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

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.

► We report a previously healthy 18 y/o with Neisserial sepsis and C3 deficiency.
► The deficiency was identified as being due to accelerated consumption of C3.
► The mechanism was classical pathway C3 convertase stabilization by an autoantibody.
► Known as C4 nephritic factor, the presentation and lack of nephrosis are unique.
► We review the C4 nephritic factor literature and outline a strategy for diagnosis.