Experimental Evidence on the Immunopathogenesis of Primary Biliary Cirrhosis

Cellular & Molecular Immunology (2010) 7, 1–10 ß 2010 CSI and USTC. All rights reserved 1672-7681/10 $32.00 www.nature.com/cmi REVIEW Experimental evidence on the immunopathogenesis of primary biliary cirrhosis Carlo Selmi1,2,3,FrancescaMeda1,2,AnaidKasangian2, Pietro Invernizzi2,ZhigangTian4,ZhexiongLian4, Mauro Podda1,2 and M Eric Gershwin3 Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease for which an autoimmune pathogenesis is supported by clinical and experimental data, including the presence of autoantibodies and autoreactive T cells. The etiology remains to be determined, yet data suggest that both a susceptible genetic background and unknown environmental factors determine disease onset. Multiple infectious and chemical candidates have been proposed to trigger the disease in a genetically susceptible host, mostly by molecular mimicry. Most recently, several murine models have been reported, including genetically determined models as well as models induced by immunization with xenobiotics and bacteria. Cellular & Molecular Immunology (2010) 7, 1–10; doi:10.1038/cmi.2009.104; published online 23 December 2009 INTRODUCTION A probable diagnosis is made when two of three criteria are Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of present. unknown etiology characterized by autoimmune-mediated destruc- The most common symptoms include fatigue, which is present in tion of small- and medium-sized intrahepatic bile ducts.1 about 19% of patients at diagnosis, pruritus in about 20% of patients Serologically, PBC is characterized by the presence of increased levels at diagnosis, and jaundice,5 but because of the changing disease scen- of immunoglobulin M (IgM), a high titer of serum antimitochondrial ario jaundice is now a very rare sign at presentation.6 autoantibodies (AMAs) and, in some of patients, PBC-specific anti- Although the complete pathways of PBC pathogenesis remain nuclear antibodies (ANAs).1 From both a clinical and a pathogenetic unknown, several clinical and experimental findings strongly support point of view, PBC is considered a peculiar, yet representative, auto- autoimmune mechanisms for bile duct damage.7 However, the ques- immune disease.2 PBC preferentially affects women, with one of the tion of what causes the disease remains unanswered. highest female/male ratios (10:1) described in autoimmunity,3 and The most accepted hypothesis states that PBC results from an envir- most cases present within the fifth and sixth decades of life, with only onmental insult on a genetically susceptible background. In this scen- exceptional cases reported in teenagers. AMAs are present in about ario, adaptive, both humoral and cellular (CD4 and CD8 T cells), and 95% of PBC cases, with a disease specificity close to 100%, and are innate immunity have been proposed as coplayers in immune- therefore considered the serological hallmark of the disease. mediated liver damage. Histologically, PBC presents bile duct inflammation with consequent This review includes a critical discussion of what is known and what destruction/loss of intrahepatic bile ducts and development of fibrosis we hope will soon be known regarding the causes of onset and per- and biliary cirrhosis. There are four PBC histological stages: (i) portal petuation of liver damage in PBC. tract inflammation with bile duct obliteration and granulomas; (ii) In this regard, we will first discuss the somehow overlooked role of extension of inflammation to the periportal area; (iii) septal or female predominance in autoimmunity in general and in PBC in bridging fibrosis, with ductopenia (over half of the visible interlobular particular. We will then review what is known of the genetic basis of bile ducts having vanished); and (iv) estab-lished cirrhosis virtually PBC susceptibility and the contribution of environmental factors in its undistinguishable from end stage liver diseases of different etiologies. development. Third, we will illustrate the established evidence on the Epithelioid granulomas with no sign of caseous necrosis are the char- immunobiology of PBC with specific mention of the new line of acteristic lesions of PBC and can be found at any stage around research on innate immunity. damaged bile ducts.4 The definitive diagnosis of PBC is made when all of the following The sex ratio of autoimmune disease three criteria are fulfilled: the presence of serum AMA, increased Similar to Sjogren’s syndrome, systemic lupus erythematosus, auto- enzymes indicating cholestasis (i.e., alkaline phosphatase) for longer immune thyroid disease and scleroderma, PBC manifests the highest than 6 months and a compatible or diagnostic liver histology. predominance in females, with over 80% of patients