The complement system is an integral part of both the innate and adaptive immune responses. Although a wealth of insight into the function of the different complement proteins has been obtained by biochemical studies, real insight into the overall role of complement and specific complement proteins has been obtained by studying the rare cases of complete genetic deficiency observed in the human population. The detailed analyses of the clinical manifestations of persons genetically deficient for complement proteins identified some obvious aspects, but also several rather remarkable ones. For example the genetic deficiency of circulating C3 led to increased risk for several types of bacterial infections, but deficiency in C9, an essential component of the membrane attack complex (MAC) required for lysis did only predispose to one particular type of infections; with Neisseria. These data indicate that complement is involved in the immune defence against infections via C3, but that lysis by the MAC is except for Neisseria not so relevant.
One other remarkable observations was the association between genetic deficiency for classical pathway complement proteins with autoimmunity, especially systemic lupus erythematosus (SLE). Sspecially striking is the observation that there is a hierarchy, within the pathway, with C1q being the strongest associated with SLE, followed by C4 and C2 with almost no association with C3 deficiency. How deficiency of classical pathway proteins contributes is not yet clear but seems to be the result of an interplay between decreased clearance of dead cells and an altered adaptive immune activation threshold.
Recently we identified a new case of complete C1q deficiency and this child did not display signs of SLE (yet). We were struck by the absence of reports on follow-up data of the cases with reported C1q deficiency and conducted a questionnaire based study. From this study we could conclude that there is enormous variation in the severity of clinical symptoms between persons, with some being very affected leading to premature death and other individuals, sometimes from the same family, seemingly completely unaffected. These findings are relevant also in view of the developments of therapy as now haematopoietic stem cell transplantation (HSCT) has become a feasible option to treat such individuals. In this context we argue for a well-balanced evaluation of the pro's and con's of such treatment modalities in view of the variation in clinical symptoms and severity observed in these individuals.
Disclosure of Interest None declared