Functional autoantibodies in primary biliary cirrhosis: a reply to Peter A. Berg

We very much appreciate the thoughtful and kind comments of Peter A. Berg, and we are very cognizant of his important contributions to primary biliary cirrhosis (PBC). As the true etiology of PBC remains enigmatic, we, Berg and others, can only speculate [1xThe unfinished business of primary biliary cirrhosis. Selmi, C. et al. J. Hepatol. 2008; 49: 451–460Abstract | Full Text | Full Text PDF | PubMed | Scopus (39)See all References][1]. However, we feel obligated to respond to Berg's letter and his several comments. First, Berg notes that the innate immune system is constantly involved in the inflammatory biliary process. Second, he points out that there are other functional, active autoantibodies that might also be involved in the pathogenesis of PBC. Third, he believes that the mitochondrial autoantigen is an expression of innate autoimmunity, based on the evolutionary origin of mitochondria. Fourth, he suggests that there is a protective role for anti-mitochondrial antibodies. Finally, Berg describes data showing that the release of a neurotransmitter such as acetylcholine by the vagal nerve is involved directly in the constellation of events that lead to biliary pathology, and that so-called Gq11 protein-coupled muscarinic acetylcholine receptor family members M1, M3 and M5, but not the G1 protein-coupled muscarinic acetylcholine receptor family members M2 and M4, can protect cells from apoptosis following DNA damage.We offer the following responses to Berg's hypotheses. There is no question that the innate immune system, including major bystander events, activation of NKT cells, and generalized inflammation, are an important component of PBC [2xInnate immunity and primary biliary cirrhosis. Selmi, C. et al. Curr. Mol. Med. 2009; 9: 45–51Crossref | PubMed | Scopus (38)See all References][2]. Indeed, our group has already proposed that thesis and suggested that PBC begins with an adaptive response that then requires innate mechanisms for perpetuation. We note, for example, our work on human PBC and NKT cells, as well as our data on NKT cells in a murine model of PBC [3xNatural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis. Chuang, Y.H. et al. Hepatology. 2008; 47: 571–580Crossref | PubMed | Scopus (68)See all References, 4xLiver autoimmunity triggered by microbial activation of natural killer T cells. Mattner, J. et al. Cell Host Microbe. 2008; 3: 304–315Abstract | Full Text | Full Text PDF | PubMed | Scopus (130)See all References]. Second, it is quite reasonable to propose that there may be other autoantibodies involved in this disease [5xA comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis. Agmon-Levin, N. et al. J. Autoimmun. 2009; See all References][5]. We know about the presence of antinuclear antibodies (ANAs), and the paradoxical finding that the presence of some ANAs may have more benign prognostication [6xAntinuclear antibodies in primary biliary cirrhosis. Invernizzi, P. et al. Semin. Liver Dis. 2005; 25: 298–310Crossref | PubMed | Scopus (112)See all References][6]. We also are aware that PBC is part of a cluster of autoimmune diseases involving scleroderma, Sjogren's syndrome and systemic lupus erythematosis (SLE) [7xRisk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Gershwin, M.E. et al. Hepatology. 2005; 42: 1194–1202Crossref | PubMed | Scopus (274)See all References][7]. On the other hand, there is no such evidence for functional autoantibodies in PBC, and Berg's demonstration of autoantibodies to the muscarinic acetylcholine receptor is not found in all patients, and is indeed not specific for PBC. It is not even clear, for example, whether such antibodies are truly autoantibodies, whether they are functional, and to what extent they are merely secondary responses. Third, the major autoantigen of PBC is the E2 component of pyruvate dehydrogenase, and while it is present in mitochondria, it is not encoded by mitochondrial DNA. It is nuclear encoded and transported to the mitochondria. Hence, with all due respect, Professor Berg's comment on the evolutionary origin of mitochondria would seem irrelevant in the absence of other data.Having made these comments, there are a few final points that should be discussed. The development of autoimmune disease in the generic sense involves etiological events and then subsequent effector mechanisms [8xThe genetic basis of primary biliary cirrhosis: premises, not promises. Invernizzi, P. and Gershwin, M.E. Gastroenterology. 2008; 135: 1044–1047Abstract | Full Text | Full Text PDF | PubMed | Scopus (18)See all References][8]. We have made enormous strides in the understanding of effector mechanisms in PBC. We note in our animal models that autoimmune cholangitis appears exacerbated if one depletes B regulatory cells [9xB cells suppress the inflammatory response in a mouse model of primary biliary cirrhosis. Moritoki, Y. et al. Gastroenterology. 2009; 136: 1037–1047Abstract | Full Text | Full Text PDF | PubMed | Scopus (52)See all References][9]. We also note that the loss of T regulatory cells in both patients with IL-2 receptor alpha deficiency (CD25) and mice deleted of CD25, leads to the development of autoimmune cholangitis [10xIL-2 receptor alpha(−/−) mice and the development of primary biliary cirrhosis. Wakabayashi, K. et al. Hepatology. 2006; 44: 1240–1249Crossref | PubMed | Scopus (140)See all References][10]. While we can induce autoimmune cholangitis by immunization of a chemical mimic of the lipoyl domain of PDC-E2, we do not necessarily believe that this implies the modification of the native PDC-E2. Albumin, for example, has 60 lysine residues. Finally, one should take note of the potpourri of autoantibodies in patients with autoimmune disease [5xA comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis. Agmon-Levin, N. et al. J. Autoimmun. 2009; See all References][5]. At the end of the day we submit that PBC is caused by a genetic predisposition to loss of tolerance, followed by a specific adaptive immune response to PDC-E2. The continued pathology involves effector mechanisms that include both adaptive and innate immunity, and occurs selectively in the small bile ducts, as indicated by our unique observations regarding apotopes in intrahepatic bile duct cells [11xApotopes and the biliary specificity of primary biliary cirrhosis. Lleo, A. et al. Hepatology. 2009; 49: 871–879Crossref | PubMed | Scopus (102)See all References][11].