17.2Primary Biliary Cirrhosis (PBC)

17.2.1Definition and Diagnosis

PBC is a chronic autoimmune liver disease that has a striking female predominance (9:1). The condition is characterized by progressive bile duct destruction that leads eventually to cirrhosis and liver failure. PBC is characterized histopathologically by portal inßammation and immune-mediated destruction of the intrahepatic bile ducts. The serologic hallmark of the disease is the presence of serum AMA, which are found in 90Ð95% of cases. AMA are directed against components of the 2-oxoacid dehydrogenase complex (2-OADC) family, including the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the branched chain 2-oxo-acid dehydrogenase complex (BCOADC-E2), and the oxoglutarate dehydrogenase complex (OGDC-E2), as well as the dihydrolipoamide dehydrogenase (E3)-binding protein (E3BP) [9].

The 5Ð10% of patients with PBC who are AMA negative are referred as having autoimmune cholangitis (AIC). AMA-negative PBC or AIC manifests clinical features that are similar to those of AMA-positive PBC [10]. No clinical, biochemical, or histological differences exist between AMA-positive PBC and AIC. In the same studies, despite the AMA negativity by indirect immunoßuorescence (IIF) in the sera from AIC patients, in some cases there was evident reactivity by immunoblotting with the E2 subunits of the 2-OADC enzymes, and particularly with the lower molecular weight E2 subunits [10].

17.2.2Similarities, Differences, and Overlap Among SS and PBC

PBC and SS share several clinical, histological, and serological features, as well as pathogenetic mechanisms. Symptoms that are characteristic of SS Ð for example, dry mouth or dry eyes Ð are also found commonly in PBC (47Ð73%). In addition, objective Þndings of dry eyes or dry mouth (such as abnormal Schirmer test, or diminished salivary ßow rate) are also found in 30Ð50% of patients with PBC while radiological Þndings of sialectasia were demonstrated in 25% of PBC cases. Furthermore, such PBC patients often manifest histological changes compatible with the diagnosis of SS at salivary gland biopsies (4) [11, 12].

Despite these similarities, patients with PBC differ from those with primary SS. They rarely have serious sequelae and their serological and immunogenetic features are not identical to those observed in patients with primary SS. Anti-Ro autoantibodies are rarely observed in PBC and the frequency of HLA-B8, -DR3, and DRW52 is lower compared to patients with primary SS. Thus, the association of SS with PBC is considered to be similar to that of secondary SS that complicates RA [13].

PBC has also been described to overlap with other diseases such as systemic sclerosis (SSc). Interestingly, the majority of the PBC-SSc patients suffer from the limited cutaneous form of the disease and are positive for anticentromere antibodies. Their clinical course and natural history of the disease seems to be milder than those of patients with PBC [14].

17.2.3Epithelium Involvement

In both PBC and SS, the autoantibody targets (AMA, anti-Ro, and anti-La antibodies) are ubiquitous proteins expressed in all nucleated cells. Nevertheless, PBC and, to a lesser degree, SS are organ-speciÞc diseases, indicating that epithelia (biliary epithelial cells and salivary gland epithelial cells for PBC and SS, respectively) are unlikely to be innocent victims but rather are active participants in disease pathogenesis. In agreement with the notion that epithelia play a major role are the kidney Þndings in SS. Indeed, the renal histopathological lesions in SS patients resemble those of the salivary glands (focal inÞltrates around tubular epithelium that extend into and occupy the interstitium, resulting in tubular dysfunction) [15].

Several lines of evidence support the major role of epithelium for both PBC and SS. Biliary epithelial cells (BEC, i.e., cholangiocytes) express cell surface adhesion molecules that permit adhesion and recognition of lymphocytes. In addition, BECs of healthy as well as diseased liver have the capacity to increase the expression of adhesion molecules, MHC class I and II molecules, TNF-alpha, interferon (IFN)- gamma, and IL-1 upon stimulation with proinßammatory cytokines [16]. Most recently, a solid theory based on the unique apoptosis features in bile duct cells has been proposed [17]. It was Þrst demonstrated that PDC-E2 remains intact and retains its immunogenicity during cholangiocyte apoptosis, secondary to a cell-speciÞc lack of glutathionylation of BECs [18]. The intact PDC-E2 in apoptotic blebs (i.e., apotopes) could be then taken up by local antigen-presenting cells and transferred to regional lymph nodes for priming of cognate T cells, thereby initiating PBC [19].

