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New aspects of the etiopathogenesis of systemic lupus erythematosus
Arthritis Res Ther volume 5, Article number: 154 (2003)
Impaired clearance of apoptotic cells has been supposed to be involved in the etiopathogenesis of systemic lupus erythematosus (SLE). Furthermore, antibodies against retroviral proteins can frequently be detected in sera of SLE patients without overt retroviral infections. Decreased levels of serum DNase I activities as well as deficiencies in components of the classical complement pathway are well established to predispose to SLE.
We analysed the role of serum factors that could be responsible for the degradation and clearance of human chromatin, and followed up the processing of the HERV-K-10gag polyprotein during apoptosis of Tera-1 cells. Furthermore, we investigated the clearance of apoptotic cells in the germinal centers of patients with SLE and controls.
The chromatin degradation and uptake was monitored by measuring the residual DNA content by flow cytometry. The HERV-K-10gag polyprotein was used to investigate the processing of viral proteins during apoptosis. Lymph node biopsies obtained from SLE patients and non-SLE patients with benign follicular hyperplasia were stained with monoclonal antibodies against macrophages (CD68) and follicular dendritic cells (CR2/CD21). Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining was performed to detect apoptotic nuclei.
Whereas an excess of recombinant DNase I degraded human necrotic cell-derived chromatin in the absence of C1q, an efficient uptake of the predigested material by monocyte-derived phagocytes required the presence of C1q. During apoptotic cell death, Tera-1 cells showed an altered HERV-K-10gag processing compared with viable cells. In addition, granzyme B was able to cleave HERV-K-10gag isolated from viable Tera-1 cells. Regarding the fate of dying cells in germinal centers of SLE patients, we found that the numbers of tingible body macrophages were significantly reduced in a subgroup of patients with SLE. TUNEL-positive apoptotic material was observed to be associated with the surfaces of follicular dendritic cells.
We conclude that C1q or DNase I deficiencies may precipitate human autoimmunity. Furthermore, the immunogenicity of retroviral antigens in SLE patients may result from a similar mechanism as described for nuclear autoantigens. In general, nuclear autoantigens bound to follicular dendritic cells may provide a survival signal for autoreactive B cells, thereby over-riding an important initial control mechanism of B-cell tolerance.
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Gaipl, U., Beyer, T., Voll, R. et al. New aspects of the etiopathogenesis of systemic lupus erythematosus. Arthritis Res Ther 5 (Suppl 3), 154 (2003). https://doi.org/10.1186/ar955