Autoantibodies and Autoantigens in Autoimmune Hepatitis

Christian P. Strassburg, MD, Michael P. Manns, MD


Semin Liver Dis. 2002;22(4) 

In This Article

Autoimmune Hepatitis Type 2

AIH type 2 is characterized by the presence of LKM-1 autoantibodies against CYP 2D6. In 10%, LKM-3 autoantibodies against UGTs are also present.[4,72,81] In contrast to AIH type 1, additional organ-specific autoantibodies are frequently present, such as anti-thyroid, anti-parietal cell, and anti-Langerhans' cell autoantibodies. The number of extrahepatic immune syndromes such as diabetes, vitiligo, and autoimmune thyroid disease is also more prevalent. Serum immunoglobulin levels are moderately elevated with a reduction of IgA. AIH type 2 is a rare disorder that affects up to 20% of AIH patients in Europe but only 4% in the United States.[11,93] There is a predominance of women. The average age at onset is around 10 years, but AIH type 2 is also observed in adults, especially in Europe. AIH type 2 carries a higher risk of progression to cirrhosis and of a fulminant course. When AIH type 2 is diagnosed in children, cirrhosis is very frequently present at the time of diagnosis.

LKM autoantibodies have been extensively studied not only for their role as markers of AIH type 2 but also for differential diagnostic purposes in order to offset other hepatic diseases, to gain insight into the immunologic mechanisms involved in AIH, and to evaluate their prognostic role. Manns et al[58] tested 26 LKM-positive sera using Western blotting with partial sequences of recombinant CYP 2D6. Eleven of these sera recognized a short minimal epitope of eight amino acids with the sequence DPAQPPRD. Twelve other clones recognized a larger epitope containing this eight-amino acid core sequence. The search of electronic databases revealed an interesting match of the minimal epitope with the primary structure of the immediate early protein IE 175 of herpes simplex virus type 1 (HSV-1) (Fig. 3). Sequence identity is present for the sequence PAQPPR.[58] Therefore, affinity-purified LKM-1 (anti- CYP 2D6) autoantibodies were used in Western blots with lysates of BHK cells infected with HSV. The autoantibody specifically detected a band at 175 kD, which demonstrates cross-reactivity with a HSV-specific protein of 175 kD.[58] The hypothesis that molecular mimicry may underlie this form of autoimmunity was further suggested by a case study. In a pair of identical twins, one sister suffered from AIH type 2; the other one was healthy. Interestingly, only the sister suffering from AIH was HSV positive, and her serum recognized the viral 175 kD protein in lysates of HSV-infected cells.[94] Molecular mimicry might contribute to the development of AIH-2 by weakening self-tolerance to certain protein targets. So far evidence for the mimicry hypothesis in AIH is not convincing.

Figure 3.

Overall evidence for mimicry as a driving force of autoimmune hepatitis is not convincing. However, the homology of herpes virus antigens and epitopes recognized by LKM-1 autoantibodies in AIH type 2 is an attractive model for this hypothesis.

Further work on epitope mapping was performed by Yamamoto, resulting in the identification of three minor epitopes on CYP 2D6.[64] Yamamoto et al[64] confirmed that most patients with AIH-2 recognize the epitope of aa 257-269, including the core sequence of DPAQPPRD. With lower frequencies, another epitope of aa 373-389 was detected and two infrequent epitopes consisting of aa 373-389 or 410-429.[64] Because linear peptides were unable to absorb the inhibitory activity of LKM-1 autoantibodies of CYP 2D6 activity, Duclos-Vallee et al[61] suggested the presence of conformational autoantibodies in LKM-1 sera. Another major epitope located at aa 321-373 that appears to be three dimensional and is no longer reactive when cut into overlapping pieces has been characterized (Sugimura et al, unpublished results by the authors' laboratory, 2000).


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