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• W2080441623 abstract "Mouse mammary tumor virus in anti-mitochondrial antibody producing mouse modelsJournal of HepatologyVol. 55Issue 4PreviewA human betaretrovirus resembling the mouse mammary tumor virus (MMTV) has been characterized in primary biliary cirrhosis (PBC) and associated with aberrant pyruvate dehydrogenase complex (PDC)–E2-like expression. As MMTV is prevalent in mice as either an exogenous or endogenous infection, we tested the hypothesis that MMTV is linked with anti-mitochondrial antibody (AMA) production in models with severe immune dysfunction. Full-Text PDF It is now widely accepted that primary biliary cirrhosis (PBC) is a complex disorder, with both genetic and environmental factors contributing to its pathogenesis. Over the last two years significant light has been shed on the potential genetic factors contributing to PBC, with several genome-wide associations studies (GWAS) showing highly consistent results, all pointing to a strong genetic susceptibility to PBC relating, typically, to genes which regulate the immune response in general and antigen presentation and T-cell priming in particular [1Hirschfield G.M. Liu X. Xu C. Lu Y. Xie G. Lu Y. et al.Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.N Engl J Med. 2009; 360: 2544-2555Crossref PubMed Scopus (501) Google Scholar, 2Liu X. Invernizzi P. Lu Y. Kosoy R. Lu Y. Bianchi I. et al.Genome-wide metaanalyses identify three loci associated with primary biliary cirrhosis.Nat Genet. 2010; 42: 658-660Crossref PubMed Scopus (326) Google Scholar]. Taken together, these studies all point to dysregulated immunity playing an important role in the disease. Less progress has been made, however, in identifying environmental factors which could be triggering the disease process in susceptible individuals, although the existence of such a factor is strongly supported by epidemiological studies which have identified disease clusters [3Prince M.I. Chetwynd A. Diggle P. Jarner M. Metcalf J.V. James O.F.W. The geographical distribution of primary biliary cirrhosis in a well-defined cohort.Hepatology. 2001; 34: 1083-1088Crossref PubMed Scopus (136) Google Scholar, 4McNally R.J. Ducker S. James O.F. Are transient environmental agents involved in the cause of primary biliary cirrhosis/evidence form space-time clustering?.Hepatology. 2009; 50: 1169-1174Crossref PubMed Scopus (63) Google Scholar]. Although these observations have been interpreted as supporting a chemical environmental factor, they could equally well support an infectious factor. This possibility is particularly supported by the most recent clustering study, carried out in the North-East of England, which identified both temporal as well as spatial clustering in disease patterns [[4]McNally R.J. Ducker S. James O.F. Are transient environmental agents involved in the cause of primary biliary cirrhosis/evidence form space-time clustering?.Hepatology. 2009; 50: 1169-1174Crossref PubMed Scopus (63) Google Scholar]; an observation compatible with person-to-person or vector transmission.To date, however, no infectious agent has been unequivocally linked with PBC risk. There are some data to support chronic urinary tract infections (UTI), although causality has always proved difficult (the issue is whether patients with recurrent urinary tract infections are predisposed to developing PBC or, conversely, whether the trophic changes within the urinary tract seen in PBC patients predispose to UTI). One of the most contentious postulated models for infectious triggering of PBC has been the betaretrovirus model postulated by the Mason Group [5Mason A.L. Xu L. Guo L. Munoz S. Jaspen J.B. Bryer-Ash M. et al.Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic liver disorders.Lancet. 1998; : 351PubMed Google Scholar, 6Xu L. Shen S. Guo L. Fodera B. Keogh A. Joplin R. et al.Does a betaretrovirus infection trigger primary biliary cirrhosis?.Proc Natl Acad Sci USA. 2003; 100: 8454-8459Crossref PubMed Scopus (201) Google Scholar, 7Xu L. Sakalian M. Shen Z. Loss G. Neuberger J. Mason A. Cloning the human betaretrovirus proviral genome form patients with primary biliary cirrhosis.Hepatology. 