Yonsei Med J.  2020 Jan;61(1):100-102. 10.3349/ymj.2020.61.1.100.

Autoimmune Hepatic Failure Following Acute Hepatitis A is Accompanied by Inflammatory Conversion of Regulatory T Cells

• Leem G
• Kim BK
• Shin EC
• Park JY

• KMID: 2466342
• DOI: http://doi.org/10.3349/ymj.2020.61.1.100

Abstract

To evaluate the pathophysiology of autoimmune hepatitis (AIH) following acute hepatitis A (AHA) in immunologic aspects, we performed multi-color flow cytometry with peripheral blood mononuclear cells of a patient who underwent liver transplantation due to AIH-induced liver failure. Unlike general AHA patients, the proportion of tumor necrosis factor-α-producing Treg cells remained high for 6 months after diagnosis of AHA until she underwent a liver transplantation. The conversion of Treg cells into mediators of inflammation may have played a role in the autoimmune pathogenesis following AHA.

Keyword

Autoimmune hepatitis; acute hepatitis A; regulatory T cells; inflammatory conversion of Treg cells

MeSH Terms

Diagnosis
Flow Cytometry
Hepatitis A*
Hepatitis*
Hepatitis, Autoimmune
Humans
Inflammation Mediators
Liver Failure*
Liver Transplantation
Necrosis
T-Lymphocytes, Regulatory*
Inflammation Mediators

Figure

• 

  Fig. 1 (A) The results of subsequent liver function tests. The total bilirubin (blue line), aspartate aminotransferase (AST) (red line), and alanine aminotransferase (ALT) (yellow line) levels showed repeated deterioration during the course of the disease. Clinical courses, including admission, discharge, and liver transplantation, are marked by black arrows. Three months after initial hospitalization, the patient was revealed to be positive for anti-nuclear antibody (ANA) (>1:640) and perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA). Her immunoglobulin M (IgM) anti-hepatitis A virus (anti-HAV) antibody status remained positive until after liver transplantation. (B-D) Flow cytometric analyses of Treg cells producing tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-17A (IL-17A). Treg cells expressed higher levels of TNF-α (B), IFN-γ (C), and IL-17A (D) compared to Treg cells from a healthy donor. Healthy donor data are representative of those from six healthy donors. (E) TNF-α, IFN-γ, and IL-17A production by Treg cells of the patient gradually decreased to normal levels over the 6 months following liver transplantation (black arrow represents the time-point of liver transplantation).

Reference

1. Yoon EL, Sinn DH, Lee HW, Kim JH. Current status and strategies for the control of viral hepatitis A in Korea. Clin Mol Hepatol. 2017; 23:196–204.

2. Koff RS. Hepatitis A. Lancet. 1998; 351:1643–1649.

3. Shin EC, Jeong SH. Natural history, clinical manifestations, and pathogenesis of hepatitis A. Cold Spring Harb Perspect Med. 2018; 8:a031708.

4. Vento S, Garofano T, Di Perri G, Dolci L, Concia E, Bassetti D. Identification of hepatitis A virus as a trigger for autoimmune chronic hepatitis type 1 in susceptible individuals. Lancet. 1991; 337:1183–1187.

5. Huppertz HI, Treichel U, Gassel AM, Jeschke R, Meyer zum. Autoimmune hepatitis following hepatitis A virus infection. J Hepatol. 1995; 23:204–208.

6. Vento S, Cainelli F. Is there a role for viruses in triggering autoimmune hepatitis? Autoimmun Rev. 2004; 3:61–69.

7. Mikata R, Yokosuka O, Imazeki F, Fukai K, Kanda T, Saisho H. Prolonged acute hepatitis A mimicking autoimmune hepatitis. World J Gastroenterol. 2005; 11:3791–3793.

8. Tabak F, Özdemir F, Tabak O, Erer B, Tahan V, Ozaras R. Autoimmune hepatitis induced by the prolonged hepatitis A virus infection. Ann Hepatol. 2008; 7:177–179.

9. Choi YS, Lee J, Lee HW, Chang DY, Sung PS, Jung MK, et al. Liver injury in acute hepatitis A is associated with decreased frequency of regulatory T cells caused by Fas-mediated apoptosis. Gut. 2015; 64:1303–1313.

10. Choi YS, Jung MK, Lee J, Choi SJ, Choi SH, Lee HW, et al. Tumor necrosis factor-producing T-regulatory cells are associated with severe liver injury in patients with acute hepatitis A. Gastroenterology. 2018; 154:1047–1060.

11. Jung MK, Lee JS, Kwak JE, Shin EC. Tumor necrosis factor and regulatory T cells. Yonsei Med J. 2019; 60:126–131.