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Clinical Review Science, medicine, and the future

Tolerance and autoimmunity

BMJ 2000; 321 doi: https://doi.org/10.1136/bmj.321.7253.93 (Published 08 July 2000) Cite this as: BMJ 2000;321:93

Another example of molecular mimicry

To the Editor - In addition to the autoimmune disease models
discussed in the excellent review by Ian Mackay (1) we would like to
mention another example of molecular mimicry which is triggered by a
hepatotropic virus (hepatitis C virus, HCV) and linked to autoimmunity in
the liver (autoimmune hepatitis (AIH) type 2).
AIH type 2 is defined by the presence of type I anti liver kidney
microsomal autoantibodies recognizing cytochrome P450 (CYP) 2D6 (2).
Hepatitis C virus (HCV) infection is more frequent among patients with AIH
type 2 compared to the normal population at least in some studies and HCV
infection has been documented to precede AIH type 2 in some cases (3).
We have recently shown that peripheral blood derived cytotoxic T cells
from HLA-A2 positive patients with chronic hepatitis C specific for HCV
core (aa 178-187: LLALLSCLTV) can recognize and kill target cells
presenting peptides derived from CYP2A6 and 2A7 (aa 8-17: LVALLVCLTV and
LVALLACLTV, respectively) or transfected to produce CYP2A6. We could also
show that the HCV-derived stimulus is required to brake tolerance i.e.
selfpeptides
themselves were not able to activate CYP-specific autoreactive T cells
(4).
The coexpression and colocalization of virus and autoantigen in the liver
underscore the possible role of molecular mimicry in the induction of HCV-
associated AIH type 2.
Molecular mimicry is a mechanism leading to postinfectious autoimmunity
(the virus triggers an antiviral response which turns against self
antigens) but may also lead to viral escape (the virus looks like self and
is thus not recognized) (5). The degree of tolerance to self (ignorance of
self antigens versus deletion of self-reactive T cells) determines which
of the two outcomes prevails.
We do believe that some cases of AIH type 2 may be due to molecular
mimicry between HCV and self proteins in the liver. Further prospective
studies of the cellular and humoral immune response in patients with HCV-
associated
AIH will be required to test this hypothesis.

Andreas R. Kammer, PhD
Dept. of Clinical Research
University Hospital
3010 Bern, Switzerland

Andreas Cerny, MD
Dept. of Medicine
Ospedale Civico
6900 Lugano, Switzerland

References:

1. Mackay IR. Science, medicine, and the future: Tolerance and
autoimmunity. B M J 2000;321:93-96.

2. Manns MP, Johnson EF, Griffin KJ, Tan EM, Sullivan KF.
Major antigen of liver kidney microsomal autoantibodies in idiopathic
autoimmune hepatitis is cytochrome P450db1. J Clin Invest 1989;83:1066-72.

3. Vento S, Cainelli F, Renzini C, Ercole C. Autoimmune
hepatitis type 2 induced by HCV and persisting after viral clearence.
Lancet 1997;350:1298-9.

4. Kammer AR, van der Burg SH, Grabscheid B, et al. Molecular mimicry
of human cytochrome P450 by hepatitis C virus at the level of cytotoxic T
cell recognition. J Exp Med 1999;190:169-76.

5. Cerny A, Chisari FV. Pathogenesis of chronic hepatitis C:
Immunological features of hepatic injury and viral persistence. Hepatology
1999;30:595-601.

Competing interests: No competing interests

20 July 2000
Andreas Cerny