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Abstract

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by damage to small intrahepatic bile ducts. The etiology and pathogenesis of PBC remain unknown. It is often considered to be related to an immunological disorder induced by genetics and environmental factors. Antimitochondrial antibodies (AMAs) along with specific antinuclear antibodies such as gp210 and Sp100 are specific markers of the disease. Middle-aged and elderly women are the main patients. The clinical manifestations of PBC are non-specific, which presents as fatigue and skin itching usually. However, patients gradually develop cholestasis and liver fibrosis, eventually dying as the disease progressed to cirrhosis and liver failure. Currently, ursodeoxycholic acid (UDCA) is the treatment of choice, which is recommended for all patients. PBC may coexist with other autoimmune disorders that may arise from multiple systems, such as inflammatory bowel disease (IBD), Sjögren’s syndrome (SS) and type 1 diabetes mellitus (T1DM). The causal relationship between PBC and extrahepatic autoimmune diseases (EHAIDs) is unclear. This article summarizes the new developments in the study of primary biliary cholangitis and aims to provide a reference for scientific and clinical workers in the field of research on this disease.

Keywords

primary biliary cholangitis pathogenesis extrahepatic autoimmune diseases

Introduction

Primary biliary cholangitis (PBC) is the most prevalent autoimmune liver disease characterized by chronic non-purulent destructive cholangitis.¹ The primary pathological feature is the selective destruction of intrahepatic bile ducts by inflammatory cells, leading to progressive bile duct damage. This ultimately results in the loss of bile ducts and fibrosis, causing intrahepatic cholestasis.² During the initial phase of PBC, symptoms are typically absent in most patients. When present, the symptoms may encompass feelings of tiredness, itching, jaundice, and upper abdominal pain. As the disease progresses, it gradually advances to liver fibrosis, cirrhosis, and liver failure.³

PBC has seen a rising global prevalence, especially in North America and Europe, where the disease is reported at higher rates than in the Asia-Pacific region.^4,5 Epidemiological studies indicate significant regional variations, with Europe showing a pooled point prevalence of 22.27 per 100,000 inhabitants and an annual incidence of 1.87 per 100,000.⁶ In Italy, the prevalence reaches 27.90 per 100,000 with an incidence of 5.31 per 100,000,⁷ while a U.S. study noted an incidence of 4.9 per 100,000 person-years.⁸ In South Korea, the age- and sex-standardized prevalence has increased from 4.30 to 12.32 per 100,000 between 2009 and 2019, reflecting a significant annual growth rate of 10.9%.⁹ PBC predominantly affects middle-aged women and is associated with other autoimmune conditions, influencing treatment responses and patient outcomes.^10,11 Advances in diagnostic methods have contributed to earlier detection and improved management of the disease, resulting in better survival rates, although patients still face higher mortality risks and complications compared to those with primary sclerosing cholangitis.^12–14

Although the exact cause of PBC remains unclear, its pathogenesis is increasingly understood as the result of multiple factors, including genetic susceptibility, immune dysregulation, and environmental triggers. The characteristic pathological changes in PBC primarily involve the progressive destruction of small bile ducts, accompanied by chronic inflammation and fibrosis within the liver. However, growing evidence suggests that PBC is not confined to the liver and can lead to various extrahepatic manifestations, including thyroid dysfunction,¹⁵ Sjögren’s syndrome, as well as skin and skeletal disorders. These extrahepatic manifestations are closely linked to the immunopathological processes of PBC, further supporting the view of PBC as a systemic autoimmune disease. Therefore, a comprehensive understanding of the pathogenesis of PBC and its diverse extrahepatic manifestations is crucial for early diagnosis and intervention. This review will discuss the latest research findings on these aspects in detail.

The pathogenesis of PBC

The pathogenesis of PBC remains unclear. It is believed that individuals with a genetic predisposition lose immune tolerance to mitochondrial antigens under environmental factors. This loss subsequently induces a humoral immune response, leading to autoimmune-mediated damage to the intrahepatic bile ducts (Figure 1).

Figure 1.

Scheme of the pathogenic model in PBC. In the progression of PBC, genetic and environmental factors intricately interact, driving the disease's initiation and advancement. For example, smoking can enhance the action of pro-inflammatory cytokines. This complex interplay shapes the immune system's response to internal and external triggers. When exposed in specific simulated conditions (eg., microbiome, xenobiotics), the modified E2 subunit of the mitochondrial pyruvate dehydrogenase complex (PDC-E2) induces a sophisticated immune response against biliary epithelial cells (BECs). These cells express major histocompatibility complex class II (MHC-II) and interact with antigen-presenting cells (APCs) to activate the adaptive immune system, positioning BECs as targets for autoreactive CD4+ T cells that subsequently attack these cells. At the same time, BECs influence the local inflammatory response by secreting chemokines like CX3CL1, which attract immune cells to the biliary region. This activation also stimulates the differentiation of B cells into plasma cells that produce anti-mitochondrial antibodies (AMAs), which are distinctive markers of PBC. In apoptotic vesicles, PDC-E2 is identified and targeted by circulating AMAs, creating antigen-antibody complexes that exacerbate the immune response. Additionally, the release of CD8+ T cells and inflammatory cytokines intensifies damage to the biliary tract, resulting in chronic biliary lesions, progressive bile duct obstruction, and cholestatic liver pathology.

