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In Murine and Human Liver Revealed by Immunofluorescen Proc; Nati. Acad. Sci. USA Vol. 76, No. 8, pp. 4112-4116, August 1979 Medical Sciences Formation and involution of Mallory bodies ("alcoholic hyalin") in murine and human liver revealed by immunofluorescence microscopy with antibodies to prekeratin (alcoholic hepatitis/liver pathology/keratin/intermediate filaments/tonofilaments) HELMUT DENK*, WERNER W. FRANKEt, ROMANA ECKERSTORFER*, ERIKA SCHMIDt, AND DONTSCHO KERJASCHKI* *Division of Gastroenterologic Pathology and Hepatopathology (Hans Popper Laboratory), Department of Pathology, University of Vienna School of Medicine, Vienna, Austria; and tDivision of Membrane Biology and Biochemistry, Institute of Experimental Pathology, German Cancer Research Center, Heidelberg, West Germany Communicated by Hans Popper, May 29, 1979 ABSTRACT Antibodies raised against prekeratin intensely In the present communication the following findings are and specifically stain, in immunofluorescence microscopy, reported. (i) Antibodies t6 bovine prekeratin react with MBs Mallory bodies ("alcoholic hyalin") present in livers of human alcoholics and griseofulvin-treated mice. The high sensitivity of human origin, thus extending our original observation in of this method allows the identification of small distinct cyto- experimental animals (5) to human disease. (ii) Immunofluo- plasmic structures that are observed during early stages of rescence microscopy using such antibodies as well as antibodies Mallory body formation, especially frequent in the perinuclear to MBs of human origin allows the tracingof MB formation and cytoplasm, as well as during stages of Mallory body disinte- involution by detection of early (precursor) stages of MB for- gration and disappearance, such as after withdrawal of the drug. mation as well as MB fragments during involution. (iii) MBs of In the latter situation, the prekeratin-containing small particles exhibit a characteristic pattern of arrangement in the hepatocyte human liver differ from those in livers of griseofulvin-treated periphery. Electron microscopy illustrates that such smal bodies mice in that they immunologically crossreact with prekeratin are heap-like aggregates of typical Mallory body filaments. from desmosome-attached tonofilamepts of bovine muzzle but Immunofluorescence studies with antibodies to isolated pre- not with prekeratin polypeptide components of bovine hoof. keratin polypeptides from bovine hoof or muzzle epidermis (iv) Neither original nor colchicine- or griseofulvin-reinduced show that Mallory body filaments, in particular those in human murine MBs are related to the vimentin-type of intermedi- liver, are immunologically more closely related to prekeratin of tonofilaments from living epidermal cells (stratum spinosum). ate-sized filaments (9). The data indicate that Mallory bodies contain a pathologic form of prekeratin-like material. They also suggest that disorders of MATERIALS AND METHODS cytoskeletal structures of the intermediate-sized filament class Human Liver. Liver tissue from patients with alcoholic are associated with specific diseases and can be visualized and characterized by immunofluorescence microscopy by using hepatitis and cirrhosis was removed at autopsy. For comparison, antibodies to constitutive proteins of such filaments. samples of alcoholic fatty liver and of livers without pathologic alterations were examined. Mallory bodies (MBs) ("alcoholic hyalin") are unique cyto- Animals. Male Swiss albino mice (strain Him:OF 1 SPF; plasmic inclusions, mostly observed in hepatocytes (1). Their Institute for Laboratory Animal Research, University of Vienna major and most characteristic components are randomly oi- School of Medicine, Himberg, Austria) were fed a powdered ented, unbranched, rod-shaped filaments of 14-20 nm in di- standard diet (Altromin, LippeW West Germany) containing ameter, which often exhibit a dense fimbriated coat (2-5). They 2.5% griseofulvin (Qlaxo, Greenford, England) as de- are characteristic morphologic features of alcoholic hepatitis scribed (6). Animals were killed after 1, 2, 3, 4, 6, 8, and 12 (1) but have also been observed in diverse liver disorders not weeks of continuous griseofulvin feeding, and 1, 2, 3, and 10 related to alcoholism (3). Typical MBs can be experimentally days and 3, 8, and 12 weeks after withdrawal of the drug in produced in mouse liver by long-term griseofulvin feeding (6). order to trace development and involution of MBs. In addition, The major constituents of experimentally induced MB filaments some mice were kept on the following regimen: continuous are a group of polypeptides with apparent Mr values ranging griseofulvin treatment for 2.5 months, then 2.5 or 3 months on from 48,000 to 66,000 (5), and a similar composition has re- a drug-free diet, then on the griseofulvin-containing diet again cently been reported for MBs from human alcoholics (7). In this for 4 days prior to sacrifice. In another group of animals final respect, MBs resemble prekeratins from different sources that griseofulvin refeeding was replaced by the administration of all contain characteristic polypeptides in the 47,000- to colchicine for 8 days (10) by using a colchicine dosage of 0.5 68,000-Mr range (see ref. 8 for references). In addition, it has ,tg/g of body weight injected subeutaneously twice a day. been shown that antibodies to prekeratin from bovine hoof Antibodies. Antibodies were (i) guinea pig antisera to total horny layer, in immunofluorescence microscopy, specifically reconstituted, purified bovine hoof (including stratum cor- decorate murine MBs, which further strengthens the relation- neum) prekeratin (5, 8); (ii) IgG from i made monospecific for ship between MB filaments and intermediate-sized filaments prekeratin as described (11); (iii) guinea pig anitisera against of the prekeratin type present in most if not all epithelial cells electrophoretically separated individual polypeptides or ("cytokeratins") (8). On the basis of these findings it has been polypeptide fractions of bovine hoof prekeratin and desmo- proposed that MB formation represents a pathologic form of some-associated tonofilaments from bovine muzzle (11-13); hyperkeratosis (5). (iv) guinea pig IgG from antisera to prekeratin from human epidermal tissue obtained from autopsy skin material that was The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "ad- Abbreviations: MBs, Mallory bodies; DT, indicates desmosome-asso- vertisemennt" in accordance with 18 U. S. C. §1734 solely to indicate ciated tonofilament prekeratin component; PK, indicates prekeratin this fact. component from bovine hoof. 4112 Downloaded by guest on September 25, 2021 Medical Sciences: Denk et al. Proc. Natl. Acad. Sci. USA 76 (1979) 4113 prepared as described for bovine hoof prekeratin (8); (v) guinea Patterns of MB Formation and Involution. Mouse liver pig IgG from antisera to human MBs isolated from autopsy liver damaged by griseofulvin administration was examined by using according to French et al. (14) and further purified as described antibodies to bovine prekeratin, to individual prekeratin by Franke et al. (5); (vi) guinea pig antisera against murine components, and to MBs on consecutive sections of frozen liver vimentin (9). Controls included preimmune sera and sera ab- tissue. Agreement of immunolocalization was observed with sorbed with the specific antigens. the different antibody preparations. MB-like material was Immunofluorescence Microscopy. Small pieces of liver detected in some mice as early as 4 weeks after commencement were quickly frozen in isopentane cooled with liquid nitrogen. of griseofulvin feeding in the form of small granules that were Immunofluorescence microscopy was performed on frozen distributed either diffusely in the cytoplasm of scattered liver sections as described (5). cells or, more characteristically, in prominent perinuclear ar- Electron Microscopy. Mice were anesthetized with ether, rays. Such perinculear granules seem to be typical for early and the livers were perfused through the portal vein first with stages of MB formation (Fig. 1 a, d, and e and Fig. 2). After 6 Hanks' balanced salt solution and then with 2.5% glutaral- weeks of continuous griseofulvin administration, sporadic dehyde in 0.1 M sodium cacodylate buffer, pH 7.4. Small cubes hepatocytes in centrolobular position with irregularly ramified of liver tissue were postfixed for at least 4 hr in the same fixative. MB-like structures and aggregates of confluent prekeratin- They were then osmicated and processed for embedding and containing granules were observed. At 8 weeks, MB-containing electron microscopy of ultrathin sections according to con- hepatocytes were already numerous and were arranged in ventional procedures. groups of 4-10 cells, mostly in the center of the lobules sur- rounding the central veins. At this stage, MBs in many hepa- tocytes were large and exhibited irregular, reticular contours RESULTS or coiled organization. They were often, but not always, in Reaction of Murine and Human MBs with Antibodies to paranuclear position, sometimes forming thick perinuclear rings Diverse Prekeratin Preparations and to Human MBs. Anti- (Fig. le). However, despite the presence of typical fully de- bodies to prekeratin from total bovine hoof epidermis and from veloped MBs in some cells,, adjacent, hepatocytes often still bovine muzzle desmosome-associated tonofilaments strongly exhibited small granules of MB material or showed arrange- ments suggestive of
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