Systemic CXCL13 as a possible sex-dependent biomarker to identify neuroinflammation in subclinical food allergies

Introduction/Rationale: Patient cohort studies have reported an association between subclinical food allergies and behavioral issues. Using an orally challenged subclinical cow’s milk allergy (CMA) mouse model, we previously demonstrated behavioral changes that were accompanied by neuroinflammation in male mice. While these observations highlighted the importance of acknowledging one’s hypersensitivity status, identifying individuals with subclinical food allergies is difficult, as they do not exhibit common allergic symptoms. In our CMA male mice, CXCR5-immunoreactive (CXCR5+) neurons, CD45+CXCR5+ leukocytes, and CXCL13, the chemokine for CXCR5, were increased in the frontal cortex. In addition, CXCR5+ cells were found along with the superior sagittal sinuses of the dura and decreased with CXCR5-blocking antibody in male, but not in female, CMA mice. These findings suggested that CXCL13/CXCR5-mediated central chemotaxis occurs in sensitized mice in a sex-specific manner.

Methods: Hypothesizing that the elevation of circulating CXCL13 could serve as a potential sex-dependent biomarker for detecting neuroinflammation in subclinically sensitized individuals, we measured plasma CXCL13 by ELISA.

Results: Plasma CXCL13 levels were strongly correlated with brain CD45+CXCR5+ cell number and moderately correlated with allergen-specific IgE levels in male CMA mice. Males showed 100% sensitivity (AUC = 0.9349) and females showed 88% sensitivity (AUC = 0.8151) for CXCL13 at 50% specificity; however, both sexes showed similar AUCs (0.9288, 0.9132) and sensitivities (92%, 95%) for BLG-specific IgE. Therefore, at a fixed specificity (50%), CXCL13 is a more sensitive biomarker for males than females.

Conclusion: Together, plasma CXCL13 could detect food-allergen-induced neuroinflammation as a systemic sex-dependent biomarker in subclinically sensitized individuals. Validating the diagnostic value of CXCL13 in different food allergies and elucidating the mechanism of allergen-triggered CXCL13 induction are warranted in future studies.