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).