The purpose of this review is to describe the immune function of the liver, guiding the reader from the homeostatic tolerogenic status to the aberrant activation demonstrated in chronic liver disease. An extensive description of the pathways behind the inflammatory modulation of the healthy liver will be provided focusing on the complex immune cell network residing within the liver. The limit of tolerance will be presented in the context of organ transplantation, seizing the limits of homeostatic mechanisms that fail in accepting the graft, progressing eventually toward rejection. The triggers and mechanisms behind chronic activation in metabolic liver conditions and viral hepatitis will be discussed. The last part of the review will be dedicated to one of the greatest paradoxes for a tolerogenic organ, developing autoimmunity. Through the description of the three most common autoimmune liver diseases, the autoimmune reaction against hepatocytes and biliary epithelial cells will be dissected.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are characterized by the destruction of the small bile ducts and the formation of multifocal biliary strictures, respectively, impairing bile flow. This leads to the hepatic accumulation of bile acids, causing liver injury and the risk of progression to cirrhosis and liver failure. First-line therapy for PBC is ursodeoxycholic acid, although up to 40% of treated individuals are incomplete responders, and there is no effective therapy for PSC, highlighting the need for better therapeutic options in these diseases. In addition, pruritus is a common symptom of cholestasis that has severe consequences for quality of life and is often undertreated or untreated. Nuclear receptors are pharmacological targets to treat cholestasis due to their multifactorial regulation of hepatic enzymatic pathways, particularly in bile acid metabolism. The peroxisome proliferator-activated receptor (PPAR) is of significant clinical interest due to its role in regulating bile acid synthesis and detoxification pathways. PPAR agonism by fibrates has traditionally been explored due to PPARα's expression in the liver; however, recent interest has expanded to focus on newer PPAR agonists that activate other PPAR isoforms, for example, δ, γ, alone or in combination. Several PPAR agonists have been investigated as second-line therapy for people living with PBC, including the recent accelerated United States Food and Drug Administration approval of elafibranor and seladelpar. This review evaluates available data on the efficacy and safety of the five PPAR agonists investigated for the treatment of cholestasis and associated pruritus in PBC and PSC, namely fenofibrate, bezafibrate, saroglitazar, elafibranor, and seladelpar.

The aim of this review is to explore the potential of new regenerative medicine approaches in the treatment of cholestatic liver fibrosis. Cholestatic liver diseases, such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and biliary atresia (BA), due to the accumulation of bile, often progress to liver fibrosis, cirrhosis, and liver failure. When the disease becomes severe enough to require liver transplantation. Deeply understanding the disease's progression and fibrosis formation is crucial for better diagnosis and treatment. Current liver fibrosis treatments mainly target the root causes and no direct treatment method in fibrosis itself. Recent advances in regenerative medicine offer a potential approach that may help find the ways to target fibrosis directly, offering hope for improved outcomes. We also summarize, analyze, and discuss the current state and benefits of regenerative medicine therapies such as mesenchymal stem cell (MSC) therapy, induced pluripotent stem cells (iPSCs), and organoid technology, which may help the treatment of cholestatic liver diseases. Focusing on the latest research may reveal new targets and enhance therapeutic efficacy, potentially leading to more effective management and even curative strategies for cholestatic liver diseases.

Primary biliary cholangitis (PBC), a typical autoimmune liver disease, is characterized by an increased infiltration of immune cells. However, the specific molecular mechanisms regulating immune cell migration in PBC are unknown. Engulfment and cell motility 1 (ELMO1) plays an important function in cellular dynamics. In view of this, the aim of this study was to explore the expression of ELMO1 in PBC, its effects on the proliferation, migration, and secretion of inflammatory factors by the mainly regulated immune cells and the specific molecular mechanisms behind it.

To determine the expression of ELMO1 in PBC and its major regulatory immune cells in PBC. The migratory and proliferative capacities of ELMO1-deficient macrophages were measured, and their pro-inflammatory cytokine secretion was also detected and explored mechanistically.

ELMO1 expression was up-regulated in the PBC patients and positively correlated with alkaline phosphatase (ALP). ELMO1 mainly regulated macrophages in the liver of PBC patients. Knockdown of ELMO1 did not affect macrophage proliferation, however,knockdown of ELMO1 significantly inhibited macrophage migration,downstream RAC1 activity was diminished, and reduced F-actin synthesis. Knockdown of ELMO1 reduced macrophage inflammatory factor secretion and NF-κB signaling pathway activity was decreased.

ELMO1 regulates macrophage directed migration and attenuates inflammation via NF-κB signaling pathway in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by multilineage immune dysregulation, which subsequently causes inflammation, fibrosis, and even cirrhosis of liver. Due to the limitation of traditional assays, the local hepatic immunopathogenesis of PBC has not been fully characterized. Here, we utilize single-cell RNA sequencing technology to depict the immune cell landscape and decipher the molecular mechanisms of PBC patients. We reveal that cholangiocytes and hepatic stellate cells are involved in liver inflammation and fibrosis. Moreover, Kupffer cells show increased levels of inflammatory factors and decreased scavenger function related genes, while T cells exhibit enhanced levels of inflammatory factors and reduced cytotoxicity related genes. Interestingly, we identify a liver-resident Th1-like population with JAK-STAT activation in the livers of both PBC patients and murine PBC model. Finally, blocking the JAK-STAT pathway alleviates the liver inflammation and eliminates the liver-resident Th1-like cells in the murine PBC model. In conclusion, our comprehensive single-cell transcriptome profiling expands the understanding of pathological mechanisms of PBC and provides potential targets for the treatment of PBC in patients.

Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by immune-mediated injury to small bile ducts. Although PBC is an autoimmune disease, the effectiveness of conventional immunosuppressive therapy is disappointing. Nearly 40% of PBC patients do not respond to the first-line drug UDCA. Without appropriate intervention, PBC patients eventually progress to liver cirrhosis and even death. There is an urgent need to develop new therapies. The gut-liver axis emphasizes the interconnection between the gut and the liver, and evidence is increasing that gut microbiota and bile acids play an important role in the pathogenesis of cholestatic diseases. Dysbiosis of gut microbiota, imbalance of bile acids, and immune-mediated bile duct injury constitute the triad of pathophysiology in PBC. Autoimmune cholangitis has the potential to be improved through immune system modulation. Considering the failure of conventional immunotherapies and the involvement of gut microbiota and bile acids in the pathogenesis, targeting immune factors associated with them, such as bile acid receptors, microbial-derived molecules, and related specific immune cells, may offer breakthroughs. Understanding the gut microbiota-bile acid network and related immune dysfunctions in PBC provides a new perspective on therapeutic strategies. Therefore, we summarize the latest advances in research of gut microbiota and bile acids in PBC and, for the first time, explore the possibility of related immune factors as novel immunotherapy targets. This article discusses potential therapeutic approaches focusing on regulating gut microbiota, maintaining bile acid homeostasis, their interactions, and related immune factors.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease caused by intrahepatic bile duct injuries, resulting in fibrosis, cirrhosis, and eventually liver failure. T helper (Th) 17 cells are proposed to involve in the pathogenesis of PBC. However, how and which Th17 cell-derived cytokines affect PBC remains unclear. In this study, we investigated the effects of Th17 effector cytokines, including interleukin (IL)-17A, IL-17F, and IL-21 in PBC using a xenobiotic-induced mouse model of autoimmune cholangitis (inducible chemical xenobiotic models of PBC) treated with cytokine-expressing adeno-associated virus. Our results showed that administration of IL-17A, the well-known main cytokine produced by Th17 cells, did not augment liver inflammation or fibrosis. In contrast, we noted IL-17A-treated mice had lower hepatic Th1 cell numbers and higher hepatic CD11b+Ly6G+ polymorphonuclear myeloid-derived suppressor cell numbers. IL-17F did not alter liver inflammation or fibrosis. However, the administration of IL-21 exacerbated liver inflammatory responses and portal cell infiltration. IL-21 markedly increased the numbers of activated CD8+ T cells and liver tissue-resident memory CD8+ T cells. Moreover, IL-21 aggravates liver fibrosis in mice with autoimmune cholangitis. These results emphasized that not IL-17A but IL-21 in Th17 cell-derived cytokines affected the pathogenesis of PBC. IL-21 enhanced liver inflammation and progression to fibrosis by enhancing the numbers and effector activities of CD8+ T cells. Delineation of the effects of different Th17 effector cytokines in PBC offers clues for developing new therapeutic approaches.

Primary biliary cholangitis (PBC) is the most common of the autoimmune liver diseases, in which there is chronic small bile duct inflammation. The pathophysiology of PBC is multifactorial, involving immune dysregulation and damage to biliary epithelial cells, with influences from genetic factors, epigenetics, the gut-liver axis, and environmental exposures.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The most common antibody associated with PBC is the anti-mitochondrial antibody (AMA), present in 90% to 95% of patients. For patients who are AMA-negative, novel biomarkers, such as antinuclear antibody-specific antibodies Sp100 and gp210 and anti-kelch-like-12 and anti-hexokinase-1 antibodies, may further aid in the diagnosis of PBC. Several laboratory methods, including immunofluorescence, enzyme-linked immunosorbent assay, immunoblotting, and bead-based assays, exist to evaluate for the presence of antibodies. This article describes various methods used to evaluate antibodies as well as describe the antibodies present in PBC.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that can progress to cirrhosis and hepatic failure if left untreated. Ursodeoxycholic acid (UDCA) was introduced as a first-line drug for PBC around 1990; it remarkably improved patient outcomes, leading to the nomenclature change of PBC in 2015, from primary biliary "cirrhosis" to primary biliary "cholangitis." Nevertheless, 20-30% of patients exhibit an incomplete response to UDCA, resulting in significantly worse outcomes compared to those with a complete response. Therefore, improving the long-term outcomes of patients with an incomplete response to UDCA has been recognized as an unmet need. In addition, patients with PBC often suffer from a variety of debilitating symptoms, such as pruritus, fatigue and sicca syndrome, which significantly impair their health-related quality of life. Thus, appropriate management of these symptoms is currently regarded as another unmet need for PBC treatment. In this review, several compounds and drugs under clinical trials that can potentially solve these unmet needs are comprehensively discussed, and future directions of treatment policy of PBC are proposed for significantly improving long-term outcome as well as health-related quality of life of patients.

Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease that progresses to fibrosis and cirrhosis, resulting from the gradual destruction of intrahepatic bile ducts. Exploring genetic variants associated with PBC is essential to understand the pathogenesis of PBC. Here we identify a zebrafish balloon dog (blg) mutant with intrahepatic bile duct branching defects, exhibiting several key pathological PBC-like features, including immunodominant autoantigen PDC-E2 production, cholangiocyte apoptosis, immune cell infiltration, inflammatory activation, and liver fibrosis. blg encodes the protein phosphatase 1 regulatory subunit 21 (Ppp1r21), which is enriched in the liver and its peripheral tissues and plays a vital role in the early intrahepatic bile duct formation stage. Further studies show an excessive activation of the PI3K/AKT/mTOR pathway in the hepatic tissues in the mutant, while treatment with the pathway inhibitor LY294002 and rapamycin partially rescues intrahepatic bile duct branching defects and alleviates the PBC-like symptoms. These findings implicate the potential role of the Ppp1r21-mediated PI3K/AKT/mTOR pathway in the pathophysiology of PBC.

Anti-mitochondrial antibodies (AMA) and the M2 subtype are considered serological hallmarks in the diagnosis of primary biliary cholangitis (PBC). However, these autoantibodies may be undetectable in some patients. This meta-analysis aimed to evaluate the diagnostic accuracy of serum AMA and M2 for PBC.

We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library for relevant studies. Pooled sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), and diagnostic odds ratio (DOR) were calculated using a random-effects model. We also constructed hierarchical summary receiver operating characteristic curves and calculated the area under the curve values.

