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Immunity in Primary Biliary Cirrhosis Genes and Immunity (2005) 6, 543–556 & 2005 Nature Publishing Group All rights reserved 1466-4879/05 $30.00 www.nature.com/gene REVIEW Genes and (auto)immunity in primary biliary cirrhosis C Selmi1,2, P Invernizzi1, M Zuin1, M Podda1, MF Seldin2,3 and ME Gershwin2 1Division of Internal Medicine, San Paolo School of Medicine, University of Milan, Milan, Italy; 2Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA; 3Biochemistry and Rowe Program in Human Genetics, University of California at Davis, School of Medicine, Davis, CA, USA Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease most commonly encountered in postmenopausal women; it is characterized by high-titer serum autoantibodies to mitochondrial antigens, elevated serum IgM, progressive destruction of intrahepatic bile ducts, and ultimately liver cirrhosis and failure. The cytopathic mechanisms leading to the selective destruction of intrahepatic cholangiocytes are still largely unknown. The current theory on the pathogenesis of PBC indicated that environmental factors might trigger autoimmunity in genetically susceptible individuals. In fact, genetic predisposition is critical to disease onset and progression, yet peculiar among autoimmune diseases, as indicated by the lack of a strong association with major histocompatibility complex haplotypes. Further, the recently reported concordance rate among monozygotic twins strenghtens the importance of genetic factors, while also indicating that additional factors, possibly infectious agents or xenobiotics, intervene to trigger the disease. In this review, the available data regarding the genetic factors associated with PBC susceptibility and progression, as well as the available evidence regarding the immunomediated pathogenesis of PBC, will be critically illustrated and discussed. Genes and Immunity (2005) 6, 543–556. doi:10.1038/sj.gene.6364248; published online 21 July 2005 Keywords: autoimmune cholangitis; complex disease; association study; environmental factors; pathogenesis Introduction we will concentrate on the crosstalk between these two apparently independent compartments of PBC etiopatho- Primary biliary cirrhosis (PBC) is a chronic cholestatic liver genesis, and will draw possible future scenarios. disease of unknown etiology that leads to a progressive nonsuppurative destruction of small and medium-sized intrahepatic bile ducts, and eventually to liver cirrhosis and failure. PBC is currently considered as presenting Genetics of PBC autoimmune features, despite the lack of direct evidence Tackling the genetic bases of complex diseases to support this assumption. Indeed, PBC has significant Similar to other autoimmune diseases, the pathogenesis similarities with other autoimmune diseases, such as the of PBC should be regarded as complex or multifactorial, presence of highly specific autoantibodies directed against with multiple genetic and environmental factors inter- mitochondrial (AMA) or nuclear (ANA) antigens and playing to determine disease susceptibility and onset.2 In autoreactive T cells, the striking female predominance fact, it is now clear that PBC genetic components are not (estimated as a 9 : 1 female to male ratio), and the related to a single gene mutation, nor the disease coexistence of other autoimmune diseaseas in approxi- presents a complete penetrance, as indicated by data 1 mately one-third of patients with PBC. It is currently from monozygotic twin sets. Further, PBC is a complex believed, based on experimental and clinical evidence, that disease that should be defined as rare, based on its PBC onset and progression are determined by environ- prevalence in the general population (the highest mental factors acting on genetically susceptible inidivi- reported being 402 cases per million3). So far, data on duals. Both these components, in fact, appear to be the genetics of PBC are derived only from case–control necessary, albeit not being self-sufficient, to induce the studies designed to determine associations between autoimmune events that characterize PBC. In this article, specific polymorphic genes and the disease.4 This we will attempt a critical approach to the available data on approach, albeit meritory, raises some concerns due to the genetic and immunological bases of PBC. In particular, its limits. In fact, association studies present several degrees of potential bias, including those caused by sample size and selection and control-matching criteria. Correspondence: Dr ME Gershwin, Division of Rheumatology, Allergy For example, patients are often enrolled through tertiary and Clinical Immunology, University of California at Davis School of referral centers and possibly over-represent the more Medicine, GBSF