Epstein Barr virus antigen-induced autoantibodies against complement C1q exacerbate renal disease in lupus-prone mice.

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease characterized by the development of autoantibodies against multiple antigens, including complement C1q, starter molecule of the classical pathway. Anti-C1q autoantibodies (anti-C1q) are not only a biomarker of disease activity but believed to contribute to the pathogenesis of proliferative lupus nephritis. Previous studies demonstrated that a key immunogenic site of C1q (so-called 'A08') shares an identical sequence with Epstein-Barr-Virus (EBV) Nuclear antigen-1, and that anti-C1q can be induced by this EBV antigenic site in vivo. We investigated whether an EBV-derived antigen can trigger a cross-reactive anti-C1q response in lupus-prone mice and enhance renal pathology. Mertk-deficient mice, which exhibit a defective clearance of apoptotic cells, were immunized with EBV-derived peptide. Antibody responses against the EBV antigen, intact C1q and the C1q-derived antigenic site A08 were determined, and renal pathology was assessed histologically and by electron microscopy. The immunization with EBV antigen led to the generation of antibodies recognizing the C1q-derived antigen A08 in most, and the formation of anti-C1q with binding characteristics as occurring in SLE patients in a substantial subset of mice. Generation of anti-C1q was associated with accelerated mesangioproliferative glomerulonephritis and increased glomerular IgG and complement deposition. Our findings demonstrate that EBV-derived peptides can elicit pathogenic anti-C1q via molecular mimicry, thereby exacerbating renal disease in lupus-prone mice. The data provide mechanistic evidence for how an EBV antigen can accelerate SLE progression, and confirm the concept of anti-C1q being a driver of lupus nephritis.