Female preponderance of primary biliary cholangitis is all about our understanding of its autoimmune nature
Authors: Marco Carbone, Giulia Bonato, Pietro Invernizzi
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. See Article On Page 1408 Female preponderance is one of the most striking characteristics of primary biliary cholangitis (PBC), together with the organ‐specific autoimmune aggression against the small‐ and medium‐size bile ducts and the presence of disease‐specific serum autoantibodies such as antimitochondrial antibodies (AMAs), anti‐gp210, and anti‐sp100. PBC shares this feature with most of the extrahepatic autoimmune diseases, being indeed considered a prime example of the sexual dimorphism in autoimmunity with female to male (F:M) ratios of up to 10:1. Although more recent studies based on administrative data are challenging this concept by showing lower F:M ratios,1 PBC still remains a strongly female preponderant disease. A better comprehension of this would shed light on the etiopathogenesis of this biliary autoimmune disorder. However, since the first description of PBC nearly six or seven decades ago, far too little effort was made to understand why more females than males develop the disease, compared to that placed on dissecting the immunological and the downstream cholestatic pathogenetic features. A number of factors have been hypothesized to govern the female‐male inbalance in PBC, as well as in other autoimmune conditions; the most important are sex hormone abnormalities, fetal microchimerism, and sex chromosome defects. Sex hormones are indeed known to be implicated in the immune response with estrogens as enhancers of the humoral immunity and androgens and progesterone acting as immune suppressors. However, there are not solid evidences that sex hormones are key players in the female preponderance of the disease. Also, fetal microchimerism was not shown to have a role in the development of PBC. On the contrary, a number of major defects of sex chromosomes were described in patients affected by PBC, which might well explain the greater female predisposition to autoimmunity in PBC. The X chromosome encodes for many immune‐associated genes, including CD40 ligand (CD40L) and CXC chemokine receptor 3 (CXCR3), and mutations in specific X‐linked genes are known to cause a number of immunodeficiencies, often with autoimmune features. In particular, sex chromosomes instability was suggested by an enhanced monosomy X in female patients2 and an enhanced Y chromosome loss in male patients with PBC.3 Also, epigenetic alterations on the X chromosome, such as decreased DNA methylation of the CXCR3 and CD40L gene promoters, have been reported in female patients with PBC.4 To further support the role of X‐linked epigenetic change as a key player in the pathogenesis female preponderance of PBC, it has been recently shown that the X‐linked miR‐506 gene is up‐regulated in cholangiocytes and proposed that this promotes immune activation and the disease development by affecting the anion exchanger 2 and the soluble adenylyl cyclase.5 The genome‐wide association studies (GWAS) in PBC failed to find X chromosome genetic variants associated with the disease. However, these studies analyzed the X chromosome applying methods that have been designed for the autosomes, without accounting for the analytical problems arising from X's unique mode of inheritance and its consequent population genetic and evolutionary patterns.7 For this reason, the role of X in complex diseases such as PBC remains largely unknown, and approaches such as XWAS (chromosome X‐Wide Analysis toolSet), tailored for analysis of genetic variation on X in human and other species with an XX/XY system, should be performed. In this scenario, the study by Bae et al.8 has the great merit of being one of the few studies trying to address the issue of female preponderance in PBC. In particular, the investigators have highlighted the type I interferon (IFN) signaling as a key component of the sex bias in a murine model of autoimmune cholangitis. They have previously developed a murine model coined ARE‐Del‐/‐ obtained by deleting the IFN 3′ untranslated region AU‐rich element (ARE).9 This model presents an overexpression of IFN that determines features of autoimmune cholangitis similar to human PBC with a strong female predominance and the classical histological lesions, that is, portal inflammation, small bile ducts destruction, and granuloma. The same group reported in this issue of Hepatology8 the development of a novel model obtained by mating ARE‐Del‐/‐ mice with IFN type I receptor alpha chain knockout mice, called Ifnar1‐/‐. They compared histological changes of male and female double‐knockout ARE‐Del‐/‐ Ifnar1‐/‐ mice with those of ARE‐Del‐/‐ mice. Interestingly, the loss of type I IFN receptor expression led to a much milder cholangiopathy, particularly in female mice, thus abolishing sex bias. The investigators also compared AMA and anti‐sp100 autoantibodies serum levels and total bile acids of these two models; similarly to histological findings, serological markers resulted as altered with a strong female bias only in the ARE‐Del‐/‐ mice. Consistent with these results, also female‐prevalent excessive germinal center formation and follicular T helper frequency were lost after deletion of type I IFN receptor. IFNs have several effects on the immune system that may contribute to the sex bias of autoimmunity. IFN1s increase class 1 major histocompatibility complex (MHC) expression on cells, and IFN‐γ induces class II MHC and changes the nature of the proteasome, thereby affecting the nature and quantity of self‐peptides presented to T cells. There is not much evidence at present that expression of IFN1 genes is controlled directly by sex hormones. However, sex hormones affect expression of some of the pattern recognition receptors, such as the Toll‐like receptors and cytoplasmic sensors of DNA and RNA, and doing so might indirectly affect the levels of IFN1. One of the genes that controls expression of IFN1s is IFN regulatory factor 5 (IRF5). It is worth noting that this gene has been highlighted by GWAS as a risk gene for disease susceptibility in PBC.10 Moreover, IRF5 expression can be up‐regulated in vitro upon estrogen treatment, suggesting a potential mechanism for sex‐biased expression of the gene and consequent overproduction of IFN1s.11 There may be a positive feedback loop between the IFNs and estrogens, given that activation of IFN1 or IFN‐γ signaling up‐regulates the expression of estrogen receptor α12 whereas estrogen promotes IFN‐γ production. In conclusion, this study sheds light on type I IFN as a key‐player in PBC development and severity. This should boost research on the sexome, that is, the aggregate of all sex‐biasing effects on gene networks and cell systems; unraveling these complex interactions is part of the overall goal of discovering which factors protect from PBC, how the protection is exerted within specific pathways, and which protective pathways might respond to novel therapeutic interventions. Indeed, this study identifies type I IFN as a novel potential therapeutic target. Novel biological agents that act as type I IFN antagonists (i.e., sifalimumab) are currently under study in other autoimmune conditions; early‐phase clinical trials in systemic lupus erythematosus have to date provided promising results.13 If IFN dysregulation turns out to be involved in PBC development and progression, targeting this pathway could represent a promising approach to develop a disease‐modifying drug in PBC.