Our meta-analysis included 28 studies, of which 24 examined the diagnostic accuracy of AMA for PBC. Pooled sensitivity and specificity of AMA were 84% (95% confidence intervals [CI] 77-90%) and 98% (96-99%), respectively. Pooled LR+, LR-, and DOR were 42.2 (22.1-80.5), 0.16 (0.11-0.24), and 262 (114-601), respectively. Sixteen studies explored the diagnostic value of the M2 subtype, demonstrating pooled sensitivity and specificity of 89% (81-94%) and 96% (93-98%), respectively. Pooled LR+, LR-, and DOR were 20.3 (8.0-51.1), 0.12 (0.05-0.26), and 169 (41-706), respectively. The hierarchical summary receiver operating characteristic curves for both of serum AMA and M2 subtype lie closer to the upper left corner of the plot with area under the curve values of 0.98 (95% CI = 0.96-0.99) and 0.98 (95% CI = 0.96-0.99) respectively.

This meta-analysis provides evidence affirming the utility of AMA and M2 as sensitive and specific serological hallmarks that can facilitate early screening and diagnosis of PBC.

A chronic autoimmune liver disease known as primary biliary cholangitis (PBC) that selectively destructs small intrahepatic biliary epithelial cells and may result in biliary cirrhosis and eventually liver transplantation or death. PBC is associated with various other extrahepatic autoimmune diseases; however, the combination of PBC with ankylosing spondylitis has been rarely reported in the literature. Here, we reported a case of PBC with ankylosing spondylitis to improve our understanding of such coexistence and provide new ideas for the treatment of such patients.

A 54-year-old man was presented to the Department of Rheumatology because of an abnormal liver function test for 7 years, chest and back pain for 1 year, and low back pain for 2 months.

Primary biliary cholangitis, ankylosing spondylitis, and old pulmonary tuberculosis.

The patient refused to use nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs, and biologic disease-modifying antirheumatic drugs; thus, he was treated with methylenediphosphonate (99Tc-MDP) and ursodeoxycholic acid (UDCA).

The patient achieved remission with UDCA and 99Tc-MDP therapy.

In the treatment of PBC combined with other disorders, the characteristics of different diseases should be considered. The patient reported herein was treated with 99Tc-MDP and UDCA, and his condition improved; thus, we consider 99Tc-MDP to be an effective treatment. Furthermore, in line with the current understanding of the pathogenesis of PBC and ankylosing spondylitis, we hypothesize that interleukin-17 inhibitor is an effective treatment for such patients.

Primary biliary cholangitis (PBC) is a severe disease with unknown aetiology and poor prognosis owing to ineffective treatment. B-cell antibodies play a regulatory role during immune responses; therefore, their role in PBC should not be overlooked. Fcγ receptors (FcγRs) of IgG and cell surface glycoproteins play an important role in autoimmune and infectious disease prevention. In this study, 60 patients with PBC and 35 healthy controls (HCs) were recruited. The number of B cells and the expression of the FcγRIIB on the peripheral blood mononuclear cells of patients with PBC were evaluated using FACS. The concentrations of soluble FcγRs were determined using ELISA, and intrahepatic FcγRIIB and CD19 expressions in patients with PBC were visualised using IHC. FcγRIIB expression in B cells was significantly higher in patients with PBC than in HCs (P < 0.0001). The soluble FcγRIIB levels in the plasma were higher in patients with PBC than in HCs (P = 0.0009). Notably, these levels were reduced by treatment with ursodeoxycholic acid (P = 0.0236). CD19 and FcγRIIB expression increased in the liver of patients with PBC relative to that in HCs. These findings can provide new insights into PBC pathogenesis and can aid the future development of treatment strategies.

Primary biliary cholangitis (PBC) is an archetypal autoimmune disease. Chronic lymphocytic cholangitis is associated with interface hepatitis, ductopenia, cholestasis, and progressive biliary fibrosis. People living with PBC are frequently symptomatic, experiencing a quality-of-life burden dominated by fatigue, itch, abdominal pain, and sicca complex. Although the female predominance, specific serum autoantibodies, immune-mediated cellular injury, as well as genetic (HLA and non-HLA) risk factors, identify PBC as autoimmune, to date treatment has focused on cholestatic consequences. Biliary epithelial homeostasis is abnormal and contributes to disease. The impact of cholangiocyte senescence, apoptosis, and impaired bicarbonate secretion enhances chronic inflammation and bile acid retention. First-line therapy is a non-specific anti-cholestatic agent, ursodeoxycholic acid. For those with residual cholestasis biochemically, obeticholic acid is introduced, and this semisynthetic farnesoid X receptor agonist adds choleretic, anti-fibrotic, and anti-inflammatory activity. Future PBC licensed therapy will likely include peroxisome proliferator activated receptor (PPAR) pathway agonists, including specific PPAR-delta agonism (seladelpar), as well as elafibrinor and saroglitazar (both with broader PPAR agonism). These agents dovetail the clinical and trial experience for off-label bezafibrate and fenofibrate use. Symptom management is essential, and encouragingly, PPAR agonists reduce itch; IBAT inhibition (eg, linerixibat) also appears promising for pruritus. For those where liver fibrosis is the target, NOX inhibition is being evaluated. Earlier stage therapies in development include therapy to impact immunoregulation in patients, as well other approaches to treating pruritus (eg, antagonists of MrgprX4). Collectively the PBC therapeutic landscape is exciting. Therapy goals are increasingly proactive and individualized and aspire to rapidly achieve normal serum tests and quality of life with prevention of end-stage liver disease.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by the immune-mediated destruction of small and medium intrahepatic bile ducts, involving predominantly females. PBC has long been described as an autoimmune liver disease, also because it is very often associated with many autoimmune conditions. More recently, another pathogenic mechanism exploring the damage of cholangiocytes has been hypothesized, i.e. a defect in the biliary umbrella which is physiologically responsible for the exchange of the ions Cl- and HCO3- and maintains the integrity of glycocalyx. To provide a state-of-the-art analysis of this topic, a systematic review of literature in PubMed, Scopus, and Science Direct was conducted (inclusive dates: 1986-2023).

