C5 inhibition restores B cell homeostasis and humoral immunity in CHAPLE disease patients.

CHAPLE disease is a monogenic disorder in which CD55 deficiency drives gastrointestinal pathology. How CD55 deficiency affects adaptive immunity is unknown. Herein, molecularly, we characterize eight patients with genetically novel CD55 deficiency. Clinically, all patients developed early-onset protein-losing enteropathy, frequently complicated by thrombotic events, inflammatory bowel disease-like lesions, and recurrent respiratory infections. Ex vivo, immunophenotyping revealed disruption of the B cell compartment, marked by depletion of transitional B cells, expansion of CD21lo B cells, and accumulation of class-switched memory B cells and plasmablasts, while T cell subsets were largely preserved. In vivo, eculizumab rapidly resolved intestinal pathology, normalized serum albumin and immunoglobulin levels, and re-established a normal B cell profile. Furthermore, C5 inhibition enabled effective humoral protection and optimal pneumococcal vaccine responses. Together, these findings establish complement inhibition as central to B cell homeostasis in CHAPLE disease.