2004; 39: 151-156Crossref PubMed Scopus (92) Google Scholar]. In a series of publications, this group has identified serological responses to retroviruses in PBC patients, described the presence of “viral” particles in cultured biliary epithelial cells (BEC) from PBC patients, and identified the presence of viral nucleic acid in draining lymph nodes from PBC patients’ livers (and, at much lower frequency, in liver and serum). The group has postulated that one of the reproducible observations made in PBC, that of surface up-regulation of pyruvate dehydrogenase complex (PDC, the auto-antigen in PBC), or a cross-reactive protein, by BEC [[8]Sadamoto T. Joplin R. Keogh A. Mason A. Carman W. Neuberger J. Expression of pyruvate-dehydrogenase complex PDC-E2 on biliary epithelial cells induced by lymph nodes from primary biliary cirrhosis.Lancet. 1998; 352: 1595-1596Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar], is a consequence of the actions of the retrovirus, co-culture of BEC from normal subjects with tissue extract from PBC-patient liver draining lymph-node resulting in, seemingly, transfer of the effect into the naive cell cultures. The model proposed by the Mason group is that the actions of the betaretrovirus on antigen expression generates neo-antigens which induce immune responses cross-reactive with self-PDC, breaking tolerance and triggering the autoimmune phase of the disease (an “altered-self” model for autoimmunity). The potential importance of the model clearly lies in the opportunity, if the model is correct, to modify retrovirus as a risk factor through the use of anti-retroviral drugs [[9]Mason A.L. Farr G.H. Xu L. Hubscher S.G. Neuberger J.M. Pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis.Am J Gastroenterol. 2004; 99: 2348-2355Crossref PubMed Scopus (57) Google Scholar].Although seductive, the retroviral aetiology model for PBC has proved highly controversial, with other groups challenging the primary findings, and no group successfully reproducing the key observations [10Selmi C. Ross S.R. Ansari A.A. Invernizzi P. Podda M. Coppel R.L. et al.Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis.Gastroenterology. 2004; 127: 493-501Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 11Selmi C. Gershwin M.E. The retroviral myth of primary biliary cirrhosis: Is this (finally) the end of the story.J Hepatol. 2009; 51: 411-412Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 12Johal H. Scott G.M. Jones R. Camaris C. Riordan S. Rawlinson W.D. Mouse mammary tumour virus-like virus (MMTC-LV) is present within the liver in a wide range of hepatic dosriders and unrelated to nuclear p53 expression of hepatocarcinogenesis.J Hepatol. 2009; 50: 548-554Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar] (although, it should be noted, no group has attempted to replicate the study of liver draining lymph nodes from PBC patients; the tissue with the highest level of viral expression in the original report [6Xu L. Shen S. Guo L. Fodera B. Keogh A. Joplin R. et al.Does a betaretrovirus infection trigger primary biliary cirrhosis?.Proc Natl Acad Sci USA. 2003; 100: 8454-8459Crossref PubMed Scopus (201) Google Scholar, 12Johal H. Scott G.M. Jones R. Camaris C. Riordan S. Rawlinson W.D. Mouse mammary tumour virus-like virus (MMTC-LV) is present within the liver in a wide range of hepatic dosriders and unrelated to nuclear p53 expression of hepatocarcinogenesis.J Hepatol. 2009; 50: 548-554Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar]). Furthermore, alternative explanations can be put forward for many of the key observations (for example cell surface expression of PDC can occur as a consequence of apoptosis meaning that any factor which could be transferred from one cell culture to another, and which induces cells to undergo apoptosis, would seemingly “transmit” the cell surface PDC expression phenotype [[13]Macdonald P. Kirby J.A. Jones D.E.J. Cell-surface expression of pyruvate dehydrogenase complex during apoptosis: a possible route for autoantigen presentation in primary biliary cirrhosis.Hepatology. 