Abstract
Deficient clearance of apoptotic cells reportedly contributes to the etiopathogenesis of the autoimmune disease systemic lupus erythematosus (SLE). Based on this knowledge, we developed a highly specific and sensitive test for the detection of SLE autoantibodies (AAb) utilizing secondary NEcrotic cell (SNEC)-derived material as a substrate. The goal of the present study was to validate the use of SNEC as an appropriate antigen for the diagnosis of SLE in large cohort of patients. We confirmed the presence of apoptotically modified autoantigens on SNEC (dsDNA, high mobility group box 1 protein, apoptosis-associated chromatin modifications, e.g., histones H3-K27-me3; H2A/H4 AcK8,12,16; and H2B-AcK12). Anti-SNEC AAb were measured in the serum of 155 patients with SLE, 89 normal healthy donors (NHD), and 169 patients with other autoimmune connective tissue diseases employing SNEC-based indirect enzyme-linked immunosorbent assay (SNEC ELISA). We compared the test performance of SNEC ELISA with the routine diagnostic tests dsDNA Farr radioimmunoassay (RIA) and nucleosome-based ELISA (anti-dsDNA-NcX-ELISA). SNEC ELISA distinguished patients with SLE with a specificity of 98.9% and a sensitivity of 70.6% from NHD clearly surpassing RIA and anti-dsDNA-NcX-ELISA. In contrast to the other tests, SNEC ELISA significantly discriminated patients with SLE from patients with rheumatoid arthritis, primary anti-phospholipid syndrome, spondyloarthropathy, psoriatic arthritis, and systemic sclerosis. A positive test result in SNEC ELISA significantly correlated with serological variables and reflected the uptake of opsonized SNEC by neutrophils. This stresses the relevance of SNECs in the pathogenesis of SLE. We conclude that SNEC ELISA allows for the sensitive detection of pathologically relevant AAb, enabling its diagnostic usage. A positive SNEC test reflects the opsonization of cell remnants by AAb, the neutrophil recruitment to tissues, and the enhancement of local and systemic inflammatory responses.
Highlights
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease
Analyzes by immunofluorescence revealed that autoreactive IgG present in the sera of patients with systemic lupus erythematosus (SLE) strongly bound to immobilized secondary NEcrotic cell (SNEC), whereas sera of normal healthy donors (NHD) lacked reactivity (Figure 1B)
This is critical since a clearance deficiency of apoptotic cells contributes to the etiopathogenesis of SLE [6, 38]
Summary
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease. Its pathogenesis is multifactorial including the involvement of genetic [1], hormonal [2], immunologic [3], and environmental factors like infections [4, 5]. Apoptotic cells that are not cleared rapidly by professional phagocytes lose their membrane integrity and, release cytoplasmic and nuclear autoantigens. These antigens are usually connected to damageassociated molecular patterns (DAMPs) like the high mobility group box 1 protein (HMGB1) [10]. After autoimmunity is established uncleared post-apoptotic material serves as autoantigen repository for the formation of pathogenic immune complexes (ICs) [17, 18] These complexes form in situ or deposit in various tissues, especially in the kidney, skin, and joints, where they trigger inflammation and tissue damage [19, 20]
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