Complement and DNase I Act as Backup Molecules in the Clearance Process

An impaired uptake of apoptotic cells by human macrophages was observed in human serum depleted of specific complement components (C1q, C3) [42, 64]. We observed that complement binding is an early event in necrosis and a rather late event in the case of apoptosis. Complement components, mainly C1q, C3, and C4 act as back-up mechanism to clear apoptotic cells before they enter the dangerous stage of secondary necrosis [21, 22]. Disturbed clearance of nuclear DNA-protein complexes, remnants of dying cells, may initiate and propagate SLE [4, 54]. This is further substantiated by decreased levels of DNase I activity, as had been observed in the sera of SLE patients [14] and patients with other autoimmune diseases such as rheumatoid arthritis (RA) (U.S. Gaipl et al., unpublished data). DNase I, being the major serum nuclease, may be responsible for the degradation of chromatin accidentally released by inappropriately cleared dead cells [39]. Furthermore, DNase I acts together with C1q to efficiently degrade necrotic cell-derived chromatin [23]. A cooperation of DNase I with the plasminogen system was also suggested to contribute to a fast and effective breakdown of chromatin during necrosis [47]. The complement component C1q was found to be necessary for an effective uptake of degraded chromatin by monocyte-derived phagocytes [23] and acts together with soluble IgM in the clearance of dying cells [50]. We tested sera of autoimmune patients with regard to their ability to degrade necrotic cell-derived chromatin. A significant activity reduction of DNase I in sera of SLE and RA patients in comparison to normal healthy donors (NHDs) was observed. Most interestingly, SLE sera showed a strongly reduced degradation capacity of necrotic cell-derived chromatin in comparison to RA sera and NHD sera (U.S. Gaipl et al., unpublished data). This might be due to reduced complement activity detected mainly in the sera of SLE patients. We conclude that an additional protection from chromatin implicated in the development of autoimmune disorders such as SLE can be achieved by the C1q and DNase-I-dependent clearance of degraded chromatin.

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