Although the etiology remains unknown, pathogenesis consists of a complex immune-mediated process resulting from a genetic susceptibility. PBC can be triggered by an immune-mediated response to an autoantigen, which leads to a progressive destruction of bile ducts and eventually to a progressive fibrosis with cirrhosis. The defect in the 'bicarbonate umbrella' acts as a protection against the toxic hydrophobic bile acids, leading to a toxic composition of bile.

This review offers a summary of the current knowledge about the pathogenesis of PBC, indicating that this is probably based on the mutual relationship between the immune insult and the unbalanced secretory mechanisms.

Primary biliary cholangitis (PBC), previously referred to as primary biliary cirrhosis, is an autoimmune disorder leading to the destruction of intra-hepatic bile ducts. If untreated, progressive bile duct damage and cholestasis can lead to ductopenia and result in cirrhosis. Ursodiol, the first drug approved for PBC, has changed the natural history of this disease and improved patient outcomes. Subsequently, several new prediction models incorporating a response to ursodiol were developed. These include the GLOBE score, which was shown to predict long-term outcomes in patients with PBC. In 2016, obeticholic acid (OCA) became the second drug to be approved by the FDA, predominantly based on improvement in alkaline phosphatase (ALP) levels. This trial has subsequently influenced the design of clinical trials. Several drugs are currently being evaluated as therapeutic options for PBC, with improvement in ALP being a main endpoint. In this review, we will discuss the impact of new therapies on GLOBE scores in patients with PBC.

In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid-the UDCA response-accurately predicts long-term outcome. Molecular characterization of patients stratified by UDCA response can improve biological understanding of the high-risk disease, thereby helping to identify alternative approaches to disease-modifying therapy. In this study, we sought to characterize the immunobiology of the UDCA response using transcriptional profiling of peripheral blood mononuclear cell subsets.

We performed bulk RNA-sequencing of monocytes and TH1, TH17, TREG, and B cells isolated from the peripheral blood of 15 PBC patients with adequate UDCA response ("responders"), 16 PBC patients with inadequate UDCA response ("nonresponders"), and 15 matched controls. We used the Weighted Gene Co-expression Network Analysis to identify networks of co-expressed genes ("modules") associated with response status and the most highly connected genes ("hub genes") within them. Finally, we performed a Multi-Omics Factor Analysis of the Weighted Gene Co-expression Network Analysis modules to identify the principal axes of biological variation ("latent factors") across all peripheral blood mononuclear cell subsets.

Using the Weighted Gene Co-expression Network Analysis, we identified modules associated with response and/or disease status (q<0.05) in each peripheral blood mononuclear cell subset. Hub genes and functional annotations suggested that monocytes are proinflammatory in nonresponders, but antiinflammatory in responders; TH1 and TH17 cells are activated in all PBC cases but better regulated in responders; and TREG cells are activated-but also kept in check-in responders. Using the Multi-Omics Factor Analysis, we found that antiinflammatory activity in monocytes, regulation of TH1 cells, and activation of TREG cells are interrelated and more prominent in responders.

We provide evidence that adaptive immune responses are better regulated in patients with PBC with adequate UDCA response.

The macrophage activation marker soluble (s)CD163 is associated with disease severity and prognosis in patients with primary biliary cholangitis (PBC). Ursodeoxycholic acid (UDCA) treatment attenuates fibrosis progression in PBC patients, but its effect on macrophage activation is unclear. We examined the effect of UDCA on macrophage activation, as determined by sCD163 levels.

We included 2 cohorts of PBC patients; 1 cohort with prevalent PBC patients, and 1 cohort of incident PBC patients before start of UDCA treatment and with follow-up after 4 weeks and 6 months. We measured sCD163 and liver stiffness in both cohorts. Further, we measured sCD163 and TNF-α shedding in vitro in monocyte-derived macrophages after UDCA and lipopolysaccharide incubation.

We included 100 patients with prevalent PBC [93% women, median age 63 y (interquartile range: 51-70)] and 47 patients with incident PBC [77% women, median age 60 y (49-67)]. Prevalent PBC patients had a lower median sCD163 of 3.54 mg/L (2.77-4.72) than incident PBC patients with a median sCD163 of 4.33 mg/L (2.83-5.99) at inclusion. Patients with an incomplete response to UDCA and patients with cirrhosis had higher sCD163 than responders to UDCA and noncirrhosis patients. After 4 weeks and 6 months of UDCA treatment median sCD163 decreased by 4.6% and 9.0%, respectively. In in vitro experiments, UDCA attenuated shedding of TNF-α, but not sCD163, from monocyte-derived macrophages.

In PBC patients, sCD163 levels correlated with liver disease severity and treatment response to UDCA. Further, after 6 months of UDCA treatment, we observed a decrease in sCD163, which may be related to the treatment.

The liver is the front line organ of the immune system. The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens. This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens, such as food antigens or pathogens. As an immune active organ, the liver functions as a gatekeeping barrier from the outside world, and it can create a rapid and strong immune response, under unfavorable conditions. However, the liver's assumed immune status is anti-inflammatory or immuno-tolerant. Dynamic interactions between the numerous populations of immune cells in the liver are key for maintaining the delicate balance between immune screening and immune tolerance. The anatomical structure of the liver can facilitate the preparation of lymphocytes, modulate the immune response against hepatotropic pathogens, and contribute to some of its unique immunological properties, particularly its capacity to induce antigen-specific tolerance. Since liver sinusoidal endothelial cell is fenestrated and lacks a basement membrane, circulating lymphocytes can closely contact with antigens, displayed by endothelial cells, Kupffer cells, and dendritic cells while passing through the sinusoids. Loss of immune tolerance, leading to an autoaggressive immune response in the liver, if not controlled, can lead to the induction of autoimmune or autoinflammatory diseases. This review mentions the unique features of liver immunity, and dysregulated immune responses in patients with autoimmune liver diseases who have a close association with inborn errors of immunity have also been the emphases.