Genetic factors

Genetic factors contribute to a framework of susceptibility. Previous studies have consistently demonstrated a strong familial aggregation of PBC. The relative risk of PBC is significantly higher among relatives, with first-degree relatives having a relative risk of 9.13. Similarly, the risk is elevated for second- and third-degree relatives, with relative risks of 3.61 and 2.59, respectively.¹⁶ Additionally, the positivity rate of AMA in first-degree relatives (13.1%) is markedly higher than that in the control group (1%).¹⁷ These findings suggest that genetic factors play a crucial role in the development of PBC. To further explore the genetic basis of PBC, recent research has focused on various aspects, including genome-wide association studies (GWAS), the human leukocyte antigen (HLA) system, single nucleotide polymorphisms (SNPs), and epigenetic mechanisms. The following sections will delve into these areas to provide a comprehensive understanding of the genetic influences on PBC.

Genome-wide association studies

Recent advances in GWAS have significantly deepened our understanding of the genetic factors underlying PBC, with studies highlighting both shared and population-specific risk loci across different ethnic groups. In an international meta-analysis, Cordell et al.¹⁸ examined GWAS data from five European cohorts and two East Asian cohorts, identifying 21 new susceptibility loci for PBC. Their findings suggest a largely shared genetic architecture of PBC between European and East Asian populations. Yet, the study also pointed to limitations in capturing rare or less frequent variants due to its reliance on common SNPs. In contrast, Qiu et al.¹⁹ focused primarily on the Chinese Han population and identified six new risk loci (IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A, and IL16), highlighting the key role of the IL-21 signaling pathway and T-cell activation in PBC within this group. This divergence underscores the need for larger multi-ethnic cohorts to reconcile findings and ensure the generalizability of genetic associations. Similarly, studies on Japanese populations by Hitomi et al.²⁰ and Kawashima et al.²¹ identified PTPN2 and PRKCB as new susceptibility loci unique to Japanese cohorts. These results suggest genetic heterogeneity in PBC pathogenesis but also highlight a potential limitation of study designs, including sample sizes and differing genotyping platforms, which may contribute to inconsistent findings.

The study by Gervais et al.²² utilized regional heritability mapping, identifying additional loci (STAT4, ULK4, KCNH5) that traditional GWAS failed to detect. While this method expands discovery potential, it introduces challenges, including the interpretation of aggregate genetic effects and distinguishing true signals from noise.

Im et al.²³ also conducted a genome-wide haplotype association study, discovering 74 genic risk haplotypes that could be involved in cis-regulation of gene expression, emphasizing the complexity of genetic factors in PBC across diverse populations. This study highlights the potential role of haplotype structures in understanding gene regulatory mechanisms, though further validation in diverse populations is needed.

Asselta et al.’s²⁴ exploration of X chromosome loci (rs7059064) within the GRIPAP1 gene illustrates another layer of complexity, as sexually dimorphic patterns in PBC genetics are still underexplored. The underrepresentation of male PBC cases in most cohorts limits the applicability of such findings.

Integrative studies combining GWAS data with other omics data have provided deeper insights into the cellular and molecular mechanisms of PBC. Xiang et al.²⁵ integrated GWAS data with single-cell RNA sequencing to identify liver cell subpopulations influenced by PBC-associated genetic factors, revealing that cholangiocytes are enriched with PBC-associated genetic signals. Notably, they identified ORMDL3 as a key gene with the highest expression proportion in cholangiocytes (22.38%), suggesting its significant role in the immune regulation of PBC. Further analysis by Xiang et al.²⁵ showed that ORMDL3-positive cholangiocytes exhibit higher metabolic activity and stronger cell communication with macrophages and monocytes, specifically activating the VEGF signaling pathway, thereby contributing to PBC pathophysiology.

Overall, while GWAS have identified numerous susceptibility loci for PBC, these studies are not without limitations. Future research must address gaps in cross-population analyses, incorporate rare variant studies, and integrate multi-omics approaches to enhance our understanding of PBC’s genetic architecture.

The association between the HLA region and PBC

The HLA genes play a crucial role in the pathogenesis of PBC. Various studies have shown that the polymorphisms of HLA genes are closely associated with the susceptibility, clinical manifestations, and progression of PBC, with significant differences observed across different ethnicities and regions. Among these, the polymorphisms in HLA-DRB1 and HLA-DQB1 alleles are central in PBC development.

For example, while HLA-DRB1*08:03 is strongly associated with an increased risk of PBC in Japanese and Chinese populations, its prevalence varies significantly even among Asian subgroups. Additionally, HLA-DQB1*03:01 is identified as a protective allele in the Japanese population (OR = 0.50, p = 6.76 × 10^-10), highlighting the importance of HLA-DQ in regulating immune responses. However, its protective role shows inconsistencies in other populations, indicating potential epistatic interactions or environmental influences.^26,27

In Chinese populations, the frequency of HLA-DRB1*08:03 is significantly higher in PBC patients compared to controls (21.2% vs. 9.0%), while the frequency of DQB1*03:01 is markedly lower (24.5% vs. 39.2%), indicating the dual role of different HLA genes in PBC pathogenesis. In Sardinian populations, however, the DRB1*08 allele is almost absent, with DRB1*03:01-DQB1*02:01 haplotypes dominating, further highlighting the genetic diversity in PBC across regions.^27,28

Further genetic studies have revealed the impact of specific amino acid positions in HLA molecules on PBC susceptibility. For instance, a study involving 2861 PBC patients and 8514 controls found that the HLA-DQA1*04:01 allele had the strongest association with PBC, and that variations at five amino acid positions in HLA molecules could explain a significant portion of the HLA-associated risk in PBC.These amino acid changes, particularly at DRβ54 and DPβ65, influence antigen binding and immune response, but their functional validation in diverse populations remains limited.^29,30

In a familial aggregation study in China, HLA-DRB1*07:01, 14:01, and 14:05 were significantly associated with PBC, with glutamine at position 54 in the HLA-DRB1 molecule identified as a risk amino acid, highlighting the importance of specific amino acid variations in antigen peptide binding.³¹ This emphasizes the value of familial studies in uncovering genetic mechanisms of disease.

