Immunologic comparison of alpha-gal sensitized and non-sensitized groups from a community based sample

Alpha-gal syndrome is delayed, IgE-mediated hypersensitivity reaction to galactose-α-1, 3-galactose (alpha-gal), a carbohydrate epitope found in non-primate mammals. Sensitization is typically triggered by tick bites, with some sensitized individuals progressing to severe allergic reactions to red meat and other alpha-gal containing substances. Despite increasing clinical recognition, the immunologic mechanisms underlying alpha-gal sensitization remain poorly defined. Therefore, this article aimed to identify whether there are distinct immunologic differences between sensitized and non-sensitized groups sampled from a well-characterized, community-based cohort.

Participants were matched by age, sex, and race/ethnicity then classified as sensitized (AG+) or non-sensitized (AG-) by laboratory criteria. Demographics, health history, and target concentration between the groups were compared using descriptive statistics, Wilcoxon tests, and multivariable logistic modeling.

AG+ participants (n=50) showed elevated concentrations of innate immune markers including CD163, Chitinase-3-like 1, gp130, and MMP2 (all p < 0.0001), and reduced levels of regulatory cytokines including IL-10, IL-12p40, IL-35, LIGHT, and interferons IFNα2 and IFNβ. Logistic regression identified three independent cytokine predictors of alpha-gal sensitization: IL-1α (OR = 2.75, 95% CI: 1.40-5.41, p = 0.004), IL-35 (OR = 0.22, 95% CI: 0.10-0.49, p < 0.001) and LIGHT (OR = 0.19, 95% CI: 0.05-0.75, p = 0.02).

Our findings showed distinct differences between AG+ and AG- groups, marked by increased pro-inflammatory signaling and decreased immune regulatory cytokines. These results support a model of immune dysregulation involving both the innate and adaptive arms of the immune system. Further research is needed to understand the functional role of these markers for those with clinical disease.