2002; 36: 420AGoogle Scholar]). The controversy surrounding the model, and the associated debate around the equivalence of methods used in the different studies, can lead the non-expert unclear as to what the findings mean (if anything) for PBC patients.The counter-view regarding PBC pathogenesis is that it is a classical autoimmune disease, a suggestion strongly supported by the high titre auto-antibodies, presence of auto-reactive T-cells, association with other auto-immune diseases, and, latterly, the strong immuno-genetic associations described in PBC [[14]Jones D.E.J. Pathogensis of primary biliary cirrhosis.Gut. 2007; 56: 1615-1624PubMed Google Scholar]. One of the recent strands of evidence supporting a purely autoimmune model for PBC pathogenesis of PBC is the work by the Gershwin group and others identifying spontaneous murine models which develop serological and histological features which are suggestive of PBC [15Irie J. Wu Y. Wicker L.S. Rainbow D. Nalesnik M.A. Hirsch R. et al.NOD.c3c4 congenic mice develop autoimmune liver disease that serologically and pathogenetically models human primary biliary cirrhosis.J Exp Med. 2006; 203: 1209-1219Crossref PubMed Scopus (157) Google Scholar, 16Oertelt S. Lian Z.X. Cheng C.M. Chuang Y.H. Padgett K.A. He X.S. et al.Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice.J Immunol. 2006; 177: 1655-1660Crossref PubMed Scopus (219) Google Scholar, 17Wakabayashi K. Lian Z.X. Moritoki Y. Lan R.Y. Tsuneyama K. Chuang Y.H. et al.IL-2 receptor alpha (−/−) mice and the development of primary biliary cirrhosis.Hepatology. 2006; 44: 1240-1249Crossref PubMed Scopus (194) Google Scholar]. These spontaneous models, in animals with specific immuno-regulatory abnormalities, would appear to support the concept emerging from the human GWAS studies that it is immune dysregulation which predisposes to PBC; the classical autoimmune model. One of the key models of this type is the NOD.c3.c4 mouse, a congenic non-diabetic derivative of the classical NOD mouse which develops intra-hepatic bile duct damage redolent of PBC in the context of anti-PDC auto-antibodies [15Irie J. Wu Y. Wicker L.S. Rainbow D. Nalesnik M.A. Hirsch R. et al.NOD.c3c4 congenic mice develop autoimmune liver disease that serologically and pathogenetically models human primary biliary cirrhosis.J Exp Med. 2006; 203: 1209-1219Crossref PubMed Scopus (157) Google Scholar, 18Yang G.-X. Wu Y. Tsukamoto H. Leung P.S. Lian Z.-X. Rainbow D.B. et al.CD8 T-cells mediate direct biliary ductule damage in nonobese diabetic autoimmune biliary disease.J Immunol. 2011; 186: 1259-1267Crossref PubMed Scopus (40) Google Scholar] (as well as some other less typical features). To date, there are no data to suggest that environmental factors might be necessary to promote the development of bile duct abnormality in these animals.In the current edition of the Journal of Hepatology the Mason group has attempted to draw together these disparate strands of research [[19]Zhang G. Chen M. DGraham D. Subsin B. McDougall C. Gilady S. et al.Mouse mammary tumour virus in anti-mitochondrial antibody producing mouse models.J Hepatol. 2011; 55: 876-884Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. In the study, they explored the biology of the NOD.c3.c4 mouse and other murine models of PBC and, in particular, looked for the presence of mouse mammary tumour virus (MMTV), a murine retrovirus which has almost complete sequence homology with the postulated human PBC betaretrovirus. NOD.c3.c4 mice expressed MMTV surface and capsid proteins on the biliary epithelium, together with a protein which was cross reactive with PBC E2. The other animal models also expressed MMTV proteins and aberrant PBC-E2-like protein in the spleen. All animals expressed MMTV gag and env in the liver. A significant correlation was seen between anti-MMTV antibody production and anti-PDC autoantibody production in the sera of the NODc3.c4 mice.MMTV transmission in mice is typically in the neonatal period through breast milk. Although causal associations are not demonstrated in this study, the model the authors propose is that such neonatal exposure to the MMTV leads to chronic infection which alters PDC (or PDC homologue) expression within tissues, predisposing to subsequent breakdown of immune tolerance resulting in the development of autoimmunity. In this model, the immuno-genetic abnormalities in the mice either predispose to chronicity of infection in the first place, or to the secondary breakdown in tolerance to PDC promoted by altered self-antigen processing or the expression of a viral homologue (or of course both processes).The findings of the study have the potential to both advance the field and to add further confusion to an already confused picture. At one end of the range of possibilities (and the end that the authors would no