HLA genes are also associated with the gut microbiome composition in PBC patients, further underscoring the role of HLA in immune regulation and disease progression. A Chinese cohort study found that PBC patients carrying high-risk HLA DRB1 alleles (FHRAC) had significantly lower gut microbial diversity, with certain genera such as Lachnospiraceae incertae sedis being more abundant in FHRAC-positive patients.²⁸ Although these findings suggest an interaction between genetic risk and gut microbiota, causality and broader applicability remain speculative.

In addition to susceptibility, HLA is linked to the clinical features of PBC. A study in Japan found that PBC patients carrying HLA-DRB1*15:01:01 and HLA-DQA1*03:03:01 were more likely to develop concomitant autoimmune hepatitis. Moreover, advanced and symptomatic PBC was associated with HLA-A*26:01:01, HLA-DRB1*09:01:02, and HLA-DQB1*03:03:02. However, these clinical associations are not consistently replicated across other populations, underscoring the need for further validation.³² Additionally, some HLA-DP alleles, such as DPB1*02:01, also show important association signals in PBC.²⁶

Subphenotype-specific genetic associations have also been explored. Wang et al.³⁰ conducted a GWAS on anti-nuclear antibody (ANA) subphenotypes in PBC patients, identifying SNPs in the major histocompatibility complex (MHC) region associated with the production of anti-sp100 antibodies (rs492899 and rs1794280) but not gp210 antibodies. They determined that specific HLA-DRβ1 and HLA-DPβ1 alleles are the main determinants for anti-sp100 antibody production, revealing a genetic predisposition to PBC subphenotypes. While these findings provide insights into disease heterogeneity, their prognostic and therapeutic implications remain uncertain. The HLA genes associated with PBC mentioned above are presented in Table 1.

Table 1.

HLA region associated with primary biliary cholangitis.

HLA	Country	Study
HLA-A26:01:01/HLA-DRB109:01:02/HLA-DQB103:03:02*	Japan	³²
HLA-DPB102:01/HLA-DQB103:01	Japan	²⁶
HLA-DQA104:01*	UK	²⁹
HLA-DRB103:01-HLA-DQB102:01	Italy	²⁷
HLA-DRB107:01/HLA-DRB114:01/HLA-DRB114:05*	China	³¹
HLA-DRB108:03*	China, Japan	^26,28
HLA-DRB115:01:01/HLA-DQA103:03:01	Japan	³²
HLA-DRβ1/HLA-DPβ1	China	³⁰

Overall, the polymorphisms of HLA genes can alter the peptide-binding sites of MHC molecules, affecting antigen presentation and triggering abnormal autoimmune responses. However, significant gaps remain in understanding how these genetic associations translate into functional consequences, particularly across diverse populations. Future studies integrating multi-omics data and environmental factors are essential to unravel the multifactorial nature of PBC pathogenesis.

Non-HLA genes and susceptibility to PBC

Several non-HLA genetic variants have been implicated in the susceptibility and progression of PBC. One key study identified functional SNPs rs9459874 and rs1012656 within the CCR6/FGFR1OP locus, which regulate CCR6 translation and FGFR1OP transcription, respectively. These SNPs were associated with an increased expression of CCR6 in the liver, correlating with PBC susceptibility.³³ In support of this, another study focusing on the Han Chinese population found that functional polymorphisms in the CCR6 locus could be categorized into “protective” and “risk” groups, with “risk” variants increasing genetic susceptibility to PBC. Notably, while these associations were replicated in Han Chinese populations, the lead SNPs differed between East Asian and European cohorts, suggesting population-specific genetic architectures.³⁴

Research on the TMEM163/MGAT5 locus identified the rs661899 T allele as a genetic variant associated with a poor prognosis and adverse outcomes in patients undergoing UDCA therapy, indicating its role in disease progression.³⁵ This highlights the need to consider genetic heterogeneity in tailoring therapeutic strategies, especially as the clinical response to UDCA remains variable across patient subgroups.

Similarly, bioinformatic analysis identified several candidate genes, including ITGAL, which showed potential in distinguishing PBC from other diseases, thus providing avenues for non-invasive diagnostic testing.³⁶ Moreover, integrative bioinformatics analysis identified differentially expressed genes such as TXNIP, CD44, and ENTPD1 as potential biomarkers for risk stratification. These genes were validated to form a three-gene panel capable of identifying patients at higher risk of disease progression with an area under the curve of 0.777.³⁷ However, the clinical utility of these biomarkers requires further validation in diverse populations. Another study using zebrafish models discovered that mutations in ppp1r21 result in bile duct defects analogous to human PBC, implicating the PI3K/AKT/mTOR pathway in the disease’s pathophysiology.³⁸ These findings highlight the translational potential of animal models but also underline the challenge of extrapolating results to human pathophysiology. Additionally, a variant in the ARID3A gene was found to be associated with PBC risk. Functional analyses showed that this variant plays a crucial role in modulating myeloid differentiation and immune responses, adding to the understanding of how non-HLA genetic factors contribute to PBC development.³⁹ However, the molecular mechanisms underlying this association remain poorly defined, and additional studies are needed to explore its interaction with other susceptibility loci.

