced tissue damages are potentially new mechanisms contributing to non-IgE food allergies due to the ability of mitochondrial DNA to induce inflammatory responses through pro-inflammatory cytokine production.

This study population consisted of six participants. Four participants were placed in a major food allergy study group (with subjects 1 to 4), along with two healthy participants (subjects 5 and 6) who were placed into a subgroup. All subjects had negative allergen-specific IgE test results. Subjects 1 and 2 had no history of adverse food-related reactions and served as the negative food controls. Both subjects 3 and 4 experienced irritable bowel syndrome (IBS) after ingestion of allergen-containing foods. Subjects 5 and 6 also had no history of non-IgE-mediated food allergies and served as additional food-negative controls. Researchers isolated neutrophils from subjects and treated them with food antigens that evoked negative and positive leukocyte activation responses using real-time polymerase chain reaction to analyze the cellular origin site of the released free DNA. Leukocyte calprotectin and S100 calcium-binding protein A12 were used as markers of NET formation. 

The results demonstrated that the cellular supernatants of neutrophils treated with food antigens that elicited positive leukocyte activation responses contained increased nuclear and mitochondrial DNA levels. However, neutrophils treated with foods that evoked a negative leukocyte activation response did not release nuclear or mitochondrial DNA. These results confirmed the objective of the researchers. The pro-inflammatory mitochondrial DNA from NET induction may be the critical link for better understanding non-IgE-mediated food allergies. However, further studies with larger sample sizes from populations with other non-IgE-mediated food allergy disorders (e.g., food protein-induced enterocolitis syndrome) are still needed to reproduce these findings and to help discover better diagnostic tests for improving clinical management of non-IgE-mediated food allergy and other inflammatory conditions. 

For patients or clients who have tested positive for non-IgE-mediated food allergies, it is important to support a healthy immune balance and mitigate the effects of food antigens. Eliminating the offending proteins (e.g., gluten, casein, soy, whey, egg, peanut) is a popular solution, which is currently considered the “gold standard” in functional and integrative medicine for helping to manage non-IgE-mediated food allergies. Total avoidance of foods that cause an immune response may be unrealistic for these individuals. Therefore, utilizing specific dietary supplements may help occasional dietary exposure to be less problematic.

Individuals who do not secrete sufficient proteolytic enzymes may suffer from multiple food allergies or sensitivities. Dipeptidyl peptidase-4 (DPP-IV) is a special protease shown to aid in the breakdown of gluteomorphin (derived from gluten-containing grains) and casomorphin (from casein proteins found in dairy products) that are less abundant in the intestinal lining of individuals with gluten sensitivity and intolerance. It is recommended that these patients use digestive enzyme products that include DPP-IV, along with other proteolytic enzymes, such as aspergillopepsin, alkaline protease, and peptidase to support the optimal breakdown of hard-to-digest proteins and help minimize any potential adverse effects from occasional consumption. Bromelain, a pineapple-derived proteolytic enzyme, also supports protein digestion.

By Caitlin H. Higgins, MS, CNS, LDN