Tumor necrosis factor receptor superfamily member 13B mutation-associated chronic cholangitis with cirrhosis: A case report and review of literature

Abstract

BACKGROUND

The transmembrane activator and calcium-modulator and cyclophilin ligand interactor, encoded by tumor necrosis factor receptor superfamily member 13B (TNFRSF13B), maintains immune homeostasis through bidirectional regulation of B-cell function. This study presents a case of a 56-year-old female with chronic cholangitis and cirrhosis associated with a heterozygous missense mutation in TNFRSF13B.

CASE SUMMARY

A 56-year-old female with thalassemia trait and recurrent ascending cholangitis following cholangiojejunostomy presented with cirrhosis of unclear etiology. Despite serial hospitalizations for cholestatic decompensation and comprehensive evaluations-including serological profiling with elevated antinuclear antibody titers and histopathological assessment-no conventional cirrhosis triggers were identified. The patient presented with elevated serum immunoglobulin A (IgA) and IgG, and no apparent immune dysfunction. Two magnetic resonance imaging examinations revealed absence of the left hepatic lobe and gallbladder, no dilation of intrahepatic bile ducts, and inflammatory lesions in the hepatic hilum, cirrhosis, and splenomegaly. Pathological review of the resected left hepatic lobe demonstrated extensive plasma cell infiltration (MUM1+/IgG+) with focal iron deposits. Whole-exome sequencing uncovered a heterozygous missense variant (c.436G>C, p.Ala146Pro) in TNFRSF13B. She was diagnosed with TNFRSF13B mutation-associated chronic cholangitis and cirrhosis. Treatment with antibiotics, hepatoprotective drugs, and ursodeoxycholic acid led to symptom resolution, and she was discharged with ongoing therapy.

CONCLUSION

TNFRSF13B mutation may impair B-cell negative regulation, promoting cholangitis, and cirrhosis. Iron overload and bacterial infection accelerate disease progression.

Key Words: Autoimmune liver disease; Chronic cholangitis; TNFRSF13B gene; B cell homeostasis; Case report

Core Tip: Tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) maintains immune homeostasis through bidirectional regulation of B cell function. This case report presents a case where a TNFRSF13B mutation that may impair TACI’s negative regulatory control over B cell activity, causing B cell hyperactivation, sustained local inflammatory responses, and chronic cholangitis progressing to cirrhosis. This finding provides a novel immunogenetic perspective for understanding certain autoimmune liver diseases of unknown etiology.

INTRODUCTION

Autoimmune liver diseases (AILDs) represent a group of hepatic disorders caused by immune dysregulation, characterized by hepatic lymphocyte infiltration, elevated circulating immunoglobulin levels, increased hepatic enzyme activity, and autoantibody production[1,2]. The interplay between hepatocytes and intrahepatic immune cells plays a pivotal role in the pathogenesis and progression of these diseases, collectively coordinating the liver's dual functions-metabolism and immunity. Notably, B lymphocytes, which are abundantly present in the liver, serve crucial roles in maintaining hepatic immune homeostasis. Dysfunction of these cells may lead to a breakdown of immune tolerance, thereby exacerbating the pathological progression of AILDs[3]. Genome-wide association studies have established that AILDs have a complex polygenic architecture[4].

Primary biliary cholangitis (PBC) is a common AILD arising from immune dysregulation driven by the interaction between genetic susceptibility and environmental factors. Its defining feature is autoimmune-mediated destruction of small intrahepatic bile ducts, classifying it as a chronic cholestatic disorder[5]. A hallmark of PBC is the breakdown of immune tolerance to the lipoic acid-containing domain of the E2 subunit of the pyruvate dehydrogenase complex, leading to the production of anti-mitochondrial antibodies (AMAs) targeting this antigen[6]. This autoimmune response ultimately results in damage to biliary epithelial cells and induces the characteristic histopathological changes of non-suppurative destructive cholangitis. Biochemically, PBC is characterized by elevated serum alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT), while immunological features include AMA positivity and increased serum immunoglobulin M (IgM) levels[7].

