Hereditary alpha-tryptasemia demonstrates relative basophil enrichment without signs of cellular hyperreactivity

Hereditary alpha-tryptasemia (HαT) is an autosomal dominant trait caused by increased tryptase alpha/beta 1 (TPSAB1) copy number, resulting in elevated serum tryptase levels. Although often asymptomatic, HαT is associated with anaphylaxis, flushing, and connective tissue abnormalities. Although mast cells are primarily implicated, basophil involvement in HαT remains poorly defined.

Our aim was to compare basophil proportions, MRGPRX2 expression, and responsiveness to IgE-dependent and IgE-independent activation in individuals with HαT, individuals with indolent systemic mastocytosis (ISM), and healthy controls (HCs).

Peripheral blood was obtained from individuals with HαT (n = 20), individuals with ISM (n = 31), and HCs (n = 8). Basophils were identified by flow cytometry; relative basophil frequencies and surface expression of FcεRI and MRGPRX2 were assessed. Basophil activation was evaluated by CD63 upregulation following stimulation with N-formylmethionyl-leucyl-phenylalanine, anti-FcεRI antibody, mastoparan, and compound 48/80.

Relative basophil proportions were higher in subjects with HαT than in subjects with ISM. FcεRI surface expression was preserved in those with HαT but reduced in those with ISM, whereas MRGPRX2 expression was not detected at functionally relevant levels. Basophils from individuals with HαT displayed nonresponsiveness to anti-FcεRI more frequently. In contrast, response to formylmethionyl-leucyl-phenylalanine was higher in subjects with ISM than in subjects with HαT and showed a trend of being higher than in HCs. Mastoparan- and compound 48/80-induced activation was undetectable across groups.

HαT features enriched basophil frequency but lacks functional hyperreactivity. An increased rate of nonresponse to FcεRI cross-linking distinguishes HαT from ISM, indicating condition-specific FcεRI signaling dysregulation rather than uniform basophil dysfunction in mast cell-associated disorders.