Another line of research highlighted the significance of cholangiocyte-related genes. Single-cell RNA sequencing revealed DUOX2+ACE2+ small cholangiocytes as pathogenic targets in PBC, demonstrating an association with disease severity. These cells exhibited high expression of the polymeric immunoglobulin receptor (pIgR), with elevated levels of anti-pIgR autoantibodies in PBC patients, further suggesting the involvement of specific non-HLA genes in the disease’s pathogenesis.⁴⁰ This finding suggests a link between cholangiocyte biology and immune dysregulation, although the functional relevance of pIgR in PBC pathogenesis warrants further investigation.

Collectively, these studies emphasize the importance of non-HLA genes in the onset and progression of PBC, providing new insights into potential biomarkers, therapeutic targets, and the underlying mechanisms of the disease. Nevertheless, the field faces challenges such as population-specific genetic differences, the lack of functional validation for many identified loci, and the need for integrative approaches combining genetics with environmental and epigenetic factors. Addressing these gaps will enhance our understanding of PBC pathogenesis and inform personalized therapeutic strategies.

Epigenetics

While genetic susceptibility, including variations in HLA and non-HLA loci, accounts for a portion of the disease, these genetic factors explain only about 20% of PBC’s heritability, indicating the presence of “missing heritability”.⁴¹ Epigenetic modification, particularly DNA methylation, histone modification, and non-coding RNAs, have been identified as crucial factors potentially filling this gap.⁴²

DNA methylation

Among these mechanisms, DNA methylation changes are one of the most well-studied epigenetic alterations in PBC. Genome-wide methylation profiling has revealed global hypomethylation in the liver tissues of PBC patients, particularly in genes involved in immune responses and fibrosis.⁴³ Specific genes, such as CXCR3 and CD40L in T and B cells, exhibit differential methylation patterns that correlate with immune dysregulation in PBC.⁴² However, some studies report inconsistencies in methylation patterns between liver and peripheral blood samples, highlighting the need for standardized sampling protocols and methods.^44,45

Further, epigenome-wide association studies (EWAS) have identified differentially methylated CpG sites in genes like NOD-like receptor family CARD domain containing 5 and human leukocyte antigen-E, further emphasizing the role of DNA methylation in PBC progression. While these findings suggest a role for DNA methylation in PBC progression, the functional significance of these changes remains largely speculative without experimental validation in disease models.⁴⁵

X Chromosome Inactivation (XCI)

Additionally, abnormalities in X chromosome inactivation (XCI) have been implicated in the female predominance of PBC. XCI-related epigenetic changes, such as aberrant methylation, may lead to an imbalance in immune regulation, contributing to the disease’s onset and progression.⁴¹

Despite these findings, the exact mechanisms linking XCI and PBC pathogenesis are poorly characterized, warranting further research into X-linked gene regulation in the context of autoimmunity.

Non-coding RNAs

MicroRNAs (miRNAs) also play a vital role in the epigenetic regulation of gene expression in PBC. Altered expression profiles of specific miRNAs, including miR-506 and miR-197-3p, have been linked to immune responses and liver pathology in PBC patients.⁴² However, the exact regulatory networks involving miRNAs, lncRNAs, and other epigenetic marks remain underexplored, particularly in diverse ethnic populations.

Histone modifications

Histone modifications represent another layer of epigenetic regulation, although research in this area is relatively limited. Available studies suggest that histone methylation and acetylation may impact the transcriptional regulation of immune-related genes in PBC, influencing chromatin structure and gene expression patterns in disease development.⁴² Nonetheless, the lack of large-scale, high-resolution studies hampers our understanding of the precise roles of histone modifications in PBC.

Multi-omics approaches

Recent multi-omics approaches, integrating transcriptomic, metabolomic, and cytokinomic analyses, have provided deeper insights into the interplay between genetic, epigenetic, and metabolic factors in PBC.⁴⁶ Transcriptomic analysis has uncovered differentially expressed mRNAs and non-coding RNAs in PBC patients, suggesting pathways involved in lipid metabolism and immune regulation.⁴⁷ Moreover, predictive model incorporating genomic, metabolic, and cytokine profiles have shown high accuracy in predicting biochemical response, illustrating the potential of epigenetic markers in forecasting disease progression and treatment outcomes.⁴⁶ However, the scalability and reproducibility of these approaches in clinical settings remain challenging due to high costs and technical variability.

Treatment implications

In terms of treatment response, molecular signatures have been identified that differentiate responders from non-responders to UDCA treatment, indicating the potential of epigenetic markers in guiding therapeutic decisions.⁴⁴ Additionally, studies in the Chinese Han population have found that genes like GTF2I may regulate IL21R, suggesting that epigenetic changes could influence immune-related gene expression in PBC.⁴⁸ In summary, the growing body of research on PBC underscores that it is not solely driven by genetic predisposition but also involves a complex network of epigenetic mechanisms. Understanding these epigenetic alterations, including DNA methylation, histone modifications, X chromosome inactivation, and miRNA regulation, has profound implications for elucidating PBC’s pathogenesis, identifying biomarkers for diagnosis, and developing individualized treatment strategies.

While epigenetic studies have significantly advanced our understanding of PBC, key challenges remain. Variability in study designs, small sample sizes, and the lack of longitudinal studies limit the interpretability and generalizability of findings. Future research should prioritize cross-population validation, integration of multi-omics data, and experimental models to uncover causal mechanisms linking epigenetic changes to PBC pathogenesis and progression.

Environmental factors

The occurrence of PBC is also influenced by certain environmental factors. Environmental factors function as triggering events. Smoking, bacterial infections, environmental pollutants, and drugs playing roles in the pathogenesis of autoimmune diseases,⁴⁹ lose immune tolerance occurs via a mechanism of molecular mimicry and subsequently induce a series of autoimmune reactions in the body.

