Autoantibody stabilization of the classical pathway C3 convertase leading to C3 deficiency and Neisserial sepsis: C4 nephritic factor revisited

• Published in: Clinical immunology (Orlando, Fla.) Fla.), 2012-12, Vol.145 (3), p.241-250
• Main Authors: Miller, Elizabeth C, Chase, Nicole M, Densen, Peter, Hintermeyer, Mary K, Casper, James T, Atkinson, John P
• Format: Article
• Language: English
• Subjects: Adolescent; Allergy and Immunology; Autoantibodies - blood; Autoimmunity; Bacterial diseases; Bacterial sepsis; Biological and medical sciences; C3 deficiency; C4 nephritic factor; Complement C3 - deficiency; Complement C3 - genetics; Complement C3 - immunology; Complement C3 Convertase, Classical Pathway - immunology; Complement C3 Convertase, Classical Pathway - metabolism; Complement C5 Convertase, Classical Pathway - immunology; Complement C5 Convertase, Classical Pathway - metabolism; Complement System Proteins; Enzyme Stability; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Human bacterial diseases; Humans; Immunoglobulin G - blood; Infectious diseases; Male; Medical sciences; Meningitis, Meningococcal - etiology; Meningitis, Meningococcal - immunology; Meningococcal Infections - etiology; Meningococcal Infections - immunology; Models, Immunological; Neisseria meningitidis; Neisserial infection; Sepsis - etiology; Sepsis - immunology; Sequence Analysis, DNA
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2012.09.007

Abstract C3 deficiency is a rare disorder that leads to recurrent pyogenic infections. Here we describe a previously healthy 18 y/o Caucasian male with severe meningococcal disease. Total hemolytic activity was zero secondary to an undetectable C3. The C3 gene was normal by sequencing. Mixing the patient's serum with normal human serum led to C3 consumption. An IgG autoantibody in the patient's serum was identified that stabilized the classical pathway C3 and C5 convertases, thus preventing decay of these enzyme complexes. This autoantibody is an example of a C4 nephritic factor, with an additional feature of stabilizing the C5 convertase. Previous patients with C4 nephritic factor had membranoproliferative glomerulonephritis. Two years after presentation, this patient's C3 remains undetectable with no evidence of renal disease. We revisit the role of autoantibodies to classical pathway convertases in disease, review the literature on C4-NeF and comment on its detection in the clinical laboratory.