Autoimmune hepatitis (AIH) is a hepatic disorder characterized by hypergammaglobulinemia, the presence of serum autoantibodies, and interface hepatitis on histology[8]. The initiation of liver injury involves the recognition of hepatic autoantigens by antigen-presenting cells, followed by their presentation to naïve Th0 lymphocytes, triggering a cascade of effector immune responses. This leads to the release of pro-inflammatory cytokines, activation of cytotoxic T lymphocytes, and subsequent hepatocellular injury. B cells play an important role in the pathogenesis of AIH, participating in the initiation of cellular immune responses by presenting autoantigens to naïve T lymphocytes and differentiating into plasma cells that produce antigen-specific IgG and autoantibodies. These antibodies can directly exacerbate hepatocyte injury through antibody-dependent cellular cytotoxicity[9].

B-cell activating factor (BAFF) is a crucial regulator of B cell survival and maturation. BAFF exerts its biological effects through binding to three TNF receptor superfamily members: BAFF receptor (BAFF-R), transmembrane activator and calcium-modulator and cyclophilin ligand interactor [TACI, encoded by the tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) gene], and B-cell maturation antigen (BCMA)[10,11]. These receptors play essential roles in B cell development, survival, and function. Through interactions with their ligands, this receptor triad promotes B cell survival, proliferation, antigen presentation, and differentiation into plasma cells, processes that are vital for proper functioning of the immune system. Notably, the interaction between BAFF and the TACI receptor plays a pivotal role in promoting T cell-dependent differentiation of autoreactive B cells[12,13]. Moreover, TACI can bind both BAFF and a proliferation-inducing ligand (APRIL)[14]. These mechanisms highlight TACI’s significance in liver autoimmune responses. TACI signaling plays a dual role in immune equilibrium by not only promoting antibody production but also suppressing B cell overactivation through its negative regulatory mechanisms.

TACI plays a critical role in maintaining immune tolerance and regulating immune responses. Its dysfunction is associated with both immunodeficiency disorders, such as common variable immunodeficiency (CVID), and autoimmune diseases, including systemic lupus erythematosus[15,16]. However, the precise mechanistic role of TACI in liver diseases remains to be fully elucidated.

This report presents a case in which a TNFRSF13B mutation potentially impairs the negative regulatory function of B cells, leading to B cell hyperactivation, subsequent plasma cell infiltration into bile ducts, and ultimately culminating in chronic cholangitis that progressed to liver cirrhosis. Additionally, we provide a comprehensive review of current research progress in this field, aiming to offer valuable references for future investigations.

CASE PRESENTATION

Chief complaints

A 56-year-old female was admitted on January 19, 2022, due to recurrent fever for 4 years, recurring again for 1 day.

History of present illness

The patient was initially diagnosed with “multiple hepatobiliary duct stones, chronic cholangitis, left hepatic lobe atrophy, and splenomegaly” at a local hospital in 2017 due to right upper quadrant pain. She subsequently underwent “cholecystectomy + left hepatectomy + Roux-en-Y hepaticojejunostomy”. Postoperative recovery was achieved with antibiotic therapy and liver-protective treatment. Following the surgery, she experienced intermittent fever and abdominal pain, diagnosed as cholangitis episodes, which resolved with antibiotic treatment. One day prior to the current admission, she developed acute-onset epigastric pain without obvious precipitating factors, accompanied by fever (peak temperature 39.1 °C), fatigue, systemic bone/muscle pain, and dizziness. The abdominal pain was colicky in nature, with palpitations during febrile episodes. These symptoms prompted the current hospitalization. Notably, she denied nausea, vomiting, dysuria, urinary frequency, cough, or sputum production (Figure 1).

Figure 1 Timeline of important events during the clinical course.

History of past illness

The patient had no history of other surgeries. Four years ago, she was diagnosed with thalassemia (heterozygous, Southeast Asian SEA deletion) at our hospital and had a history of blood transfusions (red blood cells); she denied a history of long-term heavy alcohol consumption, use of traditional Chinese medicine, exposure to toxins, and trauma.

Personal and family history

The patient reported no family history of liver disease, liver cancer, or similar conditions.

Physical examination

Vital signs were stable, with a cachectic physique and clear consciousness. The patient exhibited pallor consistent with anemia, with no jaundice of the skin; absence of spider angiomas, petechiae, and ecchymosis; and no palmar erythema. Cardiopulmonary examination revealed no significant positive signs. The abdomen was flat and soft, with an old surgical scar approximately 14 cm long visible on the right abdomen, tenderness in the liver area, negative shifting dullness, and no edema in either of the lower extremities.

