Novel autoantibodies in autoimmune hepatitis: from diagnostic challenges to molecular and spatial pathology

Autoimmune hepatitis (AIH) lacks a single disease-specific diagnostic test, particularly in acute-onset or seronegative cases with normal IgG levels. Recent progress in high-throughput autoantibody profiling has enabled systematic and unbiased identification of novel autoantibodies, offering new insights into disease diagnosis and underlying pathogenic mechanisms. This review summarizes emerging autoantibodies in AIH, primarily focusing on antibodies identified through proteome-wide approaches. We highlight anti-docking protein 2 (DOK2) antibodies, identified using a human protein microarray and validated by ELISA, immunohistochemistry, and imaging mass cytometry. These antibodies exhibit high diagnostic performance, including in patients with IgG-normal and ANA-negative AIH, and are correlated with disease activity. Spatial analyses revealed that DOK2 was expressed predominantly in hepatic macrophages and subsets of T cells, providing mechanistic insight into immune regulation in AIH. These findings illustrate how integrative serological and molecular morphology approaches can refine AIH diagnosis and deepen the understanding of disease pathogenesis.