doubt support) the findings suggest that the NOD.c3.c4 model (and to a lesser extent the other two models) fully models the changes which are present in PBC, with an immuno-genetic susceptibility and retroviral exposure combining to promote tolerance breakdown. In this scenario, the murine models would present a perfect context in which to do pre-clinical testing of anti-retroviral interventions of potential benefit to PBC patients. At the other end of the range of possibilities, the observations of un-anticipated pathogen differences in different sub-strains of animals potentially confound the validity of these models for PBC as an autoimmune disease.Critical to understanding the value or otherwise of the findings of Zhang et al. will be the extent to which they can be reproduced by other groups; a scenario identical to the situation with the human retroviral model. It is critical now that both the human and the murine retroviral stories are explored in a co-ordinated way by independent laboratories using standardised approaches and reagents. Only then, will we understand whether we now have the perfect murine model for PBC (a similar pathogenic trigger on a similar immunogenetic background) or whether we simply have artefacts. That this controversy is finally resolved is important for researchers in the field. It is, however, particularly important for patients with PBC. The issue of viral aetiology for PBC has given rise to hope for novel therapies, and the existence of clinical trials to address the effect of anti-retroviral therapies has supported this hope. Arguments about the veracity of models such as the retroviral model in PBC are normal for scientists, but confusing for patients who now don’t know whether this model does or does not offer them the potential for curative therapy. It is beholden on those who work in the field to work together to address the areas of scientific uncertainty and to give patients an answer.Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. It is now widely accepted that primary biliary cirrhosis (PBC) is a complex disorder, with both genetic and environmental factors contributing to its pathogenesis. Over the last two years significant light has been shed on the potential genetic factors contributing to PBC, with several genome-wide associations studies (GWAS) showing highly consistent results, all pointing to a strong genetic susceptibility to PBC relating, typically, to genes which regulate the immune response in general and antigen presentation and T-cell priming in particular [1Hirschfield G.M. Liu X. Xu C. Lu Y. Xie G. Lu Y. et al.Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.N Engl J Med. 2009; 360: 2544-2555Crossref PubMed Scopus (501) Google Scholar, 2Liu X. Invernizzi P. Lu Y. Kosoy R. Lu Y. Bianchi I. et al.Genome-wide metaanalyses identify three loci associated with primary biliary cirrhosis.Nat Genet. 2010; 42: 658-660Crossref PubMed Scopus (326) Google Scholar]. Taken together, these studies all point to dysregulated immunity playing an important role in the disease. Less progress has been made, however, in identifying environmental factors which could be triggering the disease process in susceptible individuals, although the existence of such a factor is strongly supported by epidemiological studies which have identified disease clusters [3Prince M.I. Chetwynd A. Diggle P. Jarner M. Metcalf J.V. James O.F.W. The geographical distribution of primary biliary cirrhosis in a well-defined cohort.Hepatology. 2001; 34: 1083-1088Crossref PubMed Scopus (136) Google Scholar, 4McNally R.J. Ducker S. James O.F. Are transient environmental agents involved in the cause of primary biliary cirrhosis/evidence form space-time clustering?.Hepatology. 2009; 50: 1169-1174Crossref PubMed Scopus (63) Google Scholar]. Although these observations have been interpreted as supporting a chemical environmental factor, they could equally well support an infectious factor. This possibility is particularly supported by the most recent clustering study, carried out in the North-East of England, which identified both temporal as well as spatial clustering in disease patterns [[4]McNally R.J. Ducker S. James O.F. Are transient environmental agents involved in the cause of primary biliary cirrhosis/evidence form space-time clustering?.Hepatology. 