Laboratory examinations

The AIH antibody panel was positive for antinuclear antibodies (ANA) at a titer of 1:160. The remaining antibodies-including anti-gp210, anti-sp100, AMA-M2, anti-smooth muscle antibody, and anti-liver-kidney microsomal type 1 antibody (anti-LKM1)-were all negative. IgG was mildly elevated. The hepatitis B serology panel showed that only hepatitis B surface antibody (323.96 mIU/mL, reference range < 10 mIU/mL) and hepatitis B core antibody (6.70 COI, reference range < 1 COI) were positive, while the other three markers were negative, suggesting a past hepatitis B virus infection with current recovery. Complement C3 was decreased. Alpha-fetoprotein, hepatitis C virus (HCV), and human immunodeficiency virus antibodies were negative. Rheumatoid factor, anti-cyclic citrullinated peptide antibody, and anti-neutrophil cytoplasmic antibody/anti-glomerular basement membrane tests were also negative. Unsaturated iron-binding capacity, ferritin, serum ceruloplasmin, erythrocyte sedimentation rate, blood lipids, renal function, cardiac enzymes, urinalysis, and immunoglobulins (IgM, and IgE) showed no abnormalities. Epstein-Barr virus (EBV) DNA, cytomegalovirus (CMV) DNA, and IgM antibodies for four viruses (EBV, CMV, rubella virus, and herpes simplex virus) were negative. Other laboratory findings are summarized in Table 1. The results indicate signs of infection, anemia, and liver function impairment.

Table 1 Laboratory test results.

Test	January 19, 2022	January 25, 2022	Reference range
WBC (× 109/L)	13.53	5.33	3.5-9.5
NEUT (%)	0.82	0.68	0.40-0.75
HGB (109/L)	81	62	115-150
MCV (fL)	65.2	63.9	80-100
MCHC (g/L)	279	292	316-354
ALT (U/L)	46	13	7-40
AST (U/L)	53	25	13-35
ALP (U/L)	149	128	50-135
GGT (U/L)	67	41	7-45
TBil (μmol/L)	54.4	27.4	5-21
DBil (μmol/L)	13.2	6.4	0-3.4
Total T lymphocyte absolute value (μL)	468	-	955-2860
T-helper cells (%)	26	-	27-51
T-helper cell absolute value (μL)	221	-	550-1440
T-suppressor cell Absolute value (μL)	223	-	320-1250
CRP (mg/L)	153	9.4	< 10
Complement C3 (g/L)	0.73	-	0.79-1.52
IgG (g/L)	17	-	7.51-15.6

WBC: Total white blood cell count; NEUT: Percentage of neutrophils; HGB: Hemoglobin; MCV: Mean corpuscular volume; MCHC: Mean corpuscular hemoglobin concentration; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyl transferase; Tbil: Total bilirubin; DBIL: Direct bilirubin; CRP: C-reactive protein; IgG: Immunoglobulin G.

Imaging examinations

January 2022 magnetic resonance imaging of the upper abdominal (plain scan + contrast) with magnetic resonance cholangiopancreatography showed absence of the left hepatic lobe and gallbladder status post resection, mild intrahepatic bile duct dilation, and abnormal rim-enhancing lesion adjacent to the hepatic hilum in the right lobe with peripheral hyperperfusion, suggestive of inflammatory pathology. Imaging features were consistent with cirrhosis and splenomegaly (Figure 2).

Figure 2 Dynamic evolution of postoperative liver lesions in patients. Upper abdominal magnetic resonance imaging with magnetic resonance cholangiopancreatography (January 2022, May 2023, November 2025): Imaging revealed post-resection absence of the left hepatic lobe and gallbladder, along with mild intrahepatic biliary dilatation. A rim-enhancing lesion with perilesional hyperperfusion was observed adjacent to the right hepatic hilum, consistent with an inflammatory process. Overall features supported cirrhosis and splenomegaly. Follow-up studies (2023, 2025) showed progressive enlargement of the abnormal perfusion area compared to the initial 2022 study. MRCP: Magnetic resonance cholangiopancreatography.

