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There are two types of AIH, type 1 (AIH\u20101) and type 2 (AIH\u20102), characterized by distinct autoimmune serology. Patients with AIH\u20101 are positive for anti\u2013smooth muscle and\/or antinuclear autoantibodies, whereas patients with AIH\u20102 have anti\u2013liver kidney microsomal type 1 and\/or anti\u2013liver cytosol type 1 autoantibodies. Cytochrome P4502D6 is the antigenic target of anti\u2013liver kidney microsomal type 1, and formiminotransferase cyclodeaminase is the antigenic target of anti\u2013liver cytosol type 1. It is known that AIH, both types 1 and 2, is strongly linked to the human leukocyte antigen (HLA) alleles \u2010DR3, \u2010DR4, and \u2010DR7. However, direct evidence of the association of HLA with AIH is lacking. We developed a novel mouse model of AIH using the HLA\u2010DR3 transgenic mouse on the nonobese\u2010diabetic background by immunization of HLA\u2010DR3<jats:sup>\u2013<\/jats:sup> and HLA\u2010DR3<jats:sup>+<\/jats:sup> nonobese\u2010diabetic mice with a DNA plasmid, coding for human cytochrome P4502D6\/formiminotransferase cyclodeaminase fusion protein. Immunization with cytochrome P4502D6\/formiminotransferase cyclodeaminase leads to a sustained elevation of alanine aminotransferase, development of antinuclear autoantibodies and anti\u2013liver kidney microsomal type 1\/anti\u2013liver cytosol type 1 autoantibodies, chronic immune cell infiltration, and parenchymal fibrosis on liver histology in HLA\u2010DR3<jats:sup>+<\/jats:sup> mice. Immunized mice also showed an enhanced T helper 1 immune response and paucity of the frequency of regulatory T cells in the liver. Moreover, HLA\u2010DR3<jats:sup>+<\/jats:sup> mice with exacerbated AIH showed reduced diversity and total load of gut bacteria. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Our humanized animal model has provided a novel experimental tool to further elucidate the pathogenesis of AIH and to evaluate the efficacy and safety of immunoregulatory therapeutic interventions <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. (H<jats:sc>epatology<\/jats:sc> 2015;62:1536\u20131550)<\/jats:p>","DOI":"10.1002\/hep.27998","type":"journal-article","created":{"date-parts":[[2015,7,16]],"date-time":"2015-07-16T23:31:13Z","timestamp":1437089473000},"page":"1536-1550","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":113,"title":["A novel \u201chumanized mouse\u201d model for autoimmune hepatitis and the association of gut microbiota with liver inflammation"],"prefix":"10.1097","volume":"62","author":[{"given":"Muhammed","family":"Yuksel","sequence":"first","affiliation":[{"name":"Section of Endocrinology,Yale University School of Medicine,New Haven,CT"},{"name":"Laboratory of Hepatology and Gastroenterology,Ghent University,Ghent,Belgium"},{"name":"Institute of Liver Studies, Faculty of Life Sciences and Medicine, King's College Hospital, King's College 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