Biomarkers Mechanism Readout Successful OIT Successful SLIT Successful EPIT References

In vivo

In vivo

In vivo

In vivo

In vivo

In vivo

In vivo

Skin Prick Test (SPT) In situ mast cell degranulation Wheal size Reduction during therapy Reduction during therapy No significant changes 107,140,160–166
Oral Food Challenge (OFC) In situ diagnostic test whereby a specific amount of allergen is ingested in a standardized setting to note threshold of responsiveness and tolerance. Clinical reactivity upon exposure Increase in threshold of tolerated food Increase in threshold of tolerated food Increase in threshold of tolerated food 96,162,167,168

Cellular

Cellular

Cellular

Cellular

Cellular

Cellular

Cellular

Basophil Activation Test (BAT)
Measures FcɛRI cross-linking and basophil activation both by IgE dependent and independent activation by in vitro exposure of basophils with extracts or allergens. May also use a passive sensitization strategy involving basophils from healthy donors and serum from allergic individuals. %CD63+ positivity, CD 203c expression Diamine Oxidase (DAO)
Reduction of %CD63+ during therapy
Reduction of %CD63+ during therapy
Transient reduction %CD63+ during therapy
15,127,162,163,169–172
Mast cell Activation Test (MAT)
Mast cells are activated through IgE crosslinking of FcɛRI expressed on cell surfaces. Measures mast cell activation through in vitro exposure of mast cells with extracts or allergens. LAD2 or hMCs (Expressing CD117+) May also use a passive sensitization strategy involving mast cells from healthy donors and serum from allergic individuals. %CD63 and CD107+ positivity
N/A
N/A
N/A
173–175 *Indirect evidence used to diagnose IgE-mediated FA.
Tregs Via IL-10 and TGF- ß release (regulatory cytokines), directly inhibiting mast cell degranulation and use CTLA-4 and PD-1 mechanisms 72 CD4+ CD25+FOXP3+ in whole blood and isolated PBMCs Increased during therapy No significant changes Induction of LAP1 Tregs *indirect evidence in mice 112,176,177
Th2a APCs present allergen to naïve T cells which provoke differentiation into Th2 responses (Th2a). 178Th2a increase sIgE, causing IL-4 to prime naïve CD4+ T cells to differentiate into Th2. CD161, CD49d, classical Th2-related surface markers in whole blood and isolated PBMCs Reduction during therapy N/A N/A 70,179–181
DCregs
DCregs produce IL-12, IL-27 and IL-10 skewing immune responses from Th2 to Th1.178 Downregulation of DC2 cell subset and an increase of DCregs support differentiation of Tregs and Bregs.182
C1QA and FCGR3A in whole blood and isolated PBMCs
N/A
Increased during therapy
N/A
183,184
Bregs Br1 cells upregulate IgG4 during their transition to plasma cells.185 Treg induction via IL-10 and TGF- ß secretion, direct suppression (IL-10) of Teff and indirect (IL-10) via DC inhibition.186 IL-10 expression and secretion Increased during therapy N/A Increased during treatment 185,187 *Indirect evidence.
ILC Type 2 cytokines ILC2s produce type 2 cytokines (IL-4, IL-5, IL-9, IL-13). Common alarmins recruit ILC2s to release proinflammatory cytokines. Antagonization of Th2 responses because of successful AIT. N/A IL-4, IL-5, IL-9, IL-13 in whole blood and isolated PBMCs Il-33 N/A Reduction during therapy Reduction during therapy Reduction during therapy N/A Tendency to decrease, however not significant during therapy 65,188 163,176,189
Tfh13 cells
Subset of Th cell found in B-cell follicles that controls antibody isotypes switching, affinity maturation and B-cell memory.
CXCR5, PD-1, Bcl-6, Il-21
N/A
N/A
N/A
190 *Continuous allergen exposure blocks CXCR5 expression in memory Tfh cells.

Antibody based

Antibody based

Antibody based

Antibody based

Antibody based

Antibody based

Antibody based

Allergen and specific IgE (sIgE)
Culprit molecule of IgE mediated allergy. Binds to high-affinity IgE receptor FcɛRI on surfaces of mast cells, basophils and eosinophils, some sub-types of APCs and via the low affinity IgE receptor FcɛRII.
Extract-specific IgE Allergen-specific IgE
Transient increase, then decrease throughout therapy
Transient increase, then decrease throughout therapy
Decrease in late phase of therapy
107,113,191–196,114,127,160,162,164–166,170
sIgG4
Soluble IgG4 directly interacts with allergens, membrane-bound IgG4 interferes with allergen-mediated IgE crosslinking and inhibits mast cells activation and basophil degranulation.
Extract-specific IgG4 Allergen-specific IgG4
Increase during therapy
Increase during therapy
Increase during therapy
113,127,191,197,198,140,160,162,164–166,170,176
sIgA
Tregs (Tr1) secrete IL-10 and TGF-ß to induce class-switch and promote IgG4, IgA production.104 Similar to IgG4, IgA may act specifically at the level of mucosal surfaces.
Extract-specific IgG4 Allergen-specific IgG4
Increase during treatment
Increased during treatment
N/A
108,194,199,200