2009; 50: 1169-1174Crossref PubMed Scopus (63) Google Scholar]; an observation compatible with person-to-person or vector transmission. To date, however, no infectious agent has been unequivocally linked with PBC risk. There are some data to support chronic urinary tract infections (UTI), although causality has always proved difficult (the issue is whether patients with recurrent urinary tract infections are predisposed to developing PBC or, conversely, whether the trophic changes within the urinary tract seen in PBC patients predispose to UTI). One of the most contentious postulated models for infectious triggering of PBC has been the betaretrovirus model postulated by the Mason Group [5Mason A.L. Xu L. Guo L. Munoz S. Jaspen J.B. Bryer-Ash M. et al.Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic liver disorders.Lancet. 1998; : 351PubMed Google Scholar, 6Xu L. Shen S. Guo L. Fodera B. Keogh A. Joplin R. et al.Does a betaretrovirus infection trigger primary biliary cirrhosis?.Proc Natl Acad Sci USA. 2003; 100: 8454-8459Crossref PubMed Scopus (201) Google Scholar, 7Xu L. Sakalian M. Shen Z. Loss G. Neuberger J. Mason A. Cloning the human betaretrovirus proviral genome form patients with primary biliary cirrhosis.Hepatology. 2004; 39: 151-156Crossref PubMed Scopus (92) Google Scholar]. In a series of publications, this group has identified serological responses to retroviruses in PBC patients, described the presence of “viral” particles in cultured biliary epithelial cells (BEC) from PBC patients, and identified the presence of viral nucleic acid in draining lymph nodes from PBC patients’ livers (and, at much lower frequency, in liver and serum). The group has postulated that one of the reproducible observations made in PBC, that of surface up-regulation of pyruvate dehydrogenase complex (PDC, the auto-antigen in PBC), or a cross-reactive protein, by BEC [[8]Sadamoto T. Joplin R. Keogh A. Mason A. Carman W. Neuberger J. Expression of pyruvate-dehydrogenase complex PDC-E2 on biliary epithelial cells induced by lymph nodes from primary biliary cirrhosis.Lancet. 1998; 352: 1595-1596Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar], is a consequence of the actions of the retrovirus, co-culture of BEC from normal subjects with tissue extract from PBC-patient liver draining lymph-node resulting in, seemingly, transfer of the effect into the naive cell cultures. The model proposed by the Mason group is that the actions of the betaretrovirus on antigen expression generates neo-antigens which induce immune responses cross-reactive with self-PDC, breaking tolerance and triggering the autoimmune phase of the disease (an “altered-self” model for autoimmunity). The potential importance of the model clearly lies in the opportunity, if the model is correct, to modify retrovirus as a risk factor through the use of anti-retroviral drugs [[9]Mason A.L. Farr G.H. Xu L. Hubscher S.G. Neuberger J.M. Pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis.Am J Gastroenterol. 2004; 99: 2348-2355Crossref PubMed Scopus (57) Google Scholar]. Although seductive, the retroviral aetiology model for PBC has proved highly controversial, with other groups challenging the primary findings, and no group successfully reproducing the key observations [10Selmi C. Ross S.R. Ansari A.A. Invernizzi P. Podda M. Coppel R.L. et al.Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis.Gastroenterology. 2004; 127: 493-501Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 11Selmi C. Gershwin M.E. The retroviral myth of primary biliary cirrhosis: Is this (finally) the end of the story.J Hepatol. 2009; 51: 411-412Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 12Johal H. Scott G.M. Jones R. Camaris C. Riordan S. Rawlinson W.D. Mouse mammary tumour virus-like virus (MMTC-LV) is present within the liver in a wide range of hepatic dosriders and unrelated to nuclear p53 expression of hepatocarcinogenesis.J Hepatol. 2009; 50: 548-554Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar] (although, it should be noted, no group has attempted to replicate the study of liver draining lymph nodes from PBC patients; the tissue with the highest level of viral expression in the original report [6Xu L. Shen S. Guo L. Fodera B. Keogh A. Joplin R. et al.Does a betaretrovirus infection trigger primary biliary cirrhosis?.Proc Natl Acad Sci USA. 2003; 100: 8454-8459Crossref PubMed Scopus (201) Google Scholar, 12Johal H. Scott G.M. Jones R. Camaris C. Riordan S. Rawlinson W.D. Mouse mammary tumour virus-like virus (MMTC-LV) is present within the liver in a wide range of hepatic dosriders and unrelated to nuclear p53 expression of hepatocarcinogenesis.J Hepatol. 