Serological biomarkers to detect food allergy

• Applicants: Dr. Magda Babina; Dr. Sabine Dölle-Bierke
• Subject Area: Clinical Immunology and Allergology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409525714

Heterogenous manifestations and overlaps with other conditions can hamper the diagnosis of FA. The aim of this project lies in the identification of sensitive molecules to assist in FA diagnosis using biofluids, that can be cryopreserved. In the previous application, we hypothesized that 1. sensible signatures of biomarkers would better capture FA than single entities, and 2. noncoding RNAs would turn out an untapped source of FA-related biomarkers. Profiling and quantification of an extensive initial catalog and application of the random forest algorithm did not only ascertain that the above assumptions are correct, but also succeeded in narrowing down the repertoire to a manageable size.Our data indicated that in addition to identifying an acute event, miRNAs may serve as markers to distinguish between patients and healthy subjects in a non-acute setting. In the second phase we will continue elaborating on this aspect to identify individuals prone to suffer a severe episode.A novelty is the inclusion of saliva as a noninvasive, miRNA-rich bioliquid. We will explore whether saliva-contained miRNAs can complement signatures found in serum to mirror a positive oral food challenge. As with serum, baseline saliva will be employed to pinpoint individuals at risk of severe food reactions. Experimental approaches with skin mast cells (MCs) and database searches revealed that the discriminative miRNAs emanate either directly from MCs or from other myelocytes. We plan to pinpoint more precisely the releasing cells, identify the RNA-containing compartments (protein-bound or exosome-encapsulated), and begin to determine the molecular underpinnings of their secretion. For the non-MC entities, we will survey two potential scenarios: A direct one involving IgG/IgE receptor-allergen complexes and an indirect route, in which MCs act as intermediaries. miR-4488 and -718 show narrow expression, as they are chiefly produced by stimulated MCs. Being not pre-formed, but released instantly after synthesis, they plausibly serve in MC-cell communication at nearby or remote locations. We will investigate their endocytosis by foreign cells to learn whether these RNAs truly qualify as messengers.Overall, this collaborative effort aims to deduce whether successful tolerance outcomes are mirrored by adaptations in cellular and molecular profiles, of which we will cover the soluble entities, assessing whether tolerized patients show reduced changes on food challenge compared to the same patients prior to desensitization. In summary, after completion, this project will have extended the repertoire of soluble biomarkers in serum and (potentially) saliva to aid in the diagnosis of acute FA, to distinguish patients from non-patients at baseline and to monitor tolerance development. Mechanistically, we will have identified the major sources of the informative miRNAs and modes of release, also advancing areas like MC physiology, effector cell communication and miRNA biology.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 339: Food Allergy and Tolerance (Food@)