Ticked Off: Allergic Effector Cells in the Pathogenesis of Alpha-gal Syndrome

Alpha-gal syndrome (AGS) is a novel allergic disease characterized by hypersensitivity responses following exposure to the glycan galactose-alpha-1,3-galactose (alpha-gal or α-Gal) attached to mammalian proteins and fats in food, supplements, and medications. Bites from hard-bodied ticks, including Amblyomma americanum (Aa or lone star tick) in the United States, have been identified as drivers of allergic sensitization to alpha-gal. Here, we review clinical presentation, epidemiology, diagnosis, and current understanding of the mechanistic drivers of AGS, with particular focus on the roles of allergic effector cells - mast cells (MCs) and basophils. We explore unique clinical characteristics of AGS through the lens of alpha-gal-specific IgE and MC activation in AGS. We propose potential explanations for delayed symptom onset, inconsistent symptom development, and persistence of allergic symptoms in some AGS patients despite removing all mammal products from the diet.

Current evidence implicate bites from hard-bodied ticks as the primary sensitizing agent in AGS. However, there is emerging evidence that other ecto- and endoparasites may also induce alpha-gal-specific IgE. Multiparameter flow and mass cytometry and RNA sequencing have demonstrated an enrichment of unique populations of T, B, invariant natural killer T (iNKT), natural killer B (NKB) and MC progenitor cells in human volunteers with AGS. Recently developed mouse models of AGS will support future studies to identify which cells are critical for the development of AGS. In vitro models of the allergic effector phase of AGS using human sera and novel human alpha-gal-specific IgE monoclonal antibodies in humanized rat allergic effector cell lines, human basophils, human MC lines, and primary human MC cultures, confirm alpha-gal-induced allergic effector cell activation. They also provide a system to study potential alpha-gal-antigen-independent drivers of MC activation in AGS. Efforts are ongoing to understand the epidemiology and immune mechanisms of AGS. Novel reagents (e.g. alpha-gal-specific monoclonal antibodies) and murine AGS models will facilitate deeper investigation of tick-driven, alpha-gal-specific IgE and allergic effector cell-induced pathology in AGS.