2009; 50: 548-554Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar]). Furthermore, alternative explanations can be put forward for many of the key observations (for example cell surface expression of PDC can occur as a consequence of apoptosis meaning that any factor which could be transferred from one cell culture to another, and which induces cells to undergo apoptosis, would seemingly “transmit” the cell surface PDC expression phenotype [[13]Macdonald P. Kirby J.A. Jones D.E.J. Cell-surface expression of pyruvate dehydrogenase complex during apoptosis: a possible route for autoantigen presentation in primary biliary cirrhosis.Hepatology. 2002; 36: 420AGoogle Scholar]). The controversy surrounding the model, and the associated debate around the equivalence of methods used in the different studies, can lead the non-expert unclear as to what the findings mean (if anything) for PBC patients. The counter-view regarding PBC pathogenesis is that it is a classical autoimmune disease, a suggestion strongly supported by the high titre auto-antibodies, presence of auto-reactive T-cells, association with other auto-immune diseases, and, latterly, the strong immuno-genetic associations described in PBC [[14]Jones D.E.J. Pathogensis of primary biliary cirrhosis.Gut. 2007; 56: 1615-1624PubMed Google Scholar]. One of the recent strands of evidence supporting a purely autoimmune model for PBC pathogenesis of PBC is the work by the Gershwin group and others identifying spontaneous murine models which develop serological and histological features which are suggestive of PBC [15Irie J. Wu Y. Wicker L.S. Rainbow D. Nalesnik M.A. Hirsch R. et al.NOD.c3c4 congenic mice develop autoimmune liver disease that serologically and pathogenetically models human primary biliary cirrhosis.J Exp Med. 2006; 203: 1209-1219Crossref PubMed Scopus (157) Google Scholar, 16Oertelt S. Lian Z.X. Cheng C.M. Chuang Y.H. Padgett K.A. He X.S. et al.Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice.J Immunol. 2006; 177: 1655-1660Crossref PubMed Scopus (219) Google Scholar, 17Wakabayashi K. Lian Z.X. Moritoki Y. Lan R.Y. Tsuneyama K. Chuang Y.H. et al.IL-2 receptor alpha (−/−) mice and the development of primary biliary cirrhosis.Hepatology. 2006; 44: 1240-1249Crossref PubMed Scopus (194) Google Scholar]. These spontaneous models, in animals with specific immuno-regulatory abnormalities, would appear to support the concept emerging from the human GWAS studies that it is immune dysregulation which predisposes to PBC; the classical autoimmune model. One of the key models of this type is the NOD.c3.c4 mouse, a congenic non-diabetic derivative of the classical NOD mouse which develops intra-hepatic bile duct damage redolent of PBC in the context of anti-PDC auto-antibodies [15Irie J. Wu Y. Wicker L.S. Rainbow D. Nalesnik M.A. Hirsch R. et al.NOD.c3c4 congenic mice develop autoimmune liver disease that serologically and pathogenetically models human primary biliary cirrhosis.J Exp Med. 2006; 203: 1209-1219Crossref PubMed Scopus (157) Google Scholar, 18Yang G.-X. Wu Y. Tsukamoto H. Leung P.S. Lian Z.-X. Rainbow D.B. et al.CD8 T-cells mediate direct biliary ductule damage in nonobese diabetic autoimmune biliary disease.J Immunol. 2011; 186: 1259-1267Crossref PubMed Scopus (40) Google Scholar] (as well as some other less typical features). To date, there are no data to suggest that environmental factors might be necessary to promote the development of bile duct abnormality in these animals. In the current edition of the Journal of Hepatology the Mason group has attempted to draw together these disparate strands of research [[19]Zhang G. Chen M. DGraham D. Subsin B. McDougall C. Gilady S. et al.Mouse mammary tumour virus in anti-mitochondrial antibody producing mouse models.J Hepatol. 