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Different sites of xenoantigen delivery lead to a virally induced late-onset hepatitis in mice through molecular mimicry
; Piché, Chantal
; Béland, Kathie
; Lapierre, Pascal
; Massie, Bernard
NRC Biotechnology Research Institute; National Research Council Canada
autoimmune hepatitis; break of immune tolerance; liver immunology
Background: Epidemiological and laboratory evidences led to the hypothesis that molecular mimicry between viruses and self-proteins could be linked to the onset of autoimmune hepatitis (AIH). Hepatotropic viruses could be good candidates, as a pro-inﬂammatory environment may facilitate the development of AIH. Aims: The aims of this study were to test a virus ability to induce an AIH through molecular mimicry and the inﬂuence of hepatic inﬂammation in this process. Methods: C57BL/6 mice were injected IV or IM with recombinant adenoviral vectors (RecAdV) encoding for human type 2 AIH antigens to target xenoantigens expression in the liver and to create a transient hepatitis (IV) or for ‘peripheral’ xenoantigens expression (IM). Liver injury and B-cell response were evaluated. Results: Late-onset hepatitis was observed 8 months after IV or IM RecAdV injections, despite presence or absence of an initial transient hepatitis. Intensity of B-cell response was similar for both type of injections, but the Ig isotypes produced were different. B-cell autoimmune response spread to several liver proteins. Conclusions: Liver autoimmune response can be initiated using molecular mimicry over a long period of time, validating the hit-and-run hypothesis. Initial liver inﬂammatory injury is neither necessary, nor detrimental to the development of AIH. These results highlight the signiﬁcance of initial events on the pathogenesis of autoimmune liver injury.