title: Variability in the expression of a beta 2-microglobulin epitope on hepatocytes in chronic type C hepatitis on treatment with interferon.
abstract: Cytotoxic CD8+ T lymphocytes recognize viral antigens in the context of human leukocyte antigen class I molecule coexpression by target cells. Analysis of beta 2-microglobulin reactivity is useful in evaluating changes in human leukocyte antigen class I antigen distribution. In this study we analyzed liver biopsy specimens obtained from 15 patients with chronic active hepatitis type C who underwent a clinical trial with recombinant interferon-alpha 2b. We comparatively studied by immunohistochemical analysis the expression of human leukocyte antigen class I antigens in frozen liver samples obtained before entry in the protocol and in specimens taken 8 mo after initiation of treatment. Six normal liver samples were used as controls. For immunohistochemical analysis, a panel of several human leukocyte antigen class I monoclonal antibodies, specific for beta 2-microglobulin or different heavy-chain determinants, was used. In addition, we included a novel monoclonal antibody (HP-1H8), characterized in this report, which is specific for a distinct beta 2-microglobulin epitope. On entry, mean serum ALT was 240 +/- 89 IU/L and mean Knodell's index was 9.9 +/- 2.4, whereas at the time of the second biopsy mean values had diminished to 45 +/- 22 IU/L and 4.7 +/- 3.0, respectively. Liver sections from controls and patients expressed human leukocyte antigen class I light- and heavy-chain determinants in hepatocytes, biliary duct epithelium, sinusoidal lining cells and lymphocytes. Remarkably, the beta 2-microglobulin epitope recognized by the HP-1H8 monoclonal antibody was undetectable on hepatocytes from normal livers but clearly evident on hepatocytes from patients with chronic active hepatitis C before interferon treatment. Positive staining was more intense in areas of piecemeal and lobular necrosis. Double immunostaining with a CD2 monoclonal antibody demonstrated that labeling with HP-1H8 was predominantly associated with T-cell infiltration. Interestingly, the reactivity of HP-1H8 with hepatocytes was diminished or disappeared in specimens obtained during interferon treatment; the pattern of reactivity then resembled that of samples from normal controls. Our data indirectly suggest that, in addition to the increased expression of human leukocyte antigen class I molecules on hepatocytes in viral infections, conformational changes may take place in these antigens. These changes can be revealed by immunostaining with the HP-1H8 monoclonal antibody. Interferon therapy could down-regulate this expression through its effect in reducing the histological activity resulting from the lysis of virus-infected hepatocytes by cytotoxic T cells.
authors.affiliation: Liver Unit, Hospital de la Princesa, Universidad Autónoma de Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: García-Buey
authors.forename: M
authors.initials: M
authors.lastname: López-Botet
authors.forename: A
authors.initials: A
authors.lastname: García-Sánchez
authors.forename: M A
authors.initials: MA
authors.lastname: Balboa
authors.forename: J
authors.initials: J
authors.lastname: Aramburu
authors.forename: C
authors.initials: C
authors.lastname: García-Monzón
authors.forename: A
authors.initials: A
authors.lastname: Acevedo
authors.forename: R
authors.initials: R
authors.lastname: Moreno-Otero
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal; D002908:Chronic Disease; D000939:Epitopes; D005260:Female; D006526:Hepatitis C / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D001613:beta 2-Microglobulin / Q000032:analysis / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D001613:beta 2-Microglobulin; D007372:Interferons