being women. To 1Department of Translational Medicine, Universita`degli Studi di Milano, Milan, Italy; 2Department of Medicine, IRCCS Istituto Clinico Humanitas Rozzano, Milan, Italy; 3Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA and 4Institute of Immunology, University of Science and Technology of China, Hefei, China Correspondence: Dr C Selmi, Department of Medicine, IRCCS Istituto Clinico Humanitas, via A. Manzoni 56, 20089 Rozzano, Milan, Italy E-mail: [email protected] Received 5 October 2009; accepted 12 October 2009 Experimental evidence on immunopathogenesis of PBC C Selmi et al 2 explain this sex bias observed in autoimmunity, three major working We have recently provided experimental data supporting a new hypotheses have been investigated so far, i.e., the role of sex hormones, fascinating hypothesis on the female predominance of autoimmunity fetal microchimerism and X-chromosome defects. based on major sex chromosome defects.17 This theory is based mainly Sex-associated hormones, e.g., estrogens, androgens and prolactin, on two observations: first, several genes that are key factors in the which not only differ between males and females but also can vary maintenance of immune functions and tolerance are located on the according to age, have been the first candidates taken into account, X chromosome and, second, diseases associated with constitutive X mainly because of their ability to modulate immune responses. monosomy or its major structural abnormalities, such as Turner’s Estrogen-mediated modulation of the immune response can act at syndrome, are frequently associated with autoimmune features and different levels, including regulation of lymphocyte homing to a target in some cases with chronic cholestasis. Quite surprisingly, only a few organ and antigen presentation, thus potentially influencing both studies have so far investigated the genetics of sex chromosomes in organ specificity of autoimmunity and breakdown of tolerance. autoimmunity. X-chromosome inheritance displays a peculiar pattern Estrogens are also capable of directly modulating both pro- and compared with autosomal chromosomes, since women are functional anti-inflammatory activities of CD4 T cells and are therefore capable mosaics for X-linked genes. In females, most genes on one X chro- of influencing the outcome of the CD4 T-cell-mediated immune res- mosome are silenced as a result of X-chromosome inactivation (XCI). ponse. Finally, sex hormones can have activational effects on the The result of XCI is to achieve equivalent levels of X-linked gene hypothalamic–pituitary–adrenal axis because of their ability to modu- products between males and females. More recent data have mined late stress responses. Based on these observations, it should be clear this dogmatic view by demonstrating that at least 15% of X-linked that sex hormones, particularly estrogens, may be central to the T genes are capable of escaping XCI in healthy women and are thus helper 1/T helper 2 balance within sites of inflammation, thus deter- expressed from both X chromosomes. Up to 10% of total X-linked 18 mining an appropriate or inappropriate inflammatory response in genes manifest variable XCI patterns in different individuals. As a infection, tolerance development or autoimmunity.8 In past decades, result of these observations, a role for the X chromosome was first various studies have reported that PBC is associated with the occur- proposed based on experimental evidence that women with auto- rence of sex hormone dysfunction. Epidemiological studies have immune diseases have a significantly higher frequency of peripheral shown a presence of menstrual dysfunctions, a higher frequency of blood cells with a single X chromosome (i.e., X monosomy) compared hysterectomy and a higher risk of osteoporosis, indirectly suggesting with healthy women. Importantly, this was observed in diseases with 19 an active role of estrogens in the pathogenesis of disease. In a recent different organ specificities, including PBC, scleroderma and auto- 20 study, taking hormone replacement therapies following menopause immune thyroid disease. Loss of an X chromosome is indeed pref- 21 was significantly associated with PBC, although this may be secondary erential and more frequently involves a parentally inherited one, to the proposed enhanced rate of bone loss in chronic cholestasis.9 suggesting a possible critical involvement of X-chromosome gene Besides their immunological functions, estrogens could have direct product defects in the female preponderance of PBC and other auto- 22 effects on cholangiocytes, the specific target of immune-mediated immune diseases, although new factors, such as microRNAs or epi- 23,24 damage in PBC. Cholangiocytes

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