Halting targeted and collateral damage to red blood cells by the complement system

• Published in: Seminars in immunopathology Vol. 43; no. 6; pp. 799 - 816
• Main Authors: Jalink, M., de Boer, E. C. W., Evers, D., Havinga, M. Q., Vos, J. M. I., Zeerleder, S., de Haas, M., Jongerius, I.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2021; Springer Nature B.V
• Subjects: Autoimmune hemolytic anemia; Biomedical and Life Sciences; Biomedicine; Complement inhibitors; Complement system; Erythrocytes; Hemolysis; Hemolytic anemia; Immunology; Internal Medicine; Lysis; Paroxysmal nocturnal hemoglobinuria; Pathology; Patients; Review; Paroxysmal nocturnal hemoglobinuria; Complement; Complement inhibitors; Complement therapeutics; Autoimmune hemolytic anemia
• ISSN: 1863-2297; 1863-2300
• DOI: 10.1007/s00281-021-00859-8

The complement system is an important defense mechanism against pathogens; however, in certain pathologies, the system also attacks human cells, such as red blood cells (RBCs). In paroxysmal nocturnal hemoglobinuria (PNH), RBCs lack certain complement regulators which sensitize them to complement-mediated lysis, while in autoimmune hemolytic anemia (AIHA), antibodies against RBCs may initiate complement-mediated hemolysis. In recent years, complement inhibition has improved treatment prospects for these patients, with eculizumab now the standard of care for PNH patients. Current complement inhibitors are however not sufficient for all patients, and they come with high costs, patient burden, and increased infection risk. This review gives an overview of the underlying pathophysiology of complement-mediated hemolysis in PNH and AIHA, the role of therapeutic complement inhibition nowadays, and the high number of complement inhibitors currently under investigation, as for almost every complement protein, an inhibitor is being developed. The focus lies with novel therapeutics that inhibit complement activity specifically in the pathway that causes pathology or those that reduce costs or patient burden through novel administration routes.