Smoking, for example, increases pro-inflammatory cytokines such as IL-1, IL-6, IL-8, and TNF-α, leading to chronic inflammation and widespread cellular damage. This cascade subsequently triggers a pathogenic Th1-mediated immune response and disrupts regulatory T cell homeostasis, consistent with the characteristic features of PBC, including Th1 infiltration and reduced T regulatory function.⁵⁰ The high homology of the self-antigen pyruvate dehydrogenase complex-E2 (PDC-E2) among different organisms provides the basis for the pathogenic mechanism of molecular mimicry.⁵¹ Recent studies have demonstrated that urinary tract infections and Escherichia coli (E. coli) increased the risk of PBC, which might be related to PDC-E2 protein.⁵² 2‐octynoic acid presented in cosmetics and some chewing gums has been confirmed to be associated with the pathogenesis of PBC through animal experiments.⁵³

At the same time, environmental factors may also play a significant role in the pathogenesis of PBC through epigenetic modifications. Emerging research suggests that environmental triggers, such as smoking and infections, may influence epigenetic modifications, including DNA methylation and histone acetylation, thereby leading to abnormal immune responses. The research by Ma et al.⁵⁴ demonstrated that gut microbiota-derived metabolites, such as butyrate, restore MDSC (myeloid-derived suppressor cell) function in UDCA non-responders through metabolic and epigenetic reprogramming (e.g., histone acetylation).

Different environmental factors may have a synergistic effect. For instance, smoking and environmental pollutants may interact to exacerbate the risk and pathogenesis of PBC through overlapping immunomodulatory mechanisms. Specifically, synergistic effects could be linked to their ability to induce chronic inflammation, disrupt regulatory T cell balance, and enhance antigen presentation.^55,56 However, these findings are primarily based on multifactorial analyses and remain limited by the inability to exclude confounding factors such as genetic predisposition and family history. Furthermore, experimental studies specifically evaluating the synergistic effects remain lacking. For example, heavy metals, although less frequently encountered in daily life, may pose a greater risk, yet data on long-term exposure remain sparse.

Immune factors

PBC is caused by the loss of multilinage tolerance to mitochondrial antigens, resulting in dysregulation of the innate and adaptive immune systems.² Immune dysregulation acts as the core mechanism. The activation of natural killer (NK) cells acts as a crucial link between the innate immune response and the adaptive autoimmune responses characteristic of PBC.⁵⁷ Studies have shown that NK cells contribute to the pathogenesis of PBC by mediating the direct or indirect destruction of BECs.⁵⁸ In PBC patients, the proportion of NK cells is significantly elevated, with widespread infiltration around the bile ducts. Other studies suggest that IFN-α and TLR4 ligands act as key stimuli for NK cells, driving their activation and inducing increased cytotoxic activity and perforin expression, thereby effectively killing self-BECs.^57,59,60 An experimental study has demonstrated that under different experimental conditions, NK cells can mediate the immune response and tissue damage in PBC through various mechanisms. Specifically, when the number of NK cells is relatively high, they directly attack BECs, causing damaged BECs to release self-antigens. These self-antigens, in the presence of APCs, activate autoreactive T cells, thereby exacerbating the immune response. In contrast, at a low NK/BEC ratio, NK cells do not directly kill BECs but instead secrete IFN-γ, which induces BECs to express HLA class II molecules. This makes BECs a target for autoreactive CD4+ T cells, which then attack the BECs.⁵⁷

BECs act as APCs in the body⁶¹ and can recruit leukocytes by expressing adhesion molecules, cytokines, and chemokines, leading to biliary injury. Chemokines have been identified to play a pivotal role in the development of PBC, with a particular emphasis on the irregularities observed within the C-X-C motif chemokine receptor 3 (CXCR3) signaling pathway, in which CX3CL1 primarily recruits CD8+ T cells and CD4+ T cells to the portal system of patients with PBC. The infiltration of mononuclear cells around the small and medium bile ducts within the portal tracts is a histological feature of PBC. Among them, CD4+ T cells, CD8+ T cells, and B cells are the primary pathogenic cells.⁵⁸ Regulatory T cells (Tregs) are anti-inflammatory immune cells that play a crucial role in maintaining peripheral tolerance. It has been reported that the number of Treg cells in the peripheral blood and liver of PBC patients is significantly reduced compared to control subjects. At the same time, Treg cells are supposed to maintain immune balance by secreting immunosuppressive factors such as TGF-β and IL-10, but dysfunctional Treg cells fail to effectively suppress immune responses, leading to autoimmune liver damage.^61,62 In the progressive phase of PBC, the inflammatory response shifts from Th1 to Th17 cell differentiation, driving the continued progression of the disease. This occurs due to the imbalance between Th17 and Treg cells, leading to the proliferation and differentiation of liver-autoreactive Th17 cells, which lose control from Treg cells, further exacerbating inflammation and damage in the portal area. The cytokines produced by Th17 cells, such as IL-17, drive chronic inflammation, which may enhance bile duct damage and fibrosis.⁶³ Interestingly, a study revealed that in PBC patients, Treg cells, under the influence of low concentrations of IL-12, can differentiate into Th1-like cells through STAT4 phosphorylation, thereby impairing their original regulatory function. On the contrary, it promotes the immune system to attack the body’s own bile ducts.⁶⁴ Recent studies have found that approximately 95% of PBC patients exhibit AMA against PDC-E2. AMA is both sensitive and specific for the diagnosis and prediction of the disease, and it can often be detected years before the onset of symptoms, whose levels are not correlated with the severity of the disease.⁶⁵ These findings underscore the critical role of cellular immune responses in the pathogenesis of PBC.