Primary biliary cholangitis (PBC) is a female-predominant liver autoimmune disease characterized by the specific immune-mediated destruction of the intrahepatic small bile duct. Although apoptosis of biliary epithelial cells (BECs) and alterations in gut microbiota are observed in patients with PBC, it is still unclear whether these events happen in the early stage and cause the breakdown of tolerance in PBC. In this study, we examined the early events in the loss of tolerance in our well-defined 2-OA-OVA-induced murine autoimmune cholangitis (AIC) model. We report herein that apoptosis of BECs was notable in the early stage of murine AIC. An altered gut microbiota, in particular, an increased percentage of gram-positive Firmicutes in AIC mice was also observed. BECs in AIC mice expressed adhesion molecule ICAM-1, cytokines/chemokines TNF-α, CCL2, CXCL9, CXCL10, and toll-like receptor (TLR) 2. Moreover, BECs treated with TLR2 ligand had elevated apoptosis and CXCL10 production. These data collectively suggest a new mechanism of tolerance breakdown in AIC. Altered gut microbiota induces apoptosis of BECs through TLR2 signaling. BECs secrete chemokines to recruit CD8 T cells to damage BECs further.

Primary biliary cholangitis (PBC) is an autoimmune disease that involves chronic inflammation and injury to biliary epithelial cells. To identify critical genetic factor(s) in PBC patients, we performed whole-exome sequencing of five female siblings, including one unaffected and four affected sisters, in a multi-PBC family, and identified 61 rare heterozygote variants that segregated only within the affected sisters. Among them, we were particularly interested in caspase-10, for although several caspases are involved in cell death, inflammation and autoimmunity, caspase-10 is little known from this perspective. We generated caspase-10 knockout macrophages, and then investigated the obtained phenotypes in comparison to those of its structurally similar protein, caspase-8. Unlike caspase-8, caspase-10 does not play a role during differentiation into macrophages, but after differentiation, it regulates the process of inflammatory cell deaths such as necroptosis and pyroptosis more strongly. Interestingly, caspase-10 displays better protease activity than caspase-8 in the process of RIPK1 cleavage, and an enhanced ability to form a complex with RIPK1 and FADD in human macrophages. Higher inflammatory cell death affected the fibrotic response of hepatic stellate cells; this effect could be recovered by treatment with UDCA and OCA, which are currently approved for PBC patients. Our findings strongly indicate that the defective roles of caspase-10 in macrophages contribute to the pathogenesis of PBC, thereby suggesting a new therapeutic strategy for PBC treatment.

Clinical epidemiological studies have reported that viral infections cause autoimmune pathology in humans. Host-pathogen protein sequences and structure-based molecular mimicry cause autoreactive T cells to cross-activate. The aim of the current study was to implement immunoinformatics approaches to infer sequence- and structure-based molecular mimicry between viral and human proteomic datasets. The protein sequences of all the so far known human-infecting viruses were obtained from the VIPR database, and complete human proteome data were retrieved from the NCBI repository. Based on a predefined, stringent threshold of comparative sequence analyses, 24 viral proteins were identified with significant sequence similarity to human proteins. PathDIP identified the enrichment of these homologous proteins in nine metabolic pathways with a p-value < 0.0001. Several viral and human mimic epitopes from these homologous proteins were predicted as strong binders of human HLA alleles, with IC50 < 50 nM. Downstream molecular docking analyses identified that lead virus-human homologous epitopes feasibly interact with HLA and TLR4 types of immune receptors. The vast majority of these top-hit homolog epitopic peptides belong to the herpes simplex and poxvirus families. These lead epitope biological sequences and 3D structural-based molecular mimicry may be promising for interpreting herpes simplex virus and poxvirus infection-mediated autoimmune disorders in humans.

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a female predisposition and selective destruction of intrahepatic small bile ducts leading to nonsuppurative destructive cholangitis. It is characterized by seropositivity of antimitochondrial antibodies or PBC-specific antinuclear antibodies, progressive cholestasis, and typical liver histologic manifestations. Destruction of the protective bicarbonate-rich umbrella is attributed to the decreased expression of membrane transporters in biliary epithelial cells (BECs), leading to the accumulation of hydrophobic bile acids and sensitizing BECs to apoptosis. A recent X-wide association study reveals a novel risk locus on the X chromosome, which reiterates the importance of Treg cells.

The interferon (IFN) signaling pathways are major immunological checkpoints with clinical significance in the pathogenesis of autoimmunity. We have generated a unique murine model named ARE-Del, with chronic overexpression of IFNγ, by altering IFNγ metabolism. Importantly, these mice develop an immunologic and clinical profile similar to patients with primary biliary cholangitis, including high titers of autoantibodies and portal inflammation. We hypothesized that the downregulation of IFN signaling pathways with a JAK1/2 inhibitor would inhibit the development and progression of cholangitis. To study this hypothesis, ARE-Del+/- mice were treated with the JAK1/2 inhibitor ruxolitinib and serially studied. JAK inhibition resulted in a significant reduction in portal inflammation and bile duct damage, associated with a significant reduction in splenic and hepatic CD4+ T cells and CD8+ T cells. Functionally, ruxolitinib inhibited the secretion of the proinflammatory cytokines IFNγ and TNF from splenic CD4+ T cells. Additionally, ruxolitinib treatment also decreased the frequencies of germinal center B (GC B) cells and T follicular helper (Tfh) cells and led to lower serological AMA levels. Of note, liver and peritoneal macrophages were sharply decreased and polarized from M1 to M2 with a higher level of IRF4 expression after ruxolitinib treatment. Mechanistically, ruxolitinib inhibited the secretion of IL-6, TNF and MCP1 and the expression of STAT1 but promoted the expression of STAT6 in macrophages in vitro, indicating that M1 macrophage polarization to M2 occurred through activation of the STAT6-IRF4 pathway. Our data highlight the significance, both immunologically and clinically, of the JAK/STAT signaling pathway in autoimmune cholangitis.

