The
complement system plays a crucial role in host defense, homeostasis, and tissue regeneration and bridges the innate and the adaptive immune systems. Although the genetic variants in
complement C2 (c.839_849+17del; p.(Met280Asnfs*5)) and C8B (c.1625C>T; p.(Thr542Ile)) are known individually, here, we report on a patient carrying their combination in a heterozygous form. The patient presented with a reduced general condition and suffers from a wide variety of
autoimmune diseases. While no
autoimmune disease-specific
autoantibodies could be detected, genetic analysis revealed abnormalities in the two
complement genes C2 and C8B. Therefore, we performed a comprehensive investigation of the innate immune system on a cellular and humoral level to define the functional consequences. We found slightly impaired functionality of neutrophils and monocytes regarding phagocytosis and
reactive oxygen species generation and a diminished expression of the C5aR1. An extensive
complement analysis revealed a declined activation potential for the alternative and classical pathway. Reconstitution with purified C2 and C8 into patient serum failed to normalize the dysfunction, whereas the addition of C3 improved the hemolytic activity. In clinical transfer, in vitro supplementation of the patient's plasma with FFP as a
complement source could fully restore full
complement functionality. This study describes for the first time a combined heterozygous genetic variation in
complement C2 and C8B which, however, cannot fully explain the overall dysfunctions and calls for further
complement deficiency research and corresponding
therapies.