2011; 55: 876-884Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. In the study, they explored the biology of the NOD.c3.c4 mouse and other murine models of PBC and, in particular, looked for the presence of mouse mammary tumour virus (MMTV), a murine retrovirus which has almost complete sequence homology with the postulated human PBC betaretrovirus. NOD.c3.c4 mice expressed MMTV surface and capsid proteins on the biliary epithelium, together with a protein which was cross reactive with PBC E2. The other animal models also expressed MMTV proteins and aberrant PBC-E2-like protein in the spleen. All animals expressed MMTV gag and env in the liver. A significant correlation was seen between anti-MMTV antibody production and anti-PDC autoantibody production in the sera of the NODc3.c4 mice. MMTV transmission in mice is typically in the neonatal period through breast milk. Although causal associations are not demonstrated in this study, the model the authors propose is that such neonatal exposure to the MMTV leads to chronic infection which alters PDC (or PDC homologue) expression within tissues, predisposing to subsequent breakdown of immune tolerance resulting in the development of autoimmunity. In this model, the immuno-genetic abnormalities in the mice either predispose to chronicity of infection in the first place, or to the secondary breakdown in tolerance to PDC promoted by altered self-antigen processing or the expression of a viral homologue (or of course both processes). The findings of the study have the potential to both advance the field and to add further confusion to an already confused picture. At one end of the range of possibilities (and the end that the authors would no doubt support) the findings suggest that the NOD.c3.c4 model (and to a lesser extent the other two models) fully models the changes which are present in PBC, with an immuno-genetic susceptibility and retroviral exposure combining to promote tolerance breakdown. In this scenario, the murine models would present a perfect context in which to do pre-clinical testing of anti-retroviral interventions of potential benefit to PBC patients. At the other end of the range of possibilities, the observations of un-anticipated pathogen differences in different sub-strains of animals potentially confound the validity of these models for PBC as an autoimmune disease. Critical to understanding the value or otherwise of the findings of Zhang et al. will be the extent to which they can be reproduced by other groups; a scenario identical to the situation with the human retroviral model. It is critical now that both the human and the murine retroviral stories are explored in a co-ordinated way by independent laboratories using standardised approaches and reagents. Only then, will we understand whether we now have the perfect murine model for PBC (a similar pathogenic trigger on a similar immunogenetic background) or whether we simply have artefacts. That this controversy is finally resolved is important for researchers in the field. It is, however, particularly important for patients with PBC. The issue of viral aetiology for PBC has given rise to hope for novel therapies, and the existence of clinical trials to address the effect of anti-retroviral therapies has supported this hope. Arguments about the veracity of models such as the retroviral model in PBC are normal for scientists, but confusing for patients who now don’t know whether this model does or does not offer them the potential for curative therapy. It is beholden on those who work in the field to work together to address the areas of scientific uncertainty and to give patients an answer. Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript." @default.
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• W2080441623 date "2011-10-01" @default.
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• W2080441623 title "A potential retroviral aetiology for mouse PBC: More answers or more questions?" @default.
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• W2080441623 cites W1982865990 @default.
• W2080441623 cites W2004944019 @default.
• W2080441623 cites W2008156962 @default.
• W2080441623 cites W2029184661 @default.
• W2080441623 cites W2031252695 @default.
• W2080441623 cites W2044119777 @default.
• W2080441623 cites W2066244253 @default.
• W2080441623 cites W2074202083 @default.
• W2080441623 cites W2087236782 @default.
• W2080441623 cites W2092884588 @default.
• W2080441623 cites W2114006962 @default.
• W2080441623 cites W2126794945 @default.
• W2080441623 cites W2138314644 @default.
• W2080441623 cites W2163005321 @default.
• W2080441623 cites W2943761615 @default.
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