Complement dysregulation at lymphatics

Abstract

The complement system is a central component of innate immunity, orchestrating pathogen clearance while regulating inflammation, tissue repair, and homeostasis. Its activation is tightly controlled by multiple inhibitors to prevent self-damage. However, complement dysregulation is implicated in numerous organ-specific diseases, including paroxysmal nocturnal hemoglobinuria (erythrocytes), atypical hemolytic uremic syndrome (kidneys), and age-related macular degeneration (eyes). Recent discoveries have revealed that complement hyperactivation also drives lymphatic dysfunction, most notably in CHAPLE (CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy) disease-a rare pediatric disorder caused by biallelic CD55 mutations. Impaired regulation of C3 and C5 convertases leads to unchecked complement and coagulation activation, resulting in membrane attack complex deposition, severe intestinal lymphangiectasia, and protein-losing enteropathy. Patients typically present with hypoalbuminemia, edema, gastrointestinal symptoms, growth retardation, and recurrent thromboembolic events, reflecting a severe thrombophilic phenotype. C5-blocking antibodies, including pozelimab and eculizumab, transformed CHAPLE management. In a phase 2/3 study, pozelimab led to normalization of serum albumin levels and notable reductions in hospitalizations and transfusion needs, leading to Food and Drug Administration approval. Emerging evidence suggests that complement-driven protein-losing enteropathy may also arise in other pathological contexts, expanding the clinical impact of complement dysregulation. As research progresses, novel diagnostic and therapeutic strategies are expected to emerge for a broader spectrum of complement-mediated lymphatic disorders.

Keywords: CD55; CHAPLE disease; complement dysregulation; complement system; eculizumab; intestinal lymphangiectasia; pozelimab; protein-losing enteropathy.