Further examination and diagnostic approach

The patient’s infection markers were elevated, and combined with imaging findings, the diagnosis of cholangitis was confirmed. However, the patient also had cirrhosis, the etiology of which remains unclear. Past medical history revealed no chronic liver disease. Laboratory tests ruled out active viral hepatitis infection, and there was no history of heavy alcohol use or hepatotoxic drug exposure. Serum ceruloplasmin was negative, and despite elevated ALP and GGT, AMA, anti-SP100, and anti-GP210 antibodies were negative. Based on the combined serological and liver histopathological findings, Wilson’s disease and PBC were excluded. Immunological tests showed positive ANA, but the liver pathology did not meet diagnostic criteria for AIH. Additionally, although the patient had mildly elevated serum IgG, liver pathology showed limited IgG4-positive plasma cell infiltration (6 cells/high-power field), and serum IgG4 was negative. Imaging studies revealed no bile duct wall thickening or strictures, ruling out IgG4-related sclerosing cholangitis and PSC (Figure 3).

Figure 3 Histopathological and immunohistochemical features of liver. A and B: Chronic cholecystitis with acute reaction (hematoxylin and eosin staining); C: Bile duct stones with cystic dilation, chronic inflammation with acute inflammation, local mucosal erosion, necrosis, and bile duct glandular hyperplasia; D: A few atrophic hepatocytes present in the liver tissue; E and F: CK7, CK19 positive biliary cells (immunohistochemistry and special staining:); G: Numerous MUM1 positive plasma cells; H: Immunoglobulin G4 positive plasma cells (6 per high power field); I: Masson staining of collagen fibers; J: Diagram summarizing key immunohistochemistry results. CK7: Cytokeratin 7; CK19: Cytokeratin 19; IgG: Immunoglobulin G; IgG4: Immunoglobulin G4; HPF: High power field; MUM1: Multiple myeloma oncogene 1.

Given the presence of cirrhosis with immune-related features after exclusion of common AILDs, whole-exome sequencing was conducted following informed consent to investigate potential genetic contributors to immune dysregulation. The results revealed a heterozygous missense variant in the TNFRSF13B gene (c.436G>C, p.Ala146Pro), inherited in an autosomal dominant/recessive pattern (Figure 4). This finding suggests that the patient’s cirrhosis may have been associated with an immune dysregulation-related genetic predisposition.

Figure 4 The patient has a missense mutation c.436G>C in the coding region of the TNFRSF13B gene.

FINAL DIAGNOSIS

Based on the relevant test results, the final diagnosis was TNFRSF13B mutation-associated chronic cholangitis with cirrhosis.

TREATMENT

The therapeutic regimen included anti-infective agents, hepatoprotective drugs, and oral ursodeoxycholic acid capsules to modulate local hepatic immune homeostasis and promote biliary drainage. The patient’s condition improved, leading to discharge.

OUTCOME AND FOLLOW-UP

The patient’s condition improved after treatment and was discharged. Post-discharge, the patient was prescribed intermittent norfloxacin for anti-infection therapy and continued ursodeoxycholic acid capsules orally for jaundice management. Follow-up studies (2023, 2025) showed progressive enlargement of the abnormal perfusion area compared to the initial 2022 study (Figure 2).

DISCUSSION

TACI maintains immune homeostasis by bidirectionally regulating B-cell functions, and mutations in its gene can lead to IgA deficiency and CVID. However, its association with AILDs remains unclear. Here, we report a case of chronic cholangitis progressing to cirrhosis associated with a TNFRSF13B mutation. The TNFRSF13B mutation may impair the negative regulatory function of B cells, resulting in excessive B-cell activation. This, in turn, may lead to persistent activation of local inflammatory responses in the bile ducts, ultimately causing chronic cholangitis and its progression to cirrhosis. This finding prompted us to explore a potential link between impaired TACI-mediated immune regulation and chronic biliary inflammation.

