title: Single-gene association between GATA-2 and autoimmune hepatitis: A novel genetic insight highlighting immunologic pathways to disease.
abstract: Background & Aims Autoimmune hepatitis (AIH), an immune-mediated liver disease, originates as a consequence of interacting genetic and environmental risk factors. Treatment remains non-specific and prone to side effects. Deficiencies in regulatory T cell (Treg) function are hypothesized to contribute to the pathogenesis of AIH. Methods We describe an adult patient who presented with AIH in the context of monocytopenia. The patient was characterized by GATA2 gene sequencing, flow cytometry of peripheral blood for leucocyte subsets, ELISA for serum Flt-3 ligand, and immunohistochemistry of liver biopsy tissue. Results Sequencing confirmed a GATA2 mutation. Peripheral Treg were absent in the context of a preserved total T cell count. Immunostaining for the Treg transcription factor FOXP3 was reduced in liver tissue as compared to a control AIH specimen. There were marked deficiencies in multiple antigen-presenting cell subsets and Flt-3 ligand was elevated. These findings are consistent with previous reports of GATA2 dysfunction. Conclusions The association of a GATA2 mutation with AIH is previously unrecognized. GATA2 encodes a hematopoietic cell transcription factor, and mutations may manifest as monocytopenia, dendritic and B cell deficiencies, myelodysplasia, and immunodeficiency. Tregs may be depleted as in this case. Our findings provide support for the role of Tregs in AIH, complement reports of other deficiencies in T cell regulation causing AIH-like syndromes, and support the rationale of attempting to modulate the Treg axis for the therapeutic benefit of AIH patients.
authors.affiliation: Centre for Liver Research, University of Birmingham and NIHR Birmingham Liver Biomedical Research Unit, Birmingham, UK.
authors.forename: Gwilym
authors.initials: G
authors.lastname: Webb
authors.affiliation: Centre for Liver Research, University of Birmingham and NIHR Birmingham Liver Biomedical Research Unit, Birmingham, UK.
authors.forename: Yung-Yi
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Centre for Liver Research, University of Birmingham and NIHR Birmingham Liver Biomedical Research Unit, Birmingham, UK.
authors.forename: Ka-Kit
authors.initials: KK
authors.lastname: Li
authors.affiliation: Department of Pathology, Queen Elizabeth Hospital, Birmingham, UK.
authors.forename: Desley
authors.initials: D
authors.lastname: Neil
authors.affiliation: Centre for Liver Research, University of Birmingham and NIHR Birmingham Liver Biomedical Research Unit, Birmingham, UK.
authors.forename: Ye Htun
authors.initials: YH
authors.lastname: Oo
authors.affiliation: Department of Immunology, Queen Elizabeth Hospital, Birmingham, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Richter
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
authors.forename: Venetia
authors.initials: V
authors.lastname: Bigley
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Collin
authors.affiliation: Centre for Liver Research, University of Birmingham and NIHR Birmingham Liver Biomedical Research Unit, Birmingham, UK.
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.affiliation: Centre for Liver Research, University of Birmingham and NIHR Birmingham Liver Biomedical Research Unit, Birmingham, UK. Electronic address: g.hirschfield@bham.ac.uk.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
mesh_terms: D000328:Adult; D000938:Antigen-Presenting Cells; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D050989:GATA2 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D019693:Hepatitis, Autoimmune / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D008565:Membrane Proteins; C084881:flt3 ligand protein; D004247:DNA
keywords: Immune-mediated liver disease; Pathogenesis; Regulatory T cell
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