In the development of PBC, genetic, environmental, and immune factors interact in a complex way to drive the onset and progression of the disease. Additionally, we have reorganized this chapter to provide a more coherent narrative. Specific genetic factors provide the basis for an individual’s susceptibility to PBC, particularly genes related to immune regulation. Variations in these genes make the immune system more likely to mistakenly recognize self-antigens, leading to the loss of immune tolerance. Environmental factors, such as infections, smoking, and drug exposure, can trigger abnormal immune responses in individuals with genetic susceptibility. Through molecular mimicry or other mechanisms, environmental factors enhance the immune system’s response to self-antigens, promoting immune activation. The loss of immune tolerance, abnormal activation of T and B cells, and the overexpression of cytokines are the core mechanisms in the pathogenesis of PBC. Both genetic and environmental factors influence immune system activity, triggering excessive immune responses that lead to liver bile duct damage and fibrosis.

In summary, genetic susceptibility may modulate individual responses to environmental exposures, such as reduced detoxification of exogenous toxins or an exaggerated immune response following infections. Environmental factors, in turn, may drive epigenetic modifications (e.g., DNA methylation, histone modifications) that further regulate immune gene expression, establishing a feedback loop that exacerbates immune dysregulation. While existing evidence highlights the interplay between genetic, environmental, and immune factors, direct evidence regarding their integrated mechanisms remains limited. For example, the specific molecular pathways linking these factors are not yet fully elucidated. We emphasized the need for future studies to employ multi-omics approaches (e.g., genomics, epigenomics, transcriptomics) and systems biology frameworks to explore these complex relationships more comprehensively.

Microbiome

In the study of PBC, the potential role of the microbiome is often closely linked to how infectious agents trigger autoimmune attacks on the bile duct epithelium. The EM’s study highlights that PBC patients exhibit antibodies and microbial markers associated with various infectious agents. Microorganisms such as retroviruses, Epstein-Barr virus (EBV), Streptococcus intermedius, and Propionibacterium acnes have been detected in the tissues and bodily fluids of PBC patients. Epidemiological studies have also established an association between PBC and infections caused by Escherichia coli, mycobacteria, chlamydia, and Helicobacter pylori. Furthermore, elevated antibody titers against Toxoplasma gondii, EBV, and Helicobacter pylori have been observed in PBC patients, suggesting a potential role of these infectious agents in the disease’s pathogenesis.⁶⁶ However, their exact role in the onset and progression of the disease remains unclear and continues to be a subject of ongoing debate. In recent years, there has been an increasing amount of research on the relationship between PBC and the gut microbiome, revealing the potential role of gut microbiota in the pathogenesis of PBC. Due to the unique anatomical and physiological connection between the liver and the gut, the microorganisms in the gut not only reach the liver via bile but also enter directly through the portal venous system, playing a crucial role in the liver’s immune responses and metabolic processes.^67,68 A study found significant differences in the gut microbiome composition between PBC patients and healthy controls. These differences were characterized by a reduction in several beneficial microbiota and an increase in opportunistic pathogens.^69,70 The exact mechanisms through which the microbiome contributes to the pathogenesis of PBC remain incompletely understood. Some studies suggest that it may be related to the interaction between the gut microbiome, immune dysregulation, and liver inflammation. Dysbiosis leads to the release of microbial-associated molecular patterns (MAMPs), which activate Toll-like receptors (TLRs) in the gut and stimulate the production of pro-inflammatory cytokines. These cytokines enhance antigen presentation and promote the formation of T-helper lymphocyte subsets (Th1, Th2, and Th17 cells) that may cross-react with host antigens. Microbial components, such as endotoxins and bacterial ligands, can breach a weakened intestinal barrier and enter the liver via the portal vein, where they activate TLRs on hepatocytes, triggering inflammation. This process induces damage-associated molecular patterns (DAMPs) and amplifies immune responses. Additionally, hepatic TLRs can increase the sensitivity of CD4 lymphocytes to bacterial ligands and self-antigens resembling bacterial components (molecular mimicry). Dysbiosis also activates inflammasomes in hepatocytes, causing tissue damage. Ultimately, this cycle exacerbates liver inflammation, potentially promoting autoimmune responses and fibrosis.^71,72 In this context, molecular mimicry between pathogen epitopes and self-peptides is considered to play a key role in disease development.⁷³ It has been found that AMA cross-reacts with antigens from Escherichia coli and Nocardia aromaticivorans.^74,75 It is worth noting that animal experiments have been conducted to explore this mechanism. In this model, mice inoculated with Nocardia aromaticivorans induce anti-mitochondrial IgG antibodies through a CD1d-dependent mechanism, and their livers develop pathological changes resembling those of PBC.⁷⁶ However, when interpreting these findings, it is crucial to account for the differences between animal models and human conditions.

PBC and extrahepatic autoimmune diseases (EHAIDs)

Roughly 33% of those diagnosed with PBC also suffer from other autoimmune diseases, most commonly including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and Sjögren’s syndrome (SS), significantly impacting their quality of life. The coexistence of PBC with EHAIDs likely involves a combination of genetic, immune, microbial, and environmental factors. Notably, the microbiome plays a key role in the pathogenesis of both PBC and extrahepatic autoimmune diseases. Among them, regarding the association between PBC and other autoimmune diseases, we have summarized the findings in a table presented as Table 2. The following is a list of some common extrahepatic autoimmune diseases that are frequently observed in patients with PBC.

Table 2.

The involved genes and organs of extrahepatic autoimmune diseases associated with PBC.