We present a case of cryptogenic cirrhosis that manifested four years post-cholangiojejunostomy, a procedure initially performed to treat intra- and extrahepatic bile duct stones. Through comprehensive clinical evaluation, no definitive evidence was found to support common etiologies of liver injury, including viral, alcoholic, drug-induced, or metabolic causes (such as hemochromatosis or Wilson’s disease). Although immunological abnormalities, such as positive ANA, were observed, the patient’s immunological profile (e.g., absence of disease-specific autoantibodies and normal IgG4 levels) and hepatic histopathological features did not meet the diagnostic criteria for classical AILDs, including AIH, PBC, or IgG4-related disease[17]. To elucidate the underlying etiology, whole-exome sequencing identified a pathogenic missense variant in the TNFRSF13B gene-a critical regulator of B-cell tolerance and antibody response. Considering the unexplained etiology of cirrhosis in this patient, together with the critical role of TACI in immune regulation and its known association with immunodeficiency disorders, particularly those involving B cell dysregulation, we hypothesize that this mutation may give rise to abnormalities in immune regulation[18], subsequently leading to chronic cholangitis and the development of cirrhosis.

B cells are one of the key immune cells essential for maintaining hepatic immune homeostasis. In the immunopathogenesis of liver diseases, B-cell dysfunction and aberrant autoantibody production constitute fundamental pathophysiological mechanisms[19,20]. Dysfunctional B cells can breach immune tolerance mechanisms, initiating and perpetuating AILD progression. Emerging evidence establishes the BAFF/receptor signaling pathway as a central regulator in hepatic disease progression. In AIH, BAFF-mediated aberrant activation of T and B cells directly induces hepatocyte injury[21,22], with serum BAFF levels showing significant positive correlation with AIH disease activity[23]. For PBC, activated B cells accelerate disease progression through dual mechanisms, suppressing anti-inflammatory cytokine production while promoting regulatory T cell apoptosis[24]. In infectious liver diseases, HCV infection triggers abnormal B cell proliferation via exosomal miR-122/Let-7b-induced TLR7/BAFF pathway activation, leading to extrahepatic manifestations like cryoglobulinemia[25]. Notably, cirrhotic patients with thrombocytopenia exhibit markedly elevated peripheral BAFF levels that positively correlate with GPIIb/IIIa antibody-producing B cells[26]. B-cell dysregulation can also exacerbate immune-mediated bile duct injury through cytokine-dependent mechanisms. For instance, IL-15Rá⁺ B cells have been shown to activate tissue-resident memory T cells, thereby promoting cytotoxic responses against biliary epithelium[27].

TACI belongs to the tumor necrosis factor receptor superfamily and is a key molecule involved in the regulation of B-cell development and survival. It is predominantly expressed on the surface of B cells and plasma cells[28]. In humans, but not in mice, the TNFRSF13B gene undergoes alternative mRNA splicing to generate two TACI isoforms, TACI-S and TACI-L, which contain one or two ligand-binding domains, respectively[29,30]. While human B cells express both TACI-S and TACI-L, TACI-S interacts with BAFF and APRIL with greater affinity[31]. B cells expressing TACI-S, but not TACI-L, exhibit reduced surface CD19 and IgG, increased CD138 expression, and a morphology consistent with plasma cell differentiation[32]. TACI exerts stage-specific regulatory functions during B-cell development. During early B-cell development, TACI participates in the negative selection of autoreactive B-cell receptors in bone marrow[33]. In later stages of B-cell maturation, TACI regulates essential biological processes including class switch recombination, plasma cell differentiation, and antibody secretion[34-36]. TACI interacts with two ligands, APRIL and BAFF, through its extracellular domain[14]. As a member of the TNF cytokine family, APRIL plays crucial regulatory roles in B-cell maturation, differentiation, and immunoglobulin production[37]. By binding to BCMA and TACI receptors, APRIL promotes B-cell survival and proliferation and modulates plasma cell development[38]. Notably, TACI possesses unique and non-redundant functions in mediating B cell responses to T-cell-independent antigens, negative regulation of the B-cell compartment, and class switch recombination[39].

