Single-gene association between GATA-2 and autoimmune hepatitis: A novel genetic insight highlighting immunologic pathways to disease - PubMed (original) (raw)

Case Reports

Single-gene association between GATA-2 and autoimmune hepatitis: A novel genetic insight highlighting immunologic pathways to disease

Gwilym Webb et al. J Hepatol. 2016 May.

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.

Keywords: Immune-mediated liver disease; Pathogenesis; Regulatory T cell.

Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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Figures

Fig. 1

Fig. 1

Liver histopathology. (A) Transjugular liver biopsy sample demonstrating dense lymphocytic infiltrate with interface hepatitis consistent with AIH (haematoxylin and eosin; 20×). (B) Fibrosis bridging between portal areas (Van Gieson; 20×). (C and D) Cells positive for the Treg transcription factor FOXP3 were scant in the inflammatory infiltrate of patient liver (C), but more frequent in a control AIH sample (D) (both 32×; example positive staining denoted by arrowheads). (E and F) CD20-positive B cells were present in patient liver biopsy specimen (E) in contrast to peripheral blood but at a reduced frequency to a control AIH sample (F; 32×). (This figure appears in colour on the web.)

Fig. 2

Fig. 2

Immunophenotyping by flow cytometry. (A) Flow cytometric analysis of peripheral blood demonstrated antigen-presenting cell deficiencies and leukocytopenias in multiple subsets with preserved total T cells. (B) Analysis of T cell populations revealed minimal CD25lowCD127hi cells and no evidence of expression of the transcription factor FOXP3 in a patient sample. This confirmed a marked deficiency in Treg. Approximately 8% of peripheral CD4+ T cells were CD25lowCD127hiFOXP3+Treg in a control sample. The absence of CD3-negative cells (blue gate, second panel) highlights B- and NK-cell deficiency. CD4:CD8 ratio was altered from the CD4-predominance seen in normality to equality, as reported in GATA2 dysfunction. (This figure appears in colour on the web.)

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