Biomarkers in food allergy
Apart from clinical determinants of food allergy and the respective gold standard, the oral food challenge, biomarkers represent an area of extensive research. In food allergy the focus is on genetic risk factors, allergen-specific and non-specific humoral and cellular biomarkers.146-148
Although genetic markers for food allergy are not yet at the level of clinical relevance, genes linked to HLA-genes, and more importantly to epithelial integrity and consequently reduced barrier function like filaggrin, SPINK5,149 and SERPINB7, are linked to eczema development and also food allergy.150-156 Given the importance of the exposome in allergy development, epigenetics may even play a more important role. Promising results in the context of peanut allergy await replication in larger cohorts.157,158 Regulation at another level has been linked to the microRNA 193a-5p. It is involved in the post-transcriptional regulation of IL-4 and downregulated in PBMCs from milk allergic children.159 Due to the importance of barrier (dys)function in atopic diseases160-162measurement of skin integrity may be a very important tool to identify high risk populations. Electrical impedance spectroscopy, successfully tested in rodents, may be capable of assessing this biomarker also in humans.163
Allergen extract-based testing methodologies like skin prick test (SPT) and/or specific IgE (sIgE) tend to over-diagnose food allergy. Thus, more specific approaches focusing on specific allergens (see Section on allergens) and epitope-specific antibody response patterns are explored.164 Diversity of IgE-binding to linear epitopes correlated with the severity of peanut and milk allergy165-167 and IgG4 and IgE antibody binding to specific milk epitopes was stronger and more diverse in children who do not outgrow their milk allergy.166 By measuring IgE and IgG4 responses with bead-immobilized milk epitopes and applying machine learning approaches, non-reactivity to baked milk could be predicted twice as successful as by conventional approaches.168-170 The soluble high affinity IgE receptor (FcεRI) may also act as a biomarker for IgE mediated pathologies in a less allergen independent way.171
Although allergen specific T-cells are extremely rare, they display a pronounced Th2 type in allergic individuals.172,173 A subset of allergen-specific memory Th2 cells called TH2a cells, which are CD45+CD27-CD45RB-CRTH2+CD161+CD49+, has been discovered. They are almost exclusively found in allergic individuals, secrete IL-5 and IL-9 and within that group the percentage of type 2 cytokine double, triple, or quadruple positive cells is higher compared to Th2 cells. Moreover, mRNA expression of IL-25-, IL-33- and TSLP-receptors is higher.174
Our understanding of B-cell regulation has significantly evolved over the last few years.175 Evidence is pointing towards an extreme rarity of IgE memory B-cells in peripheral blood of allergic individuals which may be absent in non-peanut allergic individuals.176 New therapeutic and diagnostic options opened up from data on allergen specific monoclonal antibodies that were generated via single-cell sorting of allergen-specific memory B-cells.177,178 B-cell IgE antibody mutational maturation has been associated with barrier dysfunction.179 Recently, the co-emergence of short lived IgE plasmablasts and IgG memory B-cells early in grass AIT in the absence of memory IgE+ B-cells has been reported.180,181 Both subsets shared clonotypes supporting the existence of pools of specific B-cell subsets e.g. from IgG1 positive allergen specific B-cells upon switch factors and stimulation as demonstrated in mice.180,182 Yet many questions on the emergence of IgE producing cells and their regulation have to be answered and new biomarkers in this context will arise.
Functional tests that simulate allergen exposure in vitro like the basophil activation test (BAT) offer the possibility to assess allergen induced IgE crosslinking. The BAT suggests adding significant diagnostic value to IgE based test methods.183-185Promising results on the usage of passive sensitization strategies, mast-cell lines186 or pre-cursors187have been reported.
There is still a significant need to develop biomarkers to diagnose and predict anaphylaxis to prevent near fatalities and fatalities.188,189 Beyond tryptase, which can be a very good marker in the emergency setting when baseline values exist76,190 predictors of life threatening reactions which can be measured on a routine basis or in multi-center trials are still missing.
There is the hope that the expanding array of novel mechanistic and diagnostic biomarkers provide the toolkit to develop algorithms or machine learning approaches to diagnose food allergy and predict treatment outcomes (Figure 5).