TACI plays a critical promoting role in the final execution of antibody immune responses. It serves as a key mediator of T-cell-independent class-switch recombination, and by engaging the adaptor protein MyD88, TACI activates downstream signaling pathways that drive B cells to switch from producing IgM to producing IgG and IgA, thereby enhancing antibody diversity[40]. TACI is essential for effective antibody production against both TI and TD antigens. It is highly expressed on MZ and B1 B cells and is required for mounting normal antibody responses to TI-1 and TI-2 antigens, as Taci-/- mice exhibit markedly reduced IgM and IgG production[41,42]. TACI promotes the differentiation of B cells into plasma cells by sustaining continuous Blimp-1 expression within B cells. TACI also enhances plasma cell survival by downregulating the proapoptotic molecule BIM through APRIL and BAFF signaling[43]. Recent studies further demonstrate that TACI is required for the survival of both short- and long-lived plasma cells[44]. Therefore, TACI supports humoral immunity by facilitating plasma cell generation and preventing plasma cell apoptosis, ultimately ensuring adequate antibody titers. In this patient, cirrhosis developed approximately four years after choledochojejunostomy performed for intrahepatic and extrahepatic biliary stones. The patient presented with progressive hepatic dysfunction and systemic immune dysregulation, characterized by positive ANAs, mildly elevated IgG and IgA levels, decreased complement C3, and marked infiltration of MUM1+ and IgG+ plasma cells (approximately 50 cells per high-power field) within portal and periductal areas. Liver histopathology revealed chronic immune-mediated inflammation targeting CK7/CK19-positive biliary epithelium, accompanied by prominent infiltration of MUM1+ and IgG+ plasma cells (approximately 50 cells per high-power field). These findings provide pathological evidence of a plasma cell-rich immune milieu, supporting sustained, antigen-driven B-cell and plasma cell activation rather than a phenotype consistent with primary humoral immunodeficiency. TACI is a critical bidirectional regulator in immune responses and exerts complex dual effects on B cells. TACI prevents abnormal B cell proliferation and generation of autoreactive B cells[45,46], playing a pivotal role in maintaining immune homeostasis. Although functional studies were not performed, we hypothesize that the patient’s chronic cholangitis may be related to impaired TACI-mediated negative regulatory mechanisms.

Autoimmune-associated variants of the TNFRSF13B gene (specifically the GCTGT→A insertion-deletion mutation) can generate truncated 3’UTR transcripts, resulting in the loss of miRNA binding sites. This leads to elevated soluble BAFF levels, ultimately causing increased B cell numbers and reduced circulating monocytes[15]. Moreover, TACI plays an important role in restraining B cell proliferation and maintaining appropriate B cell numbers. Animal studies demonstrate that TACI knockout mice develop dysregulated lymphocyte proliferation, leading to multi-organ (including liver and kidney) tissue damage and lymphomagenesis, accompanied by elevated circulating dsDNA and anti-nuclear autoantibody levels[47]. Its inhibitory mechanisms include inducing cell-cycle arrest by promoting sustained expression of Blimp-1 in germinal center B cells and driving the differentiation of B cells into plasma cells[43,48]. TACI regulates follicular helper T cell and germinal center B cell expansion by downregulating ICOS ligand expression on B cells, thereby limiting autoantibody production[43]. The suppressive effect of TACI on B cell numbers is also partially mediated through the promotion of apoptosis[49]. In addition, TACI may exert an indirect inhibitory effect by modulating BAFF concentrations[50]. These studies collectively confirm TACI’s essential role in B cell homeostasis and regulatory T cell function[13]. In summary, TACI exerts a pivotal bidirectional regulatory role in immune responses: On one hand, it restrains excessive B-cell proliferation through multiple mechanisms to prevent uncontrolled expansion; on the other hand, it promotes class-switch recombination and plasma cell differentiation, thereby ensuring effective and durable humoral immunity. This finely tuned dual regulation is essential for maintaining immune homeostasis. In the present patient, elevated serum IgG and IgA levels, together with the marked infiltration of MUM1+ and IgG+ plasma cells in the liver (approximately 50 cells per high-power field), indirectly supported the presence of impaired negative regulatory mechanisms in B cells.

All serum iron-related parameters in this patient, including ferritin and transferrin saturation, remained within normal limits. These findings indicate that although hepatic iron staining was positive, the overall iron burden had not reached levels typically associated with iron-driven hepatic fibrosis[51]. In transfusion-dependent thalassemia, progression to secondary hemochromatotic cirrhosis usually occurs in the context of substantial systemic iron overload, a pattern not observed in this case. Therefore, the hepatic iron deposition identified here is more consistent with a secondary change related to chronic inflammation and anemia. While such deposition may influence disease progression, it is unlikely to constitute the primary cause of cirrhosis.

