Abstract
Previous infection with Epstein-Barr virus (EBV) is believed to trigger autoimmunity and to drive autoantibody generation as occurring in patients with systemic lupus erythematosus (SLE). Complement C1q and autoantibodies targeting it (anti-C1q) are also considered to be involved in the pathogenesis of SLE, independently of the impact of environmental insults. Still, the circumstances under which these autoantibodies arise remain elusive. By studying a major antigenic site of C1q targeted by anti-C1q (A08), we aimed to determine environmental factors and possible mechanisms leading to the development of anti-C1q. First, we determined antigenic residues of A08 that were critical for the binding of anti-C1q; importantly, we found the binding to depend on amino-acid-identity. Anti-C1q of SLE patients targeting these critical antigenic residues specifically cross-reacted with the EBV-related EBNA-1 (Epstein-Barr virus nuclear antigen 1)-derived peptide EBNA348. In a cohort of 180 SLE patients we confirmed that patients that were seropositive for EBV and recognized the EBNA348 peptide had increased levels of anti-A08 and anti-C1q, respectively. The correlation of anti-EBNA348 with anti-A08 levels was stronger in SLE patients than in matched healthy controls. Finally, EBNA348 peptide-immunization of C1q−/− mice induced the generation of cross-reactive antibodies which recognized both the A08 epitope of C1q and intact C1q. These findings suggest that anti-C1q in SLE patients could be induced by an EBV-derived epitope through molecular mimicry, thereby further supporting the pathogenic role of EBV in the development of SLE. Considering the role of C1q and anti-C1q, modifying the anti-EBV response might be a promising strategy to improve the course of the disease.
Highlights
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the occurrence of autoantibodies, resulting in a broad spectrum of immunological and clinical manifestations
The extended screening, with higher numbers of sera from SLE patients (Supplementary Table 2 and Figure 1C) and normal donors confirmed the importance of the central contiguous RRGR amino acids (AAs) for anti-C1q binding
As SLE patients might form an aberrant antibody reaction to the EBNA-1-derived peptide EBNA348, we explored the association of antibodies against Epstein-Barr virus (EBV) with antibodies against intact C1q and the C1q-derived epitope A08
Summary
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the occurrence of autoantibodies, resulting in a broad spectrum of immunological and clinical manifestations. Besides the heterogeneous clinical presentation, the pathogenesis of SLE is most likely due to a combination of genetic predisposition with hormonal and environmental factors, such as ultraviolet light, chemicals, medication, and parasitic, bacterial or viral infections. The hypothesis that viral infections might initiate autoimmunity is supported by clear epidemiological, clinical and experimental data. Viruses such as Cytomegalovirus, Parvovirus B19 and Epstein-Barr virus (EBV) have been well described to be environmental triggers of SLE [1,2,3,4]. Experimental immunization of animals with EBV-derived peptides has been shown to induce typical SLE autoantibodies [5,6,7,8]
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