IgG4-related cholangitis - a mimicker of fibrosing and malignant cholangiopathies.

IgG4-related cholangitis (IRC) is the major hepatobiliary manifestation of IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder. The pathogenesis of IgG4-RD and IRC is currently viewed as multifactorial, as there is evidence of a genetic predisposition while environmental factors, such as blue-collar work, are major risk factors. Various autoantigens have been described in IgG4-RD, including annexin A11 and laminin 511-E8, proteins which may exert a partially protective function in cholangiocytes by enhancing secretion and barrier function, respectively. For the other recently described autoantigens, galectin-3 and prohibitin 1, a distinct role in cholangiocytes appears less apparent. In relation to these autoantigens, oligoclonal expansions of IgG4+ plasmablasts are present in patients with IRC and disappear upon successful treatment. More recently, specific T-cell subtypes including regulatory T cells, follicular T helper 2 cells, peripheral T helper cells and cytotoxic CD8+ and CD4+ SLAMF7+ T cells have been implicated in the pathogenesis of IgG4-RD. The clinical presentation of IRC often mimics other biliary diseases such as primary sclerosing cholangitis or cholangiocarcinoma, which may lead to inappropriate medical and potentially invalidating surgical interventions. As specific biomarkers are lacking, diagnosis is made according to the HISORt criteria comprising histopathology, imaging, serology, other organ manifestations and response to therapy. Treatment of IRC aims to prevent or alleviate organ damage and to improve symptoms and consists of (i) remission induction, (ii) remission maintenance and (iii) long-term management. Glucocorticosteroids are highly effective for remission induction, after which immunomodulators can be introduced for maintenance of remission as glucocorticosteroid-sparing alternatives. Increased insight into the pathogenesis of IRC will lead to improved diagnosis and novel therapeutic strategies in the future.

Immunoglobulin G4(+) B-cell receptor clones distinguish immunoglobulin G 4-related disease from primary sclerosing cholangitis and biliary/pancreatic malignancies.

UNLABELLED: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) of the biliary tree and pancreas is difficult to distinguish from sclerosing cholangitis and biliary/pancreatic malignancies (CA). An accurate noninvasive test for diagnosis and monitoring of disease activity is lacking. We demonstrate that dominant IgG4(+) B-cell receptor (BCR) clones determined by next-generation sequencing accurately distinguish patients with IgG4-associated cholangitis/autoimmune pancreatitis (n = 34) from those with primary sclerosing cholangitis (n = 17) and CA (n = 17). A novel, more affordable, and widely applicable quantitative polymerase chain reaction (qPCR) protocol analyzing the IgG4/IgG RNA ratio in blood also achieves excellent diagnostic accuracy (n = 125). Moreover, this qPCR test performed better than serum IgG4 levels in sensitivity (94% vs. 86%) and specificity (99% vs. 73%) and correlates with treatment response (n = 20). CONCLUSIONS: IgG4(+) BCR clones and IgG4/IgG RNA ratio markedly improve delineation, early diagnosis, and monitoring of IgG4-RD of the biliary tree and pancreas. (Hepatology 2016;64:501-507).

The Cholangiocyte Glycocalyx Stabilizes the 'Biliary HCO3 Umbrella': An Integrated Line of Defense against Toxic Bile Acids.

BACKGROUND: Destruction of cholangiocytes is the hallmark of chronic cholangiopathies such as primary biliary cirrhosis. Under physiologic conditions, cholangiocytes display a striking resistance to the high, millimolar concentrations of toxic bile salts present in bile. We recently showed that a 'biliary HCO3(-) umbrella', i.e. apical cholangiocellular HCO3(-) secretion, prevents cholangiotoxicity of bile acids, and speculated on a role for extracellular membrane-bound glycans in the stabilization of this protective layer. This paper summarizes published and thus far unpublished evidence supporting the role of the glycocalyx in stabilizing the 'biliary HCO3(-) umbrella' and thus preventing cholangiotoxicity of bile acids. KEY MESSAGES: The apical glycocalyx of a human cholangiocyte cell line and mouse liver sections were visualized by electron microscopy. FACS analysis was used to characterize the surface glycan profile of cultured human cholangiocytes. Using enzymatic digestion with neuraminidase the cholangiocyte glycocalyx was desialylated to test its protective function. Using lectin assays, we demonstrated that the main N-glycans in human and mouse cholangiocytes were sialylated biantennary structures, accompanied by high expression of the H-antigen (α1-2 fucose). Apical neuraminidase treatment induced desialylation without affecting cell viability, but lowered cholangiocellular resistance to bile acid-induced toxicity: both glycochenodeoxycholate and chenodeoxycholate (pKa ≥4), but not taurochenodeoxycholate (pKa <2), displayed cholangiotoxic effects after desialylation. A 24-hour reconstitution period allowed cholangiocytes to recover to a pretreatment bile salt susceptibility pattern. CONCLUSION: Experimental evidence indicates that an apical cholangiocyte glycocalyx with glycosylated mucins and other glycan-bearing membrane glycoproteins stabilizes the 'biliary HCO3(-) umbrella', thus aiding in the protection of human cholangiocytes against bile acid toxicity.

Immunoglobulin G4-related cholangiopathy: clinical and experimental insights.

PURPOSE OF REVIEW: The clinical spectrum of immunoglobulin G4-related disease (IgG4-RD) is diverse and the disease may affect multiple organ systems. The pancreatobiliary tract probably is the clinically most important localization of the disease but diagnosing IgG4-related cholangiopathy (synonym: IgG4-associated cholangitis) or autoimmune pancreatitis is often challenging. This review summarizes the current best practice in diagnosing and treating IgG4-related cholangiopathy and recent advances in our understanding of its cause. RECENT FINDINGS: The identification of IgG4-switched B-cell and plasma cell populations in patients with IgG4-related cholangiopathy and IgG4-RD and their disappearance upon successful treatment have established the role of these cells in the disorder. Ultimately, these findings may lead to the development of more sensitive diagnostic tests. The observation that many of the predominantly 50-70 years old male patients have been exposed lengthily to occupational hazardous compounds further supports the idea that chronic antigenic stimulation may be a pivotal etiological aspect of the disease. Immunosuppressive treatment remains the therapeutic cornerstone in IgG4-RD. SUMMARY: Currently available experimental evidence classifies IgG4-RD as an immune-mediated disorder, providing support to the use of immunosuppressants and possibly even more specific therapies targeting the B-cell and plasma cell lineages.

IgG4-associated cholangitis: a comprehensive review.

IgG4-associated cholangitis (IAC) is a major manifestation of immunoglobulin G4-related disease (IgG4-RD), an inflammatory multiorgan disorder of unknown cause. IAC and autoimmune pancreatitis (AIP) may mimic sclerosing cholangitis, cholangiocarcinoma, or pancreatic carcinoma. Typically, elderly male patients present with abdominal discomfort, weight loss, jaundice, and itch. At present, no accurate diagnostic test for IAC and IgG4-RD is at hand, often causing significant diagnostic delay. Serum IgG4 is only diagnostic when markedly raised (>4× ULN). Imaging in IAC discloses mass-forming lesions and/or strictures in the biliary tract. Histology may show tissue infiltration of IgG4-expressing plasma cells. Diagnostic criteria for histologic and imaging findings, serum tests, organ manifestation pattern, and response to immunosuppressive therapy (HISORt) criteria are used for the diagnosis of IgG4-RD. Still, considering the difficulty in diagnosing IAC and AIP, unnecessary hepatic or pancreatic resections for presumed malignancies occur. The good response to corticosteroid therapy in IAC and other manifestations of IgG4-RD suggests an immune-mediated inflammatory disease. Maintenance immunosuppression after induction of remission is needed in the majority of patients to avoid relapse. The pathogenesis of IAC and IgG4-RD remains poorly understood. Unresolved questions include: (i) Does IgG4 have a pro- or anti-inflammatory role in IAC? (ii) Is IAC a B cell- and/or T cell-mediated disease? (iii) Which are the molecular targets attacked by the immune system in IgG4-RD? Here, we review the diagnostic and therapeutic management of the disease and discuss recent pathophysiological findings, which might help to better understand the molecular mechanisms contributing to IAC and other manifestations of IgG4-RD.

IgG4-associated cholangitis.

IgG4-associated cholangitis (IAC) is the hepatobiliary manifestation of immunoglobulin G4-related disease (IgG4-RD), a systemic fibroinflammatory disorder with a wide variety of clinical presentations and organ manifestations. IgG4-RD predominantly affects the hepatobiliary tract (IAC) and pancreas (autoimmune pancreatitis) and mimics hepatobiliary, pancreatic and other malignancies. Patients typically are 60-80 years old and 80-85% are male. They often present with painless obstructive jaundice and organ swelling that can be mistaken for pancreatic or bile duct cancer, as well as primary or secondary sclerosing cholangitis. An accurate diagnostic marker is lacking and extensive surgery for presumed malignant hepatobiliary or pancreatic disease leads to the diagnosis of IgG4-RD in 1 of 3 patients. Early effective immunosuppressive treatment is often missed. The pathogenesis of IgG4-RD has been enigmatic. We recently identified dominant IgG4+ B-cell receptor clones in blood and tissue of patients with IAC, but not in healthy or disease controls, and hypothesized that specific B-cell responses are pivotal to the pathogenesis of IAC and IgG4-RD. Analysis of our Amsterdam cohort and blinded extramural validation of the Oxford cohort of patients with IgG4-RD disclosed a remarkable association with 'blue-collar work'. Thus, long-term exposure to solvents and other organic agents might predispose to IgG4-RD.

[IgG4-related disease]. / IgG4-gerelateerde ziekte.

The diagnosis IgG4-related disease (IgG4-RD) is often difficult to make. The clinical spectrum is diverse, with a variety of organ systems that may be affected simultaneously or sequentially. Patients often present with symptoms that mimic a malignant disease, for example, symptoms compatible with a pancreatic tumour. The lack of reliable tests often prolongs the diagnostic process. Limited insight into the causative disease mechanisms has confined the therapeutic options to the empirical use of immunosuppression. During the past year, the first papers on the fundamental aspects of the disease have resulted in the emergence of a new disease model for IgG4-RD. Recently published clinical and experimental findings support the hypothesis that antigenic stimulation plays a pivotal role in the aetiology of IgG4-RD. These new insights may pave the way for more sensitive diagnostic tests and more evidence-based strategies to cope with the many manifestations of IgG4-related disease.

Immunoglobulin G4+ clones identified by next-generation sequencing dominate the B cell receptor repertoire in immunoglobulin G4 associated cholangitis.

UNLABELLED: Immunoglobulin G4 (IgG4)-associated cholangitis (IAC) is a manifestation of the recently discovered idiopathic IgG4-related disease. The majority of patients have elevated serum IgG4 levels and/or IgG4-positive B-cell and plasma cell infiltrates in the affected tissue. We hypothesized that clonally expanded, class-switched IgG4-positive B cells and plasma cells could be causal to these poorly understood phenomena. In a prospective cohort of six consecutive IAC patients, six healthy controls, and six disease controls, we used a novel next-generation sequencing approach to screen the B-cell receptor (BCR) repertoires, in blood as well as in affected tissue, for IgG4+ clones. A full repertoire analysis of the BCR heavy chain was performed using GS-FLX/454 and customized bioinformatics algorithms (>10,000 sequences/sample; clones with a frequency ≥0.5% were considered dominant). We found that the most dominant clones within the IgG+ BCRheavy repertoire of the peripheral blood at baseline were IgG4+ only in IAC patients. In all IAC patients, but none of the controls, IgG4+ BCR clones were among the 10 most dominant BCR clones of any immunoglobulin isotype (IgA, IgD, IgM, and IgG) in blood. The BCR repertoires of the duodenal papilla comprised the same dominant IgG4+ clones as the paired peripheral blood samples. In all IAC patients, after 4 and 8 weeks of corticosteroid therapy the contribution of these IgG4+ clones to the IgG+ repertoire as well as to total BCR repertoire was marginalized, mirroring sharp declines in serum IgG4 titers and regression of clinical symptoms. CONCLUSION: The novel finding of highly abundant IgG4+ BCR clones in blood and tissue of patients with active IAC, which disappear upon corticosteroid treatment, suggests that specific B cell responses are pivotal to the pathogenesis of IAC. (HEPATOLOGY 2013 ).