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1.
Hepatology ; 26(5): 1123-30, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9362351

ABSTRACT

Antinuclear antibodies (ANA) staining nuclear dot structures predominantly occur in primary biliary cirrhosis (PBC) patients and recognize the Sp100 and promyelocytic leukemia protein (PML). From retrospective analysis of sera from a clinically well-defined Canadian series of 170 PBC patients included into a 24-month therapeutic trial of ursodeoxycholic acid (UDCA), we report the prevalence of these ANA and their dynamics in the course of the disease. Using an enzyme-linked immunosorbent assay (ELISA), anti-Sp100 autoantibodies were shown in 35 (21%) patients. Thirty-three patients (19%) had autoantibodies against PML as determined by indirect immunostaining of cells overexpressing PML. Altogether, anti-nuclear dot autoantibodies were present in 25% of the 170 PBC patients. Their occurrence correlated with an unfavorable disease course, because these patients progressed significantly more frequently from early stages (I/II) to late stages (III/IV) within the 24-month observation period (P < .05). During the course of the disease, the autoantibody levels against the Sp100 full-length protein remained nearly constant in all 35 positive patients. However, 9 patients showed remarkable changes in Sp100 epitope recognition as revealed by ELISA and immunoblotting. When the occurrence of these changes and the treatment of the patients were compared retrospectively, it became evident that 8 of the 9 patients had received UDCA (42% of all Sp100-positive patients treated with UDCA). These findings indicate subtle changes of the Sp100 epitope recognition pattern during the natural course of the disease and its induction or acceleration by UDCA treatment. This implies that UDCA can modulate immunoglobulin (Ig) expression not only quantitatively, but also qualitatively.


Subject(s)
Antigens, Nuclear , Autoantibodies/immunology , Autoantigens/immunology , Leukemia, Promyelocytic, Acute/metabolism , Liver Cirrhosis, Biliary/immunology , Liver Cirrhosis, Biliary/therapy , Neoplasm Proteins/immunology , Nuclear Proteins/immunology , Adult , Aged , Autoantibodies/analysis , Cell Nucleus/immunology , Cohort Studies , Enzyme-Linked Immunosorbent Assay , Epitopes/immunology , Female , Humans , Immunoblotting , Kinetics , Liver Cirrhosis, Biliary/physiopathology , Male , Middle Aged , Organelles/immunology , Prevalence
2.
J Cell Biol ; 138(2): 435-48, 1997 Jul 28.
Article in English | MEDLINE | ID: mdl-9230084

ABSTRACT

Nuclear dots containing PML and Sp100 proteins (NDs) play a role in the development of acute promyelocytic leukemia, are modified after infection with various viruses, and are autoimmunogenic in patients with primary biliary cirrhosis (PBC). PML and Sp100 gene expression is strongly enhanced by interferons (IFN). Based on immunostaining with a monoclonal antibody (mAb C8A2), a third protein, nuclear dot protein 52 (NDP52), was recently localized in NDs. Here we analyzed the cellular localization, expression, and structure of NDP52 in more detail. Our NDP52-specific sera revealed mainly cytoplasmic staining but no ND pattern, neither in untreated nor in IFN-treated cells. Cells transfected with NDP52 expression vectors showed exclusively cytoplasmic staining. In subcellular fractionation experiments, NDP52 was found in cytoplasmic and nuclear fractions. Unlike as described for Sp100 and PML, NDP52 mRNA and protein levels were only marginally enhanced by IFN gamma and not enhanced at all by IFN beta. NDP52 homodimerization but no heterodimerization with Sp100 or PML could be demonstrated. None of the 93 PBC sera tested contained autoantibodies against NDP52. Finally, mAb C8A2 reacted not only with NDP52 but also with a conformation-dependent epitope on the Sp100 protein. These data imply that NDP52 forms homodimers but no heterodimers with Sp100 and PML, lacks autoantigenicity in PBC, localizes mainly in the cytoplasm, and is associated with the nucleus, but not with NDs. Finally, unlike Sp100 and PML, NDP52 expression is neither markedly enhanced nor localization detectably altered by type I and II IFNs.


Subject(s)
Antigens, Nuclear , Cell Nucleus/chemistry , Cytoplasm/chemistry , Neoplasm Proteins , Nuclear Proteins/analysis , Nuclear Proteins/metabolism , Animals , Antibodies, Monoclonal , Autoantibodies/blood , Autoantigens/metabolism , Cell Line , Cloning, Molecular , Cross Reactions , DNA, Complementary/genetics , Dimerization , Gene Expression , HeLa Cells , Humans , Interferon-beta/pharmacology , Interferon-gamma/pharmacology , Liver Cirrhosis, Biliary/immunology , Nuclear Proteins/chemistry , Promyelocytic Leukemia Protein , RNA, Messenger/analysis , Rats , Sequence Analysis, DNA , Transcription Factors/metabolism , Tumor Suppressor Proteins
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