Disease	Genes	Involved organs and systems	Study
RA	HLA-DQB1, CTLA4 MMEL1, IRF5, STAT4 CXCR5	Heart, kidneys, lungs, digestive system, eyes, skin, and nervous system	⁷⁸
SLE	IL12RB2, IL12 A, IL12 B, STAT4, CD226, EST1, IRF5, and TNPO3	Skin and mucous membranes, bones, muscles, heart, kidneys, nervous system, blood	^82,83
SS	HLA-DR2/DR3, STAT4, IRF5, IL12 A, and CXCR5	Skin, muscles and joints, respiratory system, digestive system, nervous system, blood system, and kidneys	⁸⁵
SSc	HLA-DRB1, HLA-DQB1, IRF5, and STAT4	Skin, respiratory system, heart, kidneys, digestive system, bones, and muscles	⁸⁹
Thyroid dysfunction	MMEL1, PTPN22, and IL2RA	Endocrine, orbital, skin, musculoskeletal, cardiac, and nervous systems	⁹²
CeD	STAT4 IL18R1	Cardiovascular system, endocrine, reproductive system, skin, musculoskeletal and central nervous system	⁹⁹
IBD	GPR25, ERBB2, NDFIP1, GSDMB, ORMDL3, and IRF5	Eyes, skin, kidneys, hepatobiliary, pulmonary system and musculoskeletal system	¹⁰¹

RA

In medical practice, it has been observed that between 3.8% and 6.3% of patients with RA also suffer from PBC, while the occurrence of RA among those diagnosed with PBC varies between 1.8% and 13%.⁷⁷ Moreover, several genes, including HLA-DQB1, CTLA4, MMEL1, IRF5, STAT4, and CXCR5,⁷⁸ have been identified as common genetic factors influencing both conditions. People who share certain genetic characteristics might have a higher likelihood of being diagnosed with both RA and PBC. Variants in genes such as CTLA4 and HLA-DQB1 disrupt immune tolerance by impairing Treg cell function and promoting excessive activation of Th1/Th17 pathways. In PBC, this can result in autoimmune destruction of bile ducts, while in RA, these pathways contribute to widespread systemic inflammation. At the same time, gut microbiota imbalance is also involved in the pathogenesis of both PBC and RA. In PBC patients, gut dysbiosis enhances systemic immune responses, particularly immune activation at the joints. Studies have shown that the impact of gut microbiota on RA may involve multiple mechanisms, including the activation of antigen-presenting cells, interaction with TLRs or NOD-like receptors (NLRs), induction of antigen mimicry and cross-reactivity, and the promotion of Th17 cell-mediated mucosal inflammation.⁷⁹ These immune responses play a promotive role in the development of RA. Similarly, these mechanisms also contribute to the pathogenesis of PBC.

SLE

Additionally, SLE is another disease associated with PBC. According to a comprehensive review and meta-analysis, about 2% of individuals with PBC also suffer from SLE, in contrast to the control group.⁸⁰ Wu et al.⁸¹ utilized large public databases to perform a bidirectional Mendelian randomization (MR) analysis on PBC, discovering that SLE and PBC could potentially cause each other, indicating a mutual causality between these two diseases. Previous GWAS have identified several shared genes between PBC and SLE, including IL12RB2, IL12A, IL12B, STAT4, CD226, EST1, IRF5, and TNPO3.^82,83 Genetic polymorphisms in IRF5 and STAT4 modulate the type I interferon response and upregulate pro-inflammatory cytokines such as TNF-α and IL-17. This amplifies inflammation in target organs in both PBC and SLE, resulting in overlapping pathological features like organ-specific damage and systemic inflammation, highlighting the importance of proactive screening for potential SLE in patients with PBC.

SS

SS is the predominant EHAID associated with PBC, often overlapping in clinical manifestations and sharing epidemiological traits, with a prevalence of 35%.⁸⁴ SS and PBC both exhibit similar genetic predispositions and mechanisms of disease causation. There are several common susceptibility genes shared between PBC and SS, including HLA-DR2/DR3, STAT4, IRF5, IL12A, and CXCR5.⁸⁵ CXCR5 polymorphisms result in abnormal B-cell migration and hyperactivity. In PBC, hyperactive B cells produce AMA, damaging bile ducts. In SS, they generate anti-SSA/SSB antibodies, leading to glandular destruction, such as in salivary glands. Individuals diagnosed with both PBC and SS tend to have elevated IgG levels and a higher incidence of autoantibodies than patients who only suffer from PBC.⁸⁴ The evidence indicates that patients with PBC should undergo concurrent screening for antibodies associated with SS.

SSc

Both SSc and PBC mainly impact females and typically manifest in individuals during their middle years. The occurrence rate of PBC varies between 2.3% and 12.4%.⁸⁶ In SSc patients, fibrotic responses result in the hardening of skin and internal organs, while in PBC, these responses primarily cause the bile ducts to become fibrotic. Both conditions are marked by such fibrotic changes.⁸⁷ Current studies emphasize that both PBC and SSc exhibit elevated levels of fibrogenic cytokines, including transforming growth factor-β and IL-6. These cytokines play a crucial role in the development and activity of T helper-17 cells and regulatory T cells.^88,89 Further analysis has revealed that patients exhibit a shared antigenic pattern between centromere and mitochondrial autoantigens, highlighting further commonalities in the features of SSc and PBC. Additionally, genes predisposing individuals to both SSc and PBC have been discovered, such as HLA-DRB1, HLA-DQB1, IRF5, and STAT4.⁸⁹ In clinical settings, when dealing with patients diagnosed with PBC, it is advisable to also test for concurrent SSc. Identifying and treating this overlap early can enhance the patients’ outlook.