17.2.4Animal Models

The animal models for PBC and SS afÞrm that these two diseases share many common pathogenetic mechanisms. More speciÞcally, one of the recently proposed mouse models for PBC is the NOD.c3c4 mouse where insulin-dependent diabetes (Idd) resistance loci from chromosomes 3 and 4 (including Idd3) were modiÞed on the NOD background. These mice were diabetes resistant, yet developed extensive peribiliary lymphocytic inÞltrates, granuloma-like lesions, and chronic nonsuppurative destructive cholangitis in the liver resembling PBC. Furthermore, 50Ð60% of the NOD.c3c4 mice produce AMA that react with the inner lipoyl domain of PDC-E2 and inhibit PDC enzyme function [20]. However, it is known that NOD

strains manifest autoimmune diabetes and autoimmune exocrinopathy. More interestingly, Idd3 seems to be necessary for the manifestation of autoimmune exocrinopathy [21].

Other murine models have been described for PBC. Two animal models, that is, dnTGFbRII and IL-2Ra knockout mouse, point out the possible crucial role of Treg cell deÞciency in the loss of immune tolerance with consequent development of autoimmune response against PDC-E2 in PBC. A mouse with dominant negative form of transforming growth factor b (TGFb) receptor II, (dnTGFbRII) showed PBC-like liver disease, for example, 100% AMA positivity against PDC-E2 [22]. Of note, the depletion of B cells worsens liver disease in this model [23]. On the other hand, a mouse deÞcient for IL2 receptor a (IL-2Ra), which is highly expressed on Treg cells developed 100% AMA positivity against PDC-E2, 80% ANA positivity, and lymphocyte inÞltration around the portal tracts associated with cholangiocyte injury [24].

Other animal models strongly support the hypothesis that xenobiotics can induce autoimmunity. Among these, the induction of PBC-like lesions was obtained in a NOD background by Wakabayashi et al. and in guinea pigs by Leung et al. exposed to xenobiotic immunization [20, 25] with halogenated compounds. Finally, the induction of a PBC-like phenotype following N. aromaticivorans immunization [26] has important potential implications.

17.2.5Histology and Serology

Both SS and PBC are characterized by inÞltrates developing around ducts, with CD4+ T cells predominating in the tissue lesions [27] (liver and minor salivary gland for PBC and SS, respectively) and NK cells being absent in lesions from PBC and very rare in those from SS [28]. In addition, T regulatory cells are found to be reduced in the peripheral blood of patients with PBC as well as of patients with SS compared to healthy controls [29].

The autoantibody proÞles in PBC and SS are different, although the same wide spectrum of autoantibodies is present in both PBC and SS. Patients with SS have signiÞcantly higher frequencies of anti-Ro/SSA, anti-La/SSB, and anti-U1RNP, while patients with PBC have signiÞcantly higher frequencies of antibodies to PDC (i.e., AMA), Sm, Jo-1, collagen, and MPO [30].

The prevalence of serum ANA is higher in SS patients compared to PBC patients. In PBC, autoantibodies against nuclear antigens are found in the sera of about half of patients and are thought to be more prevalent among AMA-negative PBC patients [31]. Two patterns are highly speciÞc for PBC: the multiple nuclear dot (MND) and rim-like/membranous (RL/M) immunoßuorescence patterns. The Þrst pattern is produced by autoantibodies against gp210 and nucleoporin 62 within the nucleopore complex and the second pattern by autoantibodies against sp100, promyelocytic leukemia (PML), and small ubiquitin-like modiÞer (SUMO) proteins.