The ability to regulate B cell development has long been recognized to have therapeutic potential in a variety of autoimmune diseases. However, despite the presence of a classic autoantibody in primary biliary cholangitis (PBC), B cell depleting therapy and indeed therapy with other biologic agents has been disappointing. Unsuccessful treatment using Rituximab is associated with elevation of B-cell activating factor (BAFF) level. Indeed, therapies for PBC remain directed at modulating bile salt biology, rather than targeting effector pathways. With these data in mind, we proposed that targeting two major stages of B cell development, namely long-lived memory B cells and short-lived peripheral autoreactive plasma cells would have therapeutic potential.

To address this thesis, we administrated anti-BAFF and anti-CD20 monoclonal antibody to ARE-Del mice, a well-characterized murine model of human PBC. We evaluated and compared the therapeutic efficacy of the two agents individually and the combination of anti-BAFF and anti-CD20 in female mice with well-established disease.

Our data demonstrate that there was an increased level of B cell depletion that resulted in a significantly more effective clinical and serologic response using the combination of agents as compared with the use of the individual agents. The combination of anti-BAFF and anti-CD20 treatment was more effective in reducing serum levels of antimitochondrial antibody (AMA), total IgM and IgG compared to mice treated with the 2 individual agents. Combination treatment efficiently depleted B cells in the peripheral blood, peritoneal cavity and spleen. Importantly, we identified a unique IgM+ FCRL5+ B cell subset which was sensitive to dual B-cell targeting therapy and depletion of this unique population was associated with reduced portal infiltration and bile duct damage. Taken together, our data indicate that dual B cell targeting therapy with anti-BAFF and anti-CD20 not only led to the efficient depletion of B cells both in the peripheral blood and tissues, but also led to significant clinical improvement. These findings highlight the potential application of combination of anti-BAFF and anti-CD20 in treating patients with PBC. However, additional studies in other animal models of PBC should be undertaken before considering human trials in those PBC patients who have incomplete responses to conventional therapy.

Primary biliary cholangitis (PBC) has a wide variation in clinical presentation and course. There is no significant correlation between these symptoms and the disease stage, although patients with more advanced stages generally have more symptoms. It is important to develop biomarkers in order to identify patients with an increased risk of complications and end-stage liver disease. This study investigated surrogate markers for risk estimation of PBC-related complications, including a study population of 77 patients with PBC who underwent liver biopsy and were measured for serum levels of macrophage activation markers, soluble CD163 (sCD163), soluble mannose receptor (sMR), and zonulin. Patients with PBC were divided into symptomatic (Group S, n = 20) and asymptomatic (Group A, n = 57) groups. The correlations of histological stages based on both Scheuer and Nakanuma classifications with the three serum markers were investigated. The Nakanuma classification involves grading for liver fibrosis and bile duct loss. The three biomarkers were assessed for their diagnostic ability to identify patients with PBC having high risk of developing complications. The predictive factors of these complications were examined as well. Group S had significantly higher serum sMR (p = 0.011) and sCD163 (p = 0.048) levels versus Group A. A composite index of sMR and sCD163 measurements had significantly better prediction performance than sCD163 alone (p = 0.012), although not when compared to sMR alone (p = 0.129). Serum sMR was an independent factor for developing complications on both univariate (Odds ratio (OR) = 30.20, 95% confidence interval (95% CI): 3.410−267.0, p = 0.00220), and multivariate (OR = 33.70, 95% CI: 3.6600−311.0, p = 0.0019) analyses. Patients with PBC having sMR of ≥56.6 had a higher incidence of clinical complications versus those with a sMR of <56.6. Serum sMR predicts the development of complications in patients with PBC. sMR plus sCD163 showed better predictive power than either marker alone, although the addition of sCD163 did not improve the predictive power of sMR. Future prospective studies are required in order to validate the findings of the present study.

Autoimmune cholestatic liver disease includes both Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). Both conditions result in impairment of hepatic bile flow ultimately leading to chronic liver injury, liver fibrosis and eventually end stage cirrhosis. Early and accurate diagnosis are important for the risk stratification, follow up and management of these patients. The underlying pathogenesis of these conditions have not been completely resolved and poses a barrier for the development of new diagnostic and prognostics tools. Current research work suggests that the pathogenesis of autoimmune cholestatic liver disease results from environmental, genetic, and a large component of underlying immune dysfunction. While the current available serum biomarkers and imaging modalities showcases progression in precision medicine for the management of autoimmune cholestatic liver disease, development of new biomarkers are still an area of need in this field. In this review, we will discuss the current and emerging biomarkers in patients with PBC, PSC, and a special population that exhibit overlap syndrome with autoimmune hepatitis (AIH). The use of these biomarkers for diagnosis and prognosis of these patients will be reviewed through the lens of the current understanding of the complex immune pathophysiology of these conditions.

Primary biliary cholangitis (PBC) is a rare autoimmune disease of the liver affecting the small bile ducts. From a genetic point of view, PBC is a complex trait and several genetic and environmental factors have been called in action to explain its etiopathogenesis. Similarly to other complex traits, PBC has benefited from the introduction of genome-wide association studies (GWAS), which identified many variants predisposing or protecting toward the development of the disease. While a progressive endeavour toward the characterization of candidate loci and downstream pathways is currently ongoing, there is still a relatively large portion of heritability of PBC to be revealed. In addition, genetic variation behind progression of the disease and therapeutic response are mostly to be investigated yet. This review outlines the state-of-the-art regarding the genetic architecture of PBC and provides some hints for future investigations, focusing on the study of gene-gene interactions, the application of whole-genome sequencing techniques, and the investigation of X chromosome that can be helpful to cover the missing heritability gap in PBC.