Thyroid dysfunction

Thyroid dysfunction is notably more prevalent among patients with PBC, with occurrence rates ranging from 5.6% to 23.6%, a significantly higher percentage than in individuals without PBC.⁹⁰ Moreover, individuals diagnosed with PBC face an increased likelihood of contracting additional autoimmune conditions such as autoimmune thyroid disease (AITD), along with Hashimoto’s and Graves’ thyroiditis.⁹¹ A clinical study found that genetic variants associated with an increased risk of AITD may also influence the clinical course of PBC, The findings of this study reveal the potential roles of genes such as MMEL1, PTPN22, and IL2RA in autoimmune diseases, particularly in AITD and PBC. This suggested shared genetic susceptibility factors between the two diseases.⁹² Research in Europe involving 921 individuals with PBC revealed that thyroid issues were present in 16.3% of the cohort. Of these, Hashimoto’s thyroiditis was identified in 10.2% and Graves’ disease in 1.6%.¹⁵ In a study by Ma et al.⁹³ using a GWAS dataset with a larger cohort of AITD and PBC patients, researchers found strong evidence that PBC played a crucial role in the progression of AITD.

Celiac disease (CeD)

Numerous studies have highlighted the increased prevalence of CeD among PBC patients, suggesting a potential link between these two autoimmune disorders. A retrospective analysis found that the prevalence of CeD in the PBC group was significantly higher than in the other liver diseases group (11.8% versus 2.9%).⁹⁴ A multicenter retrospective study found that the prevalence of celiac disease in 440 PBC patients was 1.7%.⁹⁵ Research have shown that up to 7% of PBC patients also have CeD, despite none of these individuals reporting any gastrointestinal symptoms. This finding suggests that celiac disease may be more common among PBC patients than previously recognized.⁹⁶ The disruption of the gut-liver axis balance plays a central role in the development of immune dysregulation involving both the gut and the liver. CeD and PBC predominantly affect women and are both characterized by chronic inflammatory processes that result in sustained tissue damage over time. Environmental factors may contribute to the coexistence of CeD and PBC by increasing intestinal permeability and triggering immune responses through molecular mimicry mechanisms.⁹⁷ At the same time, genetic susceptibility also plays a crucial role in the development of CeD. HLA-DQ2 or HLA-DQ8 have been widely recognized as the primary haplotypes associated with susceptibility to CeD.⁹⁸ However, these haplotypes are not associated with the development of PBC. Research has also identified that, apart from the classic HLA genes, STAT4 and IL18R1 are implicated in both PBC and CeD. These genes play a critical role in T cell differentiation and the regulation of IFNγ production. These immune factors are involved in the pathogenesis of both PBC and CeD.⁹⁹

Inflammatory bower disease (IBD)

Another pathogenic model involving gut-liver axis imbalance exists in both IBD and PBC. The simultaneous occurrence of PBC and IBD has been noted, but this relationship is rarer compared to the well-established connection between IBD and primary sclerosing cholangitis (PSC).¹⁰⁰ Recent research has delved deeper into the genetic and causal links between PBC and IBD. Findings from genome-wide association studies indicate that these two conditions share a common genetic framework and exhibit a positive genetic correlation. This study identified five shared genes (GPR25, ERBB2, NDFIP1, GSDMB, ORMDL3, and IRF5) in tissues enriched for both IBD and PBC, all of which are involved in the pathogenesis of these diseases.¹⁰¹ A potential explanation is that the persistent inflammation in the intestines due to IBD results in compromised intestinal barrier function and heightened permeability, which facilitates the entry of gut microbes or antigens into the body. This, in turn, provokes an exaggerated immune response and elevates the likelihood of a co-occurrence of PBC and IBD. Gaining insight into these common pathophysiological processes could pave the way for the creation of innovative therapies that address both conditions at the same time.^102,103

Conclusion

This piece offers a concise examination of the etiology and systemic manifestations outside the liver of PBC. The prevailing notion is that the onset of PBC is primarily associated with genetically predisposed individuals. These individuals may lose their immune system’s tolerance to mitochondrial antigens due to environmental triggers. This loss of tolerance can provoke a humoral immune response, which in turn results in the autoimmune destruction of bile ducts within the liver. Among them, epigenetics acts as a crucial bridge connecting genetic predispositions and environmental factors in the development of PBC. At the same time, advancements in microbiome research have further deepened our understanding of the pathogenesis of PBC, offering new perspectives for developing targeted therapies and opening up novel possibilities for modulating the immune response in PBC patients. PBC is often associated with various extrahepatic complications, the mechanisms of which are currently unclear, and nearly all of these complications are autoimmune diseases. Future efforts should focus on optimizing screening protocols to facilitate the early detection of extrahepatic complications, ultimately improving patients’ quality of life.

Footnotes

Author contributions

Conceptualization, YLY and SJZ; writing original draft preparation, YLY; project administration, SJZ; funding acquisition, SJZ. All authors have read and agreed to the published version of the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Senior Medical Talents Program of Chongqing for Young and Middle-aged (2019-181).

ORCID iD

Yuling Yang

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Primary biliary cholangitis: Insights into genetic susceptibility and systemic manifestations

Abstract

Keywords

Introduction

The pathogenesis of PBC

Genetic factors

Genome-wide association studies

The association between the HLA region and PBC

Non-HLA genes and susceptibility to PBC

Epigenetics

DNA methylation

X Chromosome Inactivation (XCI)

Non-coding RNAs

Histone modifications

Multi-omics approaches

Treatment implications

Environmental factors

Immune factors

Microbiome

PBC and extrahepatic autoimmune diseases (EHAIDs)

RA

SLE

SS

SSc

Thyroid dysfunction

Celiac disease (CeD)

Inflammatory bower disease (IBD)

Conclusion

Footnotes

Author contributions

Declaration of conflicting interests

Funding

ORCID iD

References