Primary Biliary Cirrhosis: Bad Genes, Bad Luck

Primary biliary cirrhosis (PBC) is considered a model for autoimmune disease based upon its hallmark autoantibodies serologic response, the focused target destruction of biliary epithelial cells (BEC), and the clinical homogeneity among patients [1]. PBC is also overwhelmingly a disease of middle-aged and older females, being virtually absent in the pediatric or adolescent population. True pediatric PBC is indeed highly rare, and likely represents an etiopathogenesis that is extremely atypical compared to the classical PBC in adults. PBC also has one of the latest ages of onset out of all autoimmune diseases [2]. The etiology remains enigmatic, although various genetic and environmental factors have been implicated in the disease development and progression, many of which also provide insight as to why females are more prone to PBC [3, 4]. Both genetic and environmental factors may well contribute to the decline of an already ageing immune system, a phenomenon termed immunosenescence [5], through recurrent infections and inflammation, as well as oxidative damage. Immunosenescence is known to begin in approximately the fifth decade of life, and is characterized by a progressive decline in immunological functioning [5–8]. It is likely that the immune system may then reach a critical stage where tolerance to self is lost, thus contributing to the development of autoimmune diseases. A number of studies showing immunosenescence have provided additional evidence as to why middle age presentation often occurs in PBC. For example, changes in T cell signaling such as the decreased expression of the co-stimulatory receptor CD28, have been largely described [7, 11]. In PBC, an age-related progressive increase number of immune-related circulating cells carrying only one X chromosome, that is with monosomy X, was reported [9, 10]. Again, several phenotypical and functional changes have been also noted in the CD4 and CD8 T lymphocytes of PBC patients [1]. Of interest is for example the increased CD127 (marker of effector cells), reduced CD39 (marker of normal Treg function) expression of the CD8 Treg, and that CD8?CD28-cells from PBC patients failed to display a regulatory immune response after incubation with IL-10 [12]. A growing number of evidences suggest that not only immunosenescence but also senescence of the target organ, that is of BEC, has a role in the development of PBC. Senescence is a well-known delayed stress response induced by factors such as oxidative stress, telomere shortening, DNA damage, and autophagy [13]. First, several studies have demonstrated that oxidative stress is an inducer of cell senescence in the BEC of PBC patients [14– 16]. Sasaki et al. [14] notes that cellular senescence in early-stage PBC was associated with an infiltration of myeloperoxidase-positive inflammatory cells, indicating oxidative stress. Another study by the same group showed that Bmi1 (a suppressor of oxidative stress) was significantly reduced in damaged BEC of PBC patients [16]. Second, shortened telomere length with associated cellular senescence has been demonstrated in a study by Sasaki and colleagues [17]. In particular, they examined telomere length using quantitative fluorescent in situ hybridization of 13 patients with PBC and 13 controls and showed a significant decrease in telomere length in damaged BEC from PBC patients, in comparison to histologically normal P. Invernizzi Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano, Italy