Exposure to occupational antigens might predispose to IgG4-related disease

Evidence is mounting that the immune system of patients with IgG4-related disease (IgG4-RD) shows indications of chronic antigenic stimulation. Hypothesizing a possible role for occupational antigenic exposure, we observed in two independent cohorts of patients with IgG4-RD that the majority had had a career in blue collar occupations with prolonged exposures to potentially hazardous occupational antigens. We postulate that the chronic antigenic load associated with 'dirty' jobs could be one of the factors contributing to the development of IgG4-related disease. (Hepatology 2014;

The biliary HCO(3) (-) umbrella: A unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies

This review focuses on the hypothesis that biliary HCO(3) (-) secretion in humans serves to maintain an alkaline pH near the apical surface of hepatocytes and cholangiocytes to prevent the uncontrolled membrane permeation of protonated glycine-conjugated bile acids. Functional impairment of this biliary HCO(3) (-) umbrella or its regulation may lead to enhanced vulnerability of cholangiocytes and periportal hepatocytes toward the attack of apolar hydrophobic bile acids. An intact interplay of hepatocellular and cholangiocellular adenosine triphosphate (ATP) secretion, ATP/P2Y- and bile salt/TGR5-mediated Cl(-)/ HCO(3) (-) exchange and HCO(3) (-) secretion, and alkaline phosphatase-mediated ATP breakdown may guarantee a stable biliary HCO(3) (-) umbrella under physiological conditions. Genetic and acquired functional defects leading to destabilization of the biliary HCO(3) (-) umbrella may contribute to development and progression of various forms of fibrosing/sclerosing cholangitis. (HEPATOLOGY 2010;

IgG4-Associated Cholangitis--A Mimic of PSC

IgG4-associated cholangitis (IAC) is an inflammatory disorder of the biliary tract representing a major manifestation of IgG4-related disease (IgG4-RD) often with elevation of serum IgG4 levels, infiltration of IgG4+ plasma cells in the affected tissue and good response to immunosuppressive treatment. Its first description may go back to 150 years ago. The clinical presentation of IAC is often misleading, mimicking other biliary diseases such as primary sclerosing cholangitis (PSC) or cholangiocarcinoma. The HISORt criteria--histopathological, imaging, and serological features (sIgG4), other organ manifestations of IgG4-RD and response to treatment--are the standard for the diagnosis of IAC. In this overview of a recent lecture, we summarize our original findings on IgG4-RD that (i) dominant IgG4+ B-cell clones identified by advanced next generation sequencing (NGS) are highly specific for IgG4-RD (meanwhile confirmed by others), are a highly accurate diagnostic marker to distinguish IgG4-RD from PSC and biliary/pancreatic malignancies and may be crucial in unravelling the pathophysiology of IgG4-RD; (ii) sIgG4/sIgG1 >0.24 have additional diagnostic value in comparison to sIgG4 in differentiating IAC from PSC; (iii) blood IgG4 mRNA is a highly accurate diagnostic marker comparable to NGS and may become an easily available and affordable diagnostic standard for distinguishing IgG4-RD from PSC and biliary/pancreatic malignancies; and (iv) 'blue collar work' with long-term exposure to solvents, paints, oil products or industrial gases may be a risk factor for development of IgG4-RD. These findings may contribute to the understanding of the pathophysiology and to the early diagnosis and adequate treatment of IgG4-R

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

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

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-R

Immunoglobulin G4-related prostatitis: A case-control study focusing on clinical and pathologic characteristics

OBJECTIVE To evaluate the occurrence and histopathologic characteristics of immunoglobulin G4 (IgG4)- related prostatic involvement in patients diagnosed with autoimmune pancreatitis. METHODS Nine cases of IgG4-related prostatitis were identified among 117 men in the autoimmune pancreatitis and IgG4-associated cholangitis patient databases in 2 tertiary hospitals. Clinical information was retrieved, and available prostatic tissue samples and 18 prostatitis control samples were evaluated for characteristic IgG4-related disease (IgG4-RD) features: maximum number of IgG4-positive cells per high-power field; dense lymphoplasmacytic infiltrate; fibrosis, arranged at least focally in a storiform pattern; phlebitis with or without obliteration of the lumen; and increased number of eosinophils. RESULTS The aspecific sign of urine retention was commonly present in IgG4-RD patients with prostatic involvement. In these patients with IgG4-related prostatitis, the median number of IgG4-positive cells in prostatic tissue was 150 (interquartile range, 20-150) per high-power field compared with a median of 3 (interquartile range, 1-11) in control patients (P ¼ .008). Dense lymphoplasmacytic infiltrate was observed in most (86% in cases and 72% in control patients) tissue samples independent of the underlying cause of prostatitis. Fibrosis in at least a focally storiform pattern was seen rarely in both groups, and (obliterative) phlebitis was absent in all patients. Furthermore, eosinophil numbers were more often elevated in patients with IgG4-RD compared with controls (P <.001). In 2 cases, amelioration of the prostatitis symptoms on corticosteroid treatment was documented. CONCLUSION Prostatic involvement might not be rare in patients with pancreatic or biliary IgG4-RD. Clinicians should consider this disease entity in patients with IgG4-RD and prostatic symptom