Primary biliary cholangitis (PBC) is a common autoimmune liver disease manifested by the infiltration of CD4+ T cells, and the subsequent targeted injury of biliary epithelial cells (BECs). As important components of CD4 subsets, the Treg/Th17 axis maintains an immunological balance between self-tolerance and inflammation in the liver microenvironment. However, the role and regulatory mechanism of the Treg/Th17 axis in PBC remain unclear. In this study, we examined the Treg/Th17 axis in PBC patients and found that the Treg/Th17 axis was imbalanced in PBC at both the transcriptional and cellular levels, with Treg being a weak candidate, which correlates with the PBC progression. This imbalanced Treg/Th17 axis was likely to be affected by the FoxP3 hypermethylation, which was related to the increase of DNA methyltransferase. Furthermore, the effect of 5-Aza-2-deoxycytidine (DAC)-mediated FoxP3 demethylation on PBC mice was investigated. We verified that DAC significantly suppressed the FoxP3 methylation and rebuilt the Treg/Th17 balance, resulting in the alleviation of liver lesions and inflammation. Taken together, our data indicate that DAC plays a positive role in alleviating the progression of PBC through the inhibition of DNA methylation of FoxP3 to rebuild the balanced Treg/Th17 axis. DAC could be considered as a potential candidate for the development of new anti-inflammation strategies in the treatment of PBC.

Primary biliary cholangitis (PBC) is an autoimmune disease characterized by the destruction of intrahepatic small bile ducts and the presence of antimitochondrial antibody (AMA), eventually progresses to liver fibrosis and cirrhosis. Genetic predisposition and environmental factors are involved in the occurrence of PBC, and the epitopes exposure and the imbalance of autoimmune tolerance are the last straw. The apoptosis of biliary epithelial cell (BEC) leads to the release of autoantigen epitopes, which activate the immune system, and the disorder of innate and adaptive immunity eventually leads to the start of disease. Animal models have unique advantages in investigating the pathogenesis and drug exploitation of PBC. Multiple models have been reported, and spontaneous model and induced model have been widely used in relevant research of PBC in recent years. Currently, the only drugs licensed for PBC are ursodesoxycholic acid (UDCA) and obeticholic acid (OCA). In the last few years, as the learned more about the pathogenesis of PBC, more and more targets have been discovered, and multiple targeted drugs are being in developed. In this review, the pathogenesis, murine models and treatment strategies of PBC were summarized, and the current research status was discussed to provide insights for the further study of PBC.

Cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, which can ultimately lead to the development of cirrhosis. However, the exact relationship between the development of liver fibrosis and the progression of cholestatic liver disease remains elusive. Periductular fibroblasts located around the bile ducts seem biologically different from hepatic stellate cells (HSCs). The fibrotic events in these clinical conditions appear to be related to complex crosstalk between immune/inflammatory mechanisms, cytokine signalling, and perturbed homeostasis between cholangiocytes and mesenchymal cells. Several animal models including bile duct ligation (BDL) and the Mdr2-knockout mice have improved our understanding of mechanisms underlying chronic cholestasis. In the present review, we aim to elucidate the mechanisms of fibrosis in order to help to identify potential diagnostic and therapeutic targets.

Primary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO3- rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. Here we present an etiopathogenic view of PBC which sheds light on these puzzling facts of the disease.

PBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl-/HCO3- exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3- secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis. Recently, mitophagy was found to be inhibited by cytosolic alkalization and stimulated by acidification. Accordingly, we propose that AE2 deficiency may disturb mitophagy in BECs, thus, promoting the accumulation of defective mitochondria, oxidative stress and presentation of mitochondrial antigens to the immune cells. As women possess a more acidic endolysosomal milieu than men, mitophagy might be more affected in women in an AE2-defective background. Apart from affecting BECs function, AE2 downregulation in lymphocytes may also contribute to alter immunoregulation facilitating autoreactive T-cell responses.

PBC can be considered as a disorder of Cl-/HCO3- exchange in individuals with genetic predisposition to autoimmunity.

Primary biliary cholangitis is an autoimmune liver disease that predominantly affects women. It is characterised by a chronic and destructive, small bile duct, granulomatous lymphocytic cholangitis, with typical seroreactivity for antimitochondrial antibodies. Patients have variable risks of progressive ductopenia, cholestasis, and biliary fibrosis. Considerations for the cause of this disease emphasise an interaction of chronic immune damage with biliary epithelial cell responses and encompass complex, poorly understood genetic risks and environmental triggers. Licensed disease-modifying treatment focuses on amelioration of cholestasis, with weight-dosed oral ursodeoxycholic acid. For patients who do not respond sufficiently, or patients with ursodeoxycholic acid intolerance, conditionally licensed add-on therapy is with the FXR (NR1H4) agonist, obeticholic acid. Off-label therapy is recognised as an alternative, notably with the pan-PPAR agonist bezafibrate; clinical trial agents are also under development. Baseline characteristics, such as young age, male sex, and advanced disease, and serum markers of liver injury, particularly bilirubin and ALP, are used to stratify risk and assess treatment responsiveness. Parallel attention to the burden of patient symptoms is paramount, including pruritus and fatigue.

In approximately 13% of systemic lupus erythematosus (SLE) patients, a hallmark of primary biliary cirrhosis (PBC) can be detected: antimitochondrial M2 antibodies (AMA-M2). It has not been determined if the presence of AMA-M2 in SLE patients results in a higher risk of PBC in comparison to those with AMA but no SLE. Until now, there have been no such analyses among individuals with subacute cutaneous lupus erythematosus (SCLE).

To assess the seropositivity rates for AMA-M2 and autoantibodies associated with autoimmune hepatitis in patients with newly diagnosed SCLE and to determine the coexistence and risk of development of autoimmune liver disease in these patients within 1 year of follow-up, data from 33 patients with newly diagnosed SCLE were analyzed.

AMA-M2 was found in 20% of SCLE patients. Patients from the AMA-M2-positive group were characterized by significantly higher levels of cholestatic liver enzymes when compared to those without AMA-M2 (P < 0.05). After introducing therapy with hydroxychloroquine and prednisone, the levels of hepatocellular enzymes increased significantly only in AMA-M2 positive patients (P < 0.05).

