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Immune Tolerance Phase of Chronic Hepatitis B
Dear Editors:
We read with great interest the article of Mason et al
1and 2 related editorials2,3 debating the suitability of the
time-honored term immune tolerance phase. Their debate
was based on current molecular and immunologic findings,
and did not reach a consensus. From clinical point of view,
we concur with Dr Milich that the term/concept of immune
tolerance is still valid.
For further discussion on this issue, perhaps we better go
back to the history of the first paper proposing “immune
tolerance phase” and “immune clearance phase” to differentiate phases of chronic hepatitis B virus (HBV) infection in Taiwan.4
The idea/concept originated from a hypothesis proposed in a1972 Lancet
articleby theteam of Prof Sherlock that the competence of the T-cell
mediated immune system would decide whether the HBV infection is self-limited or
persists with varying degrees of liver damage. In particular, it was suggested that
“immunologic tolerance” owing to high antigen load would lead to little or no liver damage and continued virus proliferation.5
Following this concept, we speculated in 1983 that the frequent occurrence of abrupt
biochemical and histologic flare preceding hepatitis B e antigen(HBeAg) seroconversion we observed might represent about of enhanced host immune response that successfully “cleared” HBeAg.6
Along this line and as a course thought, the terms “immune tolerance” and
“immune clearance” were used when the relationships between serology, biochemistry and histology were constructed to create the natural history
figure of chronic HBV infection in 1985.4
We also found that HBV DNA level, HBeAg serostatus, histology, and the age of
the patients were closely interrelated, and that the younger patients generally had high HBV DNA levels and no or minimal hepatitis activity. Taken together, the characteristics of the patients in “immune tolerance phase” are young, HBeAg
positive with high HBV DNA levels, normal serum alanine aminotransferase levels, and no or minimal hepatitis activity. 7
Clearly, this nomenclature was based on clinical and virologic profiles to categorize different phenotypes of clinical presentation of chronic HBV infection. Indeed, there were no meaningful immunologic data to support this nomenclature before 1985.
We agree with Dr Milich 2 that the age and virologic, serologic, and histologic similarities between the study patients in the 2 different HBeAg-positive phases may influence the results supporting the conclusion of Mason et al.1
Other studies on the same issue also included some patients over age 30, even high up to a mean age of 34 years in a study, as patients of “immune tolerance phase.”
Given that the majority of the immune clearance events are asymptomatic,7
their older patients and those with higher hepatitis activity index or fibrosis stage might have experienced asymptomatic event(s) of “immune clearance” followed by
alanine aminotransferase normalization before recruitment.
Conceivably, their conclusion would be different if only younger patients with persistently normal alanine aminotransferase were considered as patients in the phase of “immune tolerance” for recruitment. Of note, our earlier
studies demonstrated that patients in the “immune tolerance phase”
had little or no cytoplasmic/membranous HBV core antigen and membranous HLA-I expression, which are crucial for the effector cytotoxic T cells to initiate immune-
mediated hepatocytolysis in HBV-infected patients. 8
According to the Merriam Webster dictionary, the medical definition of
“tolerance” is the capacity of the body to endure or become less responsive to a substance or to a specific antigen. Drs Protzer and Knolle 3 also indicate that
persistence of a virus requires antigen-specific “immune tolerance” that prevents the
“clearance” of a chronic infection, and that the liver has unique immune regulatory
functions that promote the induction of tolerance to antigens encountered locally, as exploited by HBV. Thus, the lack of intrahepatic inflammatory events despite the presence of HBV-specific T-cell immunity can be considered as
immune tolerance, at least from a clinical point of view. The term or concept of
“immune tolerance phase” is, therefore, still valid despite the presence of immune parameters. Itseems superfluous to replace the term widely used for 3
decades by a new one. In addition, the proposed new term“ high replication, low in
flammation” is obviously not adequate; the investigator’s own data showed no difference in hepatitis activity index between patients in the 2 different
HBeAg-positive phases,1 as pointed out by Milich.3
YUN-FAN LIAW CHIA-MING CHU
Liver Research Unit
Chang Gung Memorial Hospital
Chang Gung University College of Medicine
Taipei, Taiwan
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发表于 2017-3-9 18:29