Primary Immunodeficiencies of Complement

Abstract

Primary complement deficiencies are a complex and diverse group of over 20 distinct inherited immunodeficiency disorders. They make up 2–5% of all primary immunodeficiencies. These diseases can be divided into three broad groups. Classical pathway defects (C1, C2, C4) are associated with an increased risk of invasive pneumococcal infection and, in the case of C1q deficiency, an 80% risk of SLE-like immune complex disease. C1q deficiency has a 20% mortality rate in the first 20 years of life. Terminal complement defects (C5–C9) are largely associated with an increased risk of invasive meningococcal disease. Infection risk can be partly mitigated by vaccination. A third group includes deficiency (C3 loss of function, Factor B, properdin) or dysregulation of the C3 activity (C3 gain of function, Factor H, Factor I, membrane cofactor protein), the latter leads to endothelial damage and renal disease (aHUS or membranoproliferative glomerulonephritis) with a high risk of renal failure requiring dialysis. For most patients with primary complement deficiencies, CH50 and AH50 rather than C3 and C4, should be requested as the initial screening test. Management varies, ranging from augmenting pneumococcal and meningococcal antibody responses by immunization, antibiotic prophylaxis, immunosuppressants and HSCT for C1q deficiency, and anti-C5 monoclonal therapy for patients with aHUS.