Suite 6510, Davis, CA 95616, USA. E-mail: [email protected] advanced spectrum of PBC. As for controls, it is critical Received 17 June 2005; accepted 17 June 2005; published online 21 that these are matched also by race and geographical July 2005 background to cases to minimize false-positive results Genes and immunity of PBC C Selmi et al 544 based on population structure differences. The choice of terns, while only one affected relative could be identified candidate genes warrants further discussion; in most among 85 first-degree relatives.16 cases it is indicated by immunological features of the Several studies have addressed the hypothesis that less disease, as in the case of the major histocompatibility specific immunological disturbances rather than a complex (MHC), or is often derived from data in other definitive diagnosis of PBC might in fact be shared by autoimmune conditions. Both these methods present family members of patients. Interestingly, as many as several strengths; however, we note how the selection of 70% of PBC relatives had some degree of immunological genes with a solid rationale should in all cases be a impairment in studies from the early 1970s,17,18 while priority in association studies. The overinterpretation of somewhat conflicting results came, more recently, from data is an additional critical issue in the interpretation of two studies of patterns of immunological disorders in association data. To avoid false associations, all putative family members. First, the Liver Group in Newcastle, UK association results should be reproduced. It is disap- found that 14% of first-degree relatives of 160 PBC cases pointing to consider that the vast majority of proposed had at least one autoimmune condition, with systemic associations in complex diseases would fail this test.5 sclerosis being the most frequent diagnosis.19 In a smaller Two more issues need to be addressed. First, there needs study from Brasil, only 5/100 first-degree relatives of 26 to be correction for multiple testing. Recent utilization of patients with PBC referred an autoimmune disease (only statistical approaches such as false discovery rate can in one case PBC), while serum autoantibodies were obviate some of the problems with the conservative detected in 11% of relatives, in most cases not accom- Bonferroni correction that may cause type 1 errors.6 panied by clinical signs of autoimmunity.20 Lastly, one should also consider the publication bias that favors weakly positive associations over negative, yet Twin studies rigorous, studies, thus often causing a duplication of Disease concordance rate in monozygotic and dizygotic efforts that could be easily avoided. twin pairs estimates the weight of genetic and environ- mental factors in the susceptibility to complex diseases. Familial PBC The concordance rates in monozygotic twins for auto- Family members of patients with PBC have a higher risk immune diseases range between 12% for rheumatoid 21 22 of developing the disease, and the occurrence of multiple arthritis and 83% for celiac disease, and are on cases within the same family is referred to as ‘familial average well below 50%. Until recently, only two case PBC’7 presenting variable frequency rates, possibly reports addressed the issue for PBC, with one describing 23 24 following a geoepidemiological pattern (Table 1). Studies a concordant and the other a discordant pair defined from the UK indicate that such frequency ranges as monozygotic, although in both cases zygosity was not between 1 and 2.4%,8,9 possibly increasing over the past genetically proven. We have recently reported that decade, likely for the awareness of physicians and novel concordance rates for PBC are 63% in monozygotic and diagnostic tools. In the United States, Bach and Schaff- null in dizygotic twins, with three out of eight mono- ner10 observed a 4.3% familial prevalence in an analysis zygotic twin sets being discordant for disease occur- 25 of 396 PBC cases both retrospectively and prospectively. rence. Further, in some cases, the natural history of PBC Familial PBC was studied also in other countries and as well as the comorbidities could vary significantly data indicated frequencies of 4.5% in Sweden,11 3.8% in between concordant twins. The phenotypical discor- Italy,12 and 5.1% in Japan,13 in all cases calculated on the dance is particularly interesting as it could be caused number of unrelated index PBC cases. More recently, a by epigenetic factors, differences in exposure to environ- 26 27 population-based study from Minnesota3 identified 46 mental factors such as infections, or xenobiotics, as cases of PBC and reported a prevalence among family well as serendipity. members higher than the general population.
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