Lupus-like autoantibody development in rabbits and mice after immunization with EBNA-1 fragments

Abstract

Epstein-Barr virus has been implicated in the etiology of systemic lupus erythematosus (SLE) through serologic and immunologic studies. A potential mechanism for this influence is through molecular mimicry. The EBV nuclear antigen EBNA-1 contains a region, PPPGRRP, with considerable homology to the initial sequence targeted by antibodies in Sm B' autoimmunity, PPPGMRPP. This study examined whether immunization of rabbits and mice with peptides containing the PPPGRRP sequence from EBNA-1 constructed on a poly-lysine backbone was able to drive the development of autoantibodies against the Smith antigen (Sm) and the related antigenic complex, the U1 nuclear ribonucleoproteins (nRNP). PPPGRRP immunization, and immunization with an EBNA-1 fragment containing PPPGRRP, led to autoantibodies in both rabbits and mice at high frequency (83% of rabbits and 43% of mice). Five out of six immunized rabbits developed either leucopenia or lymphopenia or both. The fine specificity of antibody binding against the lupusassociated autoantigens Sm B', nRNP A, and nRNP C after immunization with the EBNA-1-derived peptides was very similar to the early antibody binding patterns against these proteins in human SLE. This similarity, as well as the prevalence of autoimmunity after immunization with these peptides, identifies PPPGRRP as a strong candidate for molecular mimicry in SLE etiology.

The role of the Epstein-Barr virus in the pathogenesis of some autoimmune disorders — Similarities and differences

“…This EBNA-1 sequence is recognized by the serum of SLE patients, but not by sera from healthy individuals. Following the immunization of rabbits or mice with the EBNA-1 cross-reactive epitope (PPP-GRRP), autoantibodies against the Sm B' PPPGMRPP epitope appeared in the majority of animals -in association with lupus-like manifestations [60]. Similar experimental evidence has been obtained also for the anti-Ro system.…”

EBV and Autoimmunity

“…The EBNA-1 protein contains a similar peptide sequence, PPPGRRP, also recognized by the anti-Sm B/B′ antibodies from SLE patients, suggesting that molecular mimicry could be a mechanism of SLE development in some patients (James et al 1994). James et al went on to show that this antigenic Sm B/B′ octapeptide can induce autoimmunity and epitope spreading in rabbits, leading to an SLElike disease, and that rabbits immunized with the EBNA-1 peptide PPPGRRP develop an early auto-antigen profile followed by epitope spreading similar to that seen in SLE patients positive for anti-Sm B/B′ antibodies, further supporting a link between EBV and SLE (James et al 1997;Poole et al 2008). A high sequence similarity has also been identified between a glycine-arginine repeat in the C-terminal region of SmD protein and an EBNA-1 peptide.…”

Serum concentration of immunoglobulin G-type antibodies against the whole Epstein–Barr nuclear antigen 1 and its aa35–58 or aa398–404 fragments in the sera of patients with systemic lupus erythematosus and multiple sclerosis

“…The serum concentration of this type of antibody was significantly higher in SLE patients than in healthy controls, while no difference could be found between controls and MS patients. The high serum concentration of anti-aa398-404 EBNA-1 antibodies is not surprising in SLE, as many observations in patients [14] and data from animal experiments [37] demonstrated a strong cross-reaction between this EBNA-1 epitope and an epitope (B′/B) of the Sm autoantigen, and autoantibodies against the latter are characteristic in SLE. However, it was demonstrated recently [12] that, in MS, the elevated level of anti-EBNA-1 includes antibodies directed against several epitopes of the protein, but anti-PPPGRRP antibodies have not been studied previously in MS patients.…”