A high prevalence of AMA-M2 was found in patients with SCLE. Patients with SCLE and AMA-M2 had significantly higher values of cholestatic enzymes than patients without AMA. Newly diagnosed patients with SCLE should be screened for the presence of AMA and should be clinically followed up. Avoiding drugs with potential liver toxicity should be recommended in patients with SCLE and AMA.

Pattern recognition molecules (PRMs) in the complement system contribute to homeostasis as mediators of complement activation. The contribution of PRMs to primary biliary cholangitis (PBC) is unknown. In the current study, we aimed to assess the association between PRMs and the clinical findings of PBC. A total of 122 PBC patients and 20 healthy controls were enrolled. We measured four different PRMs (mannose-binding lectin [MBL], ficolin-1, ficolin-2 and ficolin-3) using stored sera, and retrospectively analyzed the associations between PRMs and laboratory findings, histological findings, and the development of cirrhosis-related conditions. Ficolin-1 levels were significantly higher in the PBC patients than in the healthy controls (152 ng/mL vs 102 ng/mL, P = 0.034), but no significant differences were observed regarding MBL, ficolin-2, and ficolin-3 levels. Ficolin-1 was significantly correlated with alkaline phosphatase (ALP). Low ficolin-1 levels were significantly associated with the development of cirrhosis-related conditions independent for histological stage and ALP levels (hazard ratio: 0.933; 95% confidence interval: 0.875-0.994; P = 0.032). Patients with low levels of ficolin-1 (< 77 ng/mL) had a significantly increased rate of developing cirrhosis-related conditions. Low ficolin-1 levels were associated with disease progression independent of histological stage and ALP levels in patients with PBC.

Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by the destruction of the small and medium bile ducts. Its pathogenesis is still unknown. Despite the genome wide association study findings, the therapies targeting the cytokines pathway, tested so far, have failed. The concept of the biliary epithelium as a key player of the PBC pathogenesis has emerged over the last few years. It is now well accepted that the biliary epithelial cells (BECs) actively participate to the genesis of the damage. The chronic stimulation of BECs via microbes and bile changes the cell phenotype toward an active state, which, across the production of proinflammatory mediators, can recruit, retain, and activate immune cells. The consequent immune system activation can in turn damage BECs. Thus, the crosstalk between both innate and adaptive immune cells and the biliary epithelium creates a paracrine loop responsible for the disease progression. In this review, we summarize the evidence provided in literature about the role of BECs and the immune system in the pathogenesis of PBC. We also dissect the relationship between the immune system and the BECs, focusing on the unanswered questions and the future potential directions of the translational research and the cellular therapy in this area.

Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune liver disease characterized by inflammation and damage of small bile ducts. The NLRP3 inflammasome is a multimeric complex of proteins that after activation with various stimuli initiates an inflammatory process. Increasing data obtained from animal studies implicate the role of NLRP3 inflammasome in the pathogenesis of various diseases. Galectin-3 is a β-galactoside-binding lectin that plays important roles in various biological processes including cell proliferation, differentiation, transformation and apoptosis, pre-mRNA splicing, inflammation, fibrosis and host defense. The multilineage immune response at various stages of PBC development includes the involvement of Gal-3 in the pathogenesis of this disease. The role of Galectin-3 in the specific binding to NLRP3, and inflammasome activation in models of primary biliary cholangitis has been recently described. This review provides a brief pathogenesis of PBC and discusses the current knowledge about the role of Gal-3 in NLRP3 activation and PBC development.

Glycosylation of antibodies, particularly in the Fc domain, critically modulate the ability of antibodies to bind to FcRs, maintaining immune quiescence to achieve a finely orchestrated immune response. The removal of sialic acid and galactose residues dramatically alters the physiological function of IgGs, and alterations of Ig glycosylation have been associated with several autoimmune disorders. However, Ig glycosylation has not been extensively studied in autoimmune cholangitis. We applied triple quadruple mass spectroscopy with subsequent multiple reaction monitoring to elucidate the profile, composition and linkage of sugar residues of antibody glycans in patients with primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and healthy controls (HC). Agalactosylated, HexNAc terminated IgG1 glycoforms were enriched in both PBC and PSC. Levels of IgM glycans at site N439 and fucosylated glycans in J chain, were significantly decreased in PBC compared to PSC and HC. PSC patients had decreased bisecting glycoforms and increased biantennary glycoforms on IgA compared to PBC. Importantly, our data demonstrate the association of distinct branching and composition patterns of Ig glycoforms with disease severity and liver cirrhosis, which highlight the importance of glycan biology as a potential mechanism and/or a disease specific signal of inflammation.

In primary biliary cholangitis (PBC), macrophages are involved in liver inflammation and fibrosis. The macrophage activation markers, soluble (s)CD163 and mannose receptor (sMR) are associated with liver disease severity and prognosis in other chronic liver diseases. We aimed to investigate sCD163 and sMR in patients with PBC.

We investigated PBC patients from the Italian PBC Study Group cohort and measured macrophage activation markers in serum at study enrolment. Patients were followed from enrolment until they experienced an event or were censored at their last visit. Events were defined as follows: (a) death from a liver-related cause; or (b) liver transplantation (LT) for PBC. We used Cox regression to investigate the association between sCD163 and sMR and long-term prognosis.

In total, 202 PBC patients were included. Median age was 62 years (interquartile range (IQR), 53-71) at enrolment and 93% were women. Median sCD163 was 3.43 mg/L (IQR 2.48-5.35) and median sMR was 0.35 mg/L (IQR 0.28-0.45). There was an increase in sCD163 and sMR with increasing alkaline phosphatase. Two hundred and one patients were followed for a median of 8.6 years, and sCD163 and sMR predicted long-term risk of liver-related death or LT in univariate analyses, while sCD163 was also associated with outcome after confounder adjusting (adjusted HR = 1.14, 95% CI 1.00-1.30). Finally, we showed an increase in the prediction accuracy of poor outcome by adding sCD163 to the UK-PBC risk score.

The macrophage activation markers sCD163 and sMR represent a non-invasive measure of PBC disease severity that provides useful long-term prognostic information.