The patient also had a history of recurrent bacterial cholangitis following choledochojejunostomy. Recurrent episodes of infection can contribute to hepatic inflammation and fibrosis. However, at the time of evaluation, imaging studies did not reveal dilation of the intrahepatic or extrahepatic bile ducts or intraluminal filling defects and thus did not support ongoing active bacterial cholangitis. These findings suggest that the overall disease process cannot be fully accounted for by infection-related injury or reflux cholangitis associated with altered biliary anatomy. Histological examination demonstrated biliary injury with prominent plasma cell-rich inflammation, characterized by dense infiltration of MUM1-positive and IgG-positive plasma cells (approximately 50 cells per high-power field), which provides morphological support for an immune-mediated cholangiopathy. Following choledochojejunostomy, bacterial translocation likely occurred, permitting intestinal microbiota to chronically colonize the biliary system. Such translocation of enteric pathogens can activate the immune system, thereby provoking immune-mediated responses implicated in both murine and human disease[52]. Specifically, translocated intestinal pathogens can access the liver and activate distinct immune pathways-including TH17 cells and IgG3 antibody responses-that foster aberrant immune activation[53]. This sustained immune hyperactivity is regarded as a key driver in the pathogenesis of chronic cholangitis. The biliary epithelium, which shares immunological properties with mucosal surfaces, is continually exposed to microbial antigens, especially after biliary-enteric reconstruction; this exposure may predispose the bile ducts to persistent immune stimulation. The TNFRSF13B gene mutation identified in this patient suggests a genetic predisposition toward exaggerated immune responses to translocated bacteria. TNFRSF13B encodes TACI, a protein involved in negative regulation of B-cell homeostasis. Loss-of-function mutations in this gene may lead to B-cell hyperactivation, which could drive sustained immune responses and localized inflammation, contributing to immune-mediated liver injury. This process likely exacerbates cholangitis and promotes progression to cirrhosis. Thus, post-choledochojejunostomy bacterial translocation may play a pivotal role in disease pathogenesis and progression, particularly in genetically susceptible individuals.

Considering the clinical, histopathological, and immunological features together with the detection of a heterozygous missense variant in TNFRSF13B, a model in which both genetic susceptibility and acquired anatomical factors contribute to disease development appears plausible. Impaired TACI function may disturb B-cell regulatory mechanisms and favor immune-mediated injury to the bile ducts. Postoperative biliary structural alterations and intermittent microbial reflux may act as additional contributors that influence the course and severity of disease. Clinically, the presentation was characterized by progressive destruction of small intrahepatic bile ducts, intrahepatic lithiasis, and cirrhosis rather than recurrent episodes of acute bacterial cholangitis.

These findings outline a coherent pathogenic framework linking TNFRSF13B variation with B-cell-mediated biliary injury and subsequent cirrhosis. This framework may assist in identifying a subset of cholangiopathies with distinct immunogenetic features and supports consideration of immune dysregulation in patients with cholangitis who show limited response to conventional antimicrobial or supportive therapy.

Limitations and future directions

This study has several limitations. The causal relationship between the TNFRSF13B variant and the development of cholangitis has not been demonstrated in animal models. Further work using gene-edited mouse models will be needed to evaluate the impact of this mutation on B-cell function and biliary immune homeostasis in vivo. These studies will help clarify the molecular mechanisms involved in the progression from chronic cholangitis to cirrhosis and may provide a foundation for future immunologically targeted therapeutic approaches.

CONCLUSION

Mutations in the TNFRSF13B gene may disrupt the negative regulatory function of TACI-mediated B cells, leading to aberrant B-cell activation and sustained local inflammatory responses. This can subsequently induce chronic cholangitis and ultimately progress to cirrhosis. This finding suggests that for patients with AILD of unknown etiology, whole-exome sequencing should be considered to screen for genetic factors, thereby uncovering potential immune dysregulation mechanisms. Additionally, iron overload and intestinal bacterial translocation may synergistically accelerate disease progression. The interaction between gut microbiota and immune dysfunction warrants further investigation, as this process may serve as a significant accelerating factor in the progression of chronic cholangitis and cirrhosis.