The long-term impact of autoimmune pancreatitis on pancreatic function, quality of life, and life expectancy

Objective: To evaluate the long-termoutcome of autoimmune pancreatitis. Methods: Patients with at least 2 years of follow-up were included. Information was collected regarding disease characteristics, treatment outcome, diagnosedmalignancies, andmortality. In addition, pancreatic function and quality of life were assessed prospectively. Results: 107 patients were included (87% men, 90% with type 1), with a median follow-up of 74 (interquartile range, 49-108) months. One third was operated for suspected pancreatic cancer (32%). Most patients were (successfully) treated with steroids (83%), but relapses were common (52%), for which no risk factors could be identified. Pancreatic carcinoma was not observed. Prospective data were obtained from 64%, as 17% had died, 7% were lost to follow-up, and 13% refused to participate. After a median of 75 (interquartile range, 50-106) months, 46% still used active treatment. Exocrine and endocrine insufficiencieswere highly prevalent (82%and 57%, respectively). Quality of life and survival were not impaired, as compared with a reference population. Conclusions: Despite an excellent initial treatment response, relapses are common, even in type 2, and almost half of the patients require maintenance therapy. Pancreatic insufficiency is highly prevalent, which calls for active screening. Pancreatic cancer was not observed, and quality of life and survival are not impaired

Serum Immunoglobulin G4 and Immunoglobulin G1 for Distinguishing Immunoglobulin G4-Associated Cholangitis From Primary Sclerosing Cholangitis

The recent addition of immunoglobulin (Ig)G4-associated cholangitis (IAC), also called IgG4-related sclerosing cholangitis (IRSC), to the spectrum of chronic cholangiopathies has created the clinical need for reliable methods to discriminate between IAC and the more common cholestatic entities, primary (PSC) and secondary sclerosing cholangitis. The current American Association for the Study of Liver Diseases practice guidelines for PSC advise on the measurement of specific Ig (sIg)G4 in PSC patients, but interpretation of elevated sIgG4 levels remains unclear. We aimed to provide an algorithm to distinguish IAC from PSC using sIgG analyses. We measured total IgG and IgG subclasses in serum samples of IAC (n=73) and PSC (n=310) patients, as well as in serum samples of disease controls (primary biliary cirrhosis; n=22). sIgG4 levels were elevated above the upper limit of normal (ULN=>1.4 g/L) in 45 PSC patients (15%; 95% confidence interval [CI]: 11-19). The highest specificity and positive predictive value (PPV; 100%) for IAC were reached when applying the 4x ULN (sIgG4>5.6 g/L) cutoff with a sensitivity of 42% (95% CI: 31-55). However, in patients with a sIgG4 between 1x and 2x ULN (n=38/45), the PPV of sIgG4 for IAC was only 28%. In this subgroup, the sIgG4/sIgG1 ratio cutoff of 0.24 yielded a sensitivity of 80% (95% CI: 51-95), a specificity of 74% (95% CI: 57-86), a PPV of 55% (95% CI: 33-75), and a negative predictive value of 90% (95% CI: 73-97). Conclusion: Elevated sIgG4 (>1.4 g/L) occurred in 15% of patients with PSC. In patients with a sIgG4 >1.4 and <2.8 g/L, incorporating the IgG4/IgG1 ratio with a cutoff at 0.24 in the diagnostic algorithm significantly improved PPV and specificity. We propose a new diagnostic algorithm based on IgG4/IgG1 ratio that may be used in clinical practice to distinguish PSC from IAC. (Hepatology 2014;59:1954-1963