RESUMEN
Primary biliary cholangitis (PBC) is a multi-factorial disease caused by the interaction of both genetic predisposition and environmental triggers. Bacterial infection has been investigated most intensively, both epidemiologically and experimentally, as a prime environmental aetiology in PBC. The association of recurrent history of urinary tract infection (UTI) with PBC has been frequently confirmed by several large-scale, case-control studies, despite variation in geographic area or case-finding methods. Escherichia coli is a predominant pathogen in most cases with UTI. Animal studies and molecular mimicry analysis between the human and E. coli E2 subunit of the 2-oxo-acid dehydrogenase complexes demonstrated that E. coli infection is a key factor in breaking immunological tolerance against the mitochondria, resulting in the production of anti-mitochondrial autoantibodies (AMA), the disease-specific autoantibodies of PBC. Novosphingobium aromaticivorans, a ubiquitous xenobiotic-metabolizing bacterium, is another candidate which may be involved in the aetiology of PBC. Meanwhile, improved environmental hygiene and increased prevalence of PBC, especially in males, may argue against the aetiological role of bacterial infection in PBC. Multiple mechanisms can result in the loss of tolerance to mitochondrial autoantigens in PBC; nonetheless, bacterial infection is probably one of the dominant pathways, especially in female patients. Notably, there is a rising prevalence of male patients with PBC. With increasing exposure to environmental xenobiotics in both genders, studies directed towards identifying the environmental culprit with systematically designed case-control studies are much needed to further determine the environmental factors and role of bacterial infections in PBC.
Asunto(s)
Alphaproteobacteria/fisiología , Autoinmunidad , Infecciones Bacterianas/microbiología , Cirrosis Hepática Biliar/microbiología , Infecciones Urinarias/microbiología , 3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/inmunología , 3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/metabolismo , Animales , Autoanticuerpos/metabolismo , Infecciones Bacterianas/inmunología , Femenino , Interacción Gen-Ambiente , Humanos , Tolerancia Inmunológica , Cirrosis Hepática Biliar/inmunología , Masculino , Mitocondrias/inmunología , Imitación Molecular , Infecciones Urinarias/inmunologíaRESUMEN
Although antimitochondrial antibody (AMA) is the characteristic serological feature of primary biliary cirrhosis (PBC), its pathogenic role remains unclear. In our previous study, we reported a positive correlation between immunoglobulin (Ig) A class anti-2-oxo-acid dehydrogenase complex (2-OADC) and histopathological stage. To determine whether the appearance of IgA class anti-2-OADC by immunoblotting represents an early marker of more aggressive disease or whether it is late finding during the disease course of PBC, we tested not only the entire IgA class but also IgA1, IgA2 and secretory IgA class anti-2-OADC in serial serum samples from 15 patients with PBC. During the median observation period of 51 months, four cases showed histopathological progression (from stage 1 to 2, stage 1 to 3, stage 1 to 4 and stage 2 to 4). There was no statistically significant correlation between the above IgA class anti-2-OADCs and histopathological progression. There was no significant correlation between histopathological stages and IgA2 class anti-2-OADC or secretory IgA class anti-2-OADC by immunoblotting. IgA class anti-2-OADC was more frequent in stages 3-4 than in stages 1-2 (p = 0.0049), but IgA1 class anti-2-OADC was more frequent in stages 1-2 than in stages 3-4 (p = 0.0232). Our present study demonstrated that serum IgA class 2-OADC was not a predictive marker of histopathological progression but was associated with the histopathological stage of PBC. Although the IgA class AMA may have a specific pathogenic role for PBC, the discrepant results between IgA and IgA1 class anti-2-OADC should be further assessed to investigate different functional activities depending on their molecular form.
Asunto(s)
3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/inmunología , Inmunoglobulina A/sangre , Inmunoglobulina A/clasificación , Cirrosis Hepática Biliar/enzimología , Cirrosis Hepática Biliar/inmunología , Complejos Multienzimáticos/inmunología , Adulto , Anciano , Femenino , Humanos , Hígado/patología , Cirrosis Hepática Biliar/etiología , Cirrosis Hepática Biliar/patología , Masculino , Persona de Mediana Edad , Mitocondrias/inmunologíaRESUMEN
The serum reaction to anti-2-oxo-acid dehydrogenase complex (2-OADC) enzymes, the antigens recognized by antimitochondrial antibodies (AMA), can be detected by immunoblotting in patients with liver diseases other than primary biliary cirrhosis (PBC), who are negative for AMA by conventional indirect immunofluorescence. Whether the presence of anti-2-OADC is related to PBC or represents preclinical PBC in such patients is obscure at present. We examined the immunoreactivity of AMA by immunofluorescense, immunoblotting, and enzyme inhibition assay in serum samples from 59 patients with liver diseases other than PBC and 71 healthy subjects. We also examined the clinical course of the patients in whom a positive result was obtained to elucidate whether such reaction was a "true" or "false" phenomenon. None of the 130 sera was positive for AMA by indirect immunofluorescence or for anti-pyruvate dehydrogenase complex (PDC) by enzyme inhibition assay. However, seven of 71 (10%) sera from healthy subjects contained weak IgG class antibody to PDC-E2 (four sera) or E2 subunit of branched-chain oxo-acid dehydrogenase complex (BCOADC-E2) (three sera). Of the 59 sera from patients with liver diseases other than PBC, four (7%) reacted against 2-OADC by immunoblotting. Of these, three sera were from patients with chronic hepatitis C virus (HCV) infection, and contained IgG class autoantibody to BCOADC-E2. The serum reactivity to BCOADC-E2 detected by immunoblotting in these three patients diminished after absorption with recombinant BCOADC-E2 fusion protein. During the 3-5 year follow-up period, AMA by immunofluorescence and anti-PDC activity by enzyme inhibition assay were always negative in these three patients. The other one serum was from patient with alcoholic cirrhosis, and contained IgM class autoantibody to E3 binding protein (E3-BP). This patient did not develop PBC during the following 2 years. Our results showed that anti-2-OADC antibodies could be detected in some patients with liver diseases other than PBC, and even in healthy individuals. The clinical significance of the presence of these serum reactions is obscure at this stage, but the production of anti-BCOADC-E2 may be linked to the presence of HCV in certain patients. Further prospective studies of larger population should clarify whether anti-2-OADC reaction can precede the clinical development of PBC.