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

BACKGROUND AND AIMS: 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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.