Complement Disorders and Inborn Errors of Immunity

The complement system is an important component of innate and adaptive immunity. It consists of three activation pathways. The classical complement pathway plays an important role in humoral immunity. Alternative and lectin pathways enhance the innate response. Disruption (damage, deficiency, or overactivation) of any of the 50 known complement proteins can lead to increased susceptibility to infection with encapsulated organisms, autoimmunity, hereditary angioedema, or thrombosis, depending on the protein affected. Defects of the classical pathway result from deficiencies of the complement proteins C1q, C1r, C1s, C2, and C4 and are usually manifested by features of autoimmune diseases such as systemic lupus erythematosus and infections with encapsulated organisms. Defects in the alternative pathway due to factor B, factor D, and properdin deficiency may be manifested by increased susceptibility to Neisseria infections. Defects in the lectin pathway, including mannose-binding protein-associated serine protease 2 (MASP2) and ficolin 3, can have a wide spectrum of manifestations, from asymptomatic to purulent infections and autoimmunity. The complement protein C3 is common to all pathways. Its deficiency predisposes patients to severe, frequent infections and glomerulonephritis. Deficiency of factor H and factor I, which regulate the alternative pathway, can lead to hemolytic-uremic syndrome. Deficiency of the terminal components of the complement system (C5 to C9) leads to disseminated infections caused by Neisseria meningitidis. Diagnosis of complement deficiency includes functional tests, total complement activity (CH50), alternative complement pathway activity (AH50], enzyme-linked immunosorbent assay (ELISA), which are screening tests for the disorder, followed by measurement of individual complement factors by immunoassay. Treatment of complement deficiencies requires a comprehensive and individualized approach with special attention to vaccination against encapsulated bacteria, consideration of prophylactic antibiotics